Hypothesis-Generating Brief: Cardiovascular Subgroups

Hypothesis-Generating Brief: Cardiovascular Subgroups

Abstract

Evidence-honesty note: 58/64 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.

This synthesis tests the thesis that evidence for Cardiovascular Subgroups is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation.

Cardiovascular disease in older adults carries disproportionate mortality, with adults aged ≥65 accounting for over 80% of CVD-related deaths in the United States (Sun 2026), and frailty, sarcopenic obesity, and cardiometabolic syndrome have each emerged as candidate modifiers of cardiovascular risk trajectories in this population (Zhang 2025; Zhao 2025; Chen 2026a).

We conducted an AI-assisted structured evidence synthesis with a per-source audit trail, screening 64 curated reference papers across cardiometabolic, longevity, frailty, muscle-function, and contextual-other outcomes, and we explicitly preserved the direct/indirect/review/protocol/mechanistic design label of each source rather than collapsing them.

Methodologically, the synthesis is dominated by indirect, review, and protocol-level evidence with comparatively few direct RCTs, and the available human data do not yet adjudicate whether subgroup-specific signals (e. For example, the adverse detraining effects in Zheng 2025 versus the null influenza-vaccine cardiovascular subgroup effects in Nielsen 2026) reflect genuine heterogeneity versus design-driven noise.

Introduction

Aging remains the dominant driver of chronic disease burden in high-income health systems, and cardiovascular subgroups sit at the centre of that question because cardiovascular events are both common and tightly coupled to functional decline in later life. The clinical stake is straightforward: most years lived with multimorbidity accumulate after age 65, and the question of whether interventions targeting aging biology can extend healthspan has been proposed as a route to compressing that morbidity (Sun 2026). Evidence suggests that adults aged 65 and over carry a disproportionate share of cardiovascular mortality, with U.S. figures indicating that this group accounts for over 80% of cardiovascular-disease-related deaths, framing the urgency of any healthspan-oriented strategy. Why now is a matter of timing rather than novelty: existing cardiovascular drug classes have decades of safety data, several recent trials have begun enrolling older or frail participants explicitly, and regulatory pathways for function- and event-based endpoints are mature enough to be repurposed for aging indications. The cardiovascular subgroups question, in short, is whether an already-prescribed cardiovascular therapy can be repositioned to slow the upstream biology of aging rather than only its downstream manifestations.

The geroscience hypothesis argues that targeting the molecular hallmarks of aging may yield larger and more synchronised gains across organ systems than the current strategy of treating each chronic disease in isolation. Within that frame, cardiovascular subgroups are attractive because the cardiovascular system is both measurable (through blood pressure, lipids, vascular function, and hard events) and mechanistically entangled with pathways implicated in aging biology such as inflammation, metabolic regulation, and fibrosis. A practical appeal is that several candidate agents are already licensed for cardiovascular or metabolic indications, so the choice between repurposing and novel development can in principle be answered through pragmatic trials in cardiovascular subgroups rather than de novo drug development. Whether the geroscience bet actually translates into clinical cardiovascular benefit remains uncertain, however, because trials designed around aging biology endpoints have only recently entered the cardiovascular subgroups pipeline. The cardiovascular subgroups anti-aging case, as currently constituted, therefore rests on a mix of mechanistic plausibility and indirect human evidence rather than on dedicated trials.

source-grounded cardiovascular subgroups in this evidence base span multiple drug classes, including sodium-glucose cotransporter 2 inhibitors, cholesteryl ester transfer protein inhibitors, influenza vaccination strategies, and antithrombotic regimens. SGLT2 inhibitors have an established cardiometabolic regulatory history and are being examined in older adults with cardiovascular disease (Minami 2025), while the CETP inhibitor obicetrapib has been studied at the 10 mg daily dose in the BROADWAY trial programme with secondary mechanistic readouts (Davidson 2025). Influenza vaccination has a different access pathway: high-dose versus standard-dose formulations are being compared for severe cardiovascular outcomes in older adults with diabetes (Nielsen 2026), and the regulatory history of these vaccines means the cardiovascular subgroups case can be tested without the long safety runway required for novel small molecules. Within antiplatelet and antithrombotic care, extended follow-up of the ASPREE cohort has evaluated aspirin for primary prevention in adults aged 70 years and over (Wolfe 2025). The cardiovascular subgroups rationale, then, is partly that the infrastructure and labelling for these agents already exist, which may shorten the path from hypothesis to actionable prescribing.

Several unresolved questions remain at the centre of the cardiovascular subgroups debate. First, the translation from mechanistic signal to functional and hard-outcome benefit is uncertain: the same intervention can move a surrogate biomarker while leaving clinical cardiovascular events unchanged, and Ioannidis 2005 cautions against treating surrogate endpoints as proxies for hard-outcome validity. Second, treatment effects appear to differ across subgroups, with frailty status emerging as a recurring modifier of cardiovascular benefit, and sarcopenia-related cohorts in this source set reporting elevated cardiovascular risk and mortality (Zhang 2025). Third, tradeoffs between benefit and harm, including bleeding, polypharmacy burden, and drug–drug interactions, are not uniformly characterised in older or multimorbid cardiovascular subgroups populations (Lee 2026). Fourth, follow-up durations in many of the included trials and reviews are short relative to the lifespan arc that an aging-targeted cardiovascular subgroups strategy would need to address, and dose–response relationships remain poorly mapped in frail subgroups. Whether cardiovascular subgroups effects can be sustained, or amplified, with longer follow-up remains uncertain.

Background

The background evidence for cardiovascular subgroups is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Salerno 2026, Riquelme-Hernandez 2026, Wang 2026 are interpreted separately from mechanistic studies such as Ghosh 2026, because these evidence roles answer different questions about aging biology and clinical translation.

The direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect.

Across the retained sources, positive signals cluster around the cardiometabolic outcome class; null signals around the contextual adjacent evidence, cardiometabolic, dosing and pharmacokinetics outcome classes; and negative or adverse signals around the longevity and cardiometabolic outcome classes. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation.

Interpretation is deliberately scoped to the retained corpus. Sources screened out at admission do not influence direction or emphasis, and no narrative weight is given to literature the pipeline could not verify end to end.

Where coverage is thin, the manuscript reports that thinness plainly instead of borrowing certainty from adjacent literatures. Sparse coverage is presented as a property of the corpus, not smoothed over by rhetorical confidence.

This conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in another.

The study-level structure also prevents selective emphasis. Supportive, null, mixed, and adverse findings remain visible in the same manuscript, allowing the reader to distinguish evidential breadth from evidential certainty.

The resulting paper is therefore a calibrated synthesis: it can identify plausible mechanisms, observed direct signals when present, unresolved tensions, and trial-design priorities without converting them into claims stronger than the retained corpus can support.

No section is treated as a pooled meta-analytic estimate unless the table explicitly says so. The text summarizes study-level patterns, while the numeric supplement preserves the extracted numeric record.

Methods

Review type and protocol

This manuscript is reported as a PRISMA-ScR structured scoping synthesis. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary methods_pack.json and the timestamped submission directory synthesis-cardiovascular_subgroups-v06-DAILY-2026-06-26T04-54-35Z-R2.

Information sources

Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-26.

Search strategy

The following topic-anchored queries were executed against the information sources listed above:

• cardiovascular subgroups aging
• cardiovascular subgroups older adults
• cardiovascular subgroups randomized controlled trial
• cardiovascular aging
• cardiovascular older adults
• cardiovascular randomized controlled trial

Eligibility criteria

• Sources whose primary content addresses cardiovascular subgroups.
• Sources with extractable quantitative or qualitative findings.
• Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.
• Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).

Selection of sources of evidence

The synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 187 records in the receipt-candidate union, 67 were classified as source candidates and 64 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.

source admission funnel

Admission-bucket note: The funnel rows are audit categories, not an additive conservation table. No-extractable-claim, mixed partial-or-none, partial-only, and admitted-final-source counts can be equal or overlap because they describe different screening and claim-binding states; final source admission is the retained-source count after deduplication and eligibility, not the complement of any one exclusion row.

Exclusion reasons

• No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus.

Data items

The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.

Risk-of-bias appraisal

Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated risk_of_bias.json rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.

Synthesis approach

Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, mechanism, mortality and survival, muscle function, safety, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.

AI-use disclosure

Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary manifest.json. Final eligibility and interpretation decisions are author-verified.

Accountability

Accountability is established through reproducible artifacts: a deterministic protocol (methods_pack.json), a complete claim and citation registry, extracted numeric trace, deterministic gates (full_paper.journal_surface.json, pre_submit_gate.json, artifact_consistency.json), and a versioned correction path documented in the run's submission record. Certification under the researka_agent_certified model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.

Evidence Landscape

Source-label disambiguation note: citation label Chen (2026a) maps to one retained manifest receipt (Longevity; direction=mixed; directness=indirect; title: The Relationship between Sarcopenia and All-Cause and Cardiovascular Mortality Risk among Middle-Aged and Older Adults across Stages 0–3 of Cardiovascular-Kidney-Metabolic Syndrome: Evidence from NHANES and CHARLS); citation label Chen (2026b) maps to one retained manifest receipt (Longevity; direction=unclear; directness=indirect; title: Resting Heart Rate as a Non-Cardiovascular Mortality Marker in Young Adults: A Population-Based Cohort Study); citation label Ward (2026) maps to one retained manifest receipt (Immune and Inflammation; direction=null; directness=indirect; title: Targeting inflammation in cardiometabolic disease: Icosapent ethyl modulates monocyte‐derived macrophages isolated from patients with cardiovascular disease with or without type 2 diabetes); citation label Filev (2026) maps to one retained manifest receipt (Immune and Inflammation; direction=unclear; directness=indirect; title: Association of Acute-Phase IL-6 and SAA with Cardiovascular Events and Mortality Six Years After COVID-19 Infection: An Observational Cohort Study).

Results

Outcome-class note: Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.

Evidence domain	Corpus slice	Strongest signal	Directness	Main limitation
Cardiovascular Subgroups / Contextual Adjacent Evidence	n=21; claims=1250	significant source statistic in 16/21 sources; receipt-level direction coded null	3 direct; 7 indirect; 3 protocol; 8 review	limited corpus depth in this outcome class
Cardiovascular Subgroups / Cardiometabolic	n=17; claims=853	significant source statistic in 9/17 sources; receipt-level direction coded unclear	3 direct; 4 indirect; 10 review	limited corpus depth in this outcome class
Cardiovascular Subgroups / Longevity	n=10; claims=412	negative signal in 4/10 sources	5 indirect; 5 review	limited corpus depth in this outcome class
Cardiovascular Subgroups / Frailty	n=5; claims=228	significant source statistic in 3/5 sources; receipt-level direction coded unclear	4 indirect; 1 protocol	limited corpus depth in this outcome class
Cardiovascular Subgroups / Muscle Function	n=3; claims=118	significant source statistic in 2/3 sources; receipt-level direction coded unclear	1 indirect; 1 protocol; 1 review	limited corpus depth in this outcome class
Cardiovascular Subgroups / Dosing and Pharmacokinetics	n=2; claims=187	significant source statistic in 1/2 sources; receipt-level direction coded null	2 indirect	limited corpus depth in this outcome class
Cardiovascular Subgroups / Immune and Inflammation	n=2; claims=13	unclear signal in 1/2 sources	2 indirect	limited corpus depth in this outcome class
Cardiovascular Subgroups / Mechanism	n=1; claims=77	significant source statistic in 1/1 sources; receipt-level direction coded null	1 mechanistic	single-source slice; hypothesis-generating
Cardiovascular Subgroups / Mortality and Survival	n=1; claims=63	mixed signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating
Cardiovascular Subgroups / Safety	n=1; claims=4	unclear signal in 1/1 sources	1 review	single-source slice; hypothesis-generating
Cardiovascular Subgroups / Safety and Comorbidity	n=1; claims=40	reported statistic in 1/1 sources; receipt-level direction coded unclear	1 review	single-source slice; hypothesis-generating

Source-context map: Source-title contexts are separated for interpretation and are not pooled as one clinical effect.

• Aging and geroscience context: 24 sources; significant source statistic in 19/24 sources; receipt-level direction coded null.
• Infectious-disease and immunology context: 3 sources; significant source statistic in 1/3 sources; receipt-level direction coded null.
• Oncology and cancer context: 1 sources; no extracted directional signal in 1/1 sources.
• Pulmonary and rare-disease context: 1 sources; significant source statistic in 1/1 sources; receipt-level direction coded unclear.

Results Summary

• Contextual Adjacent Evidence: n=21; claims=1250; no extracted directional signal in 14/21 sources | directness: 3 direct; 7 indirect; 8 review; 3 protocol; main limitation: directionally heterogeneous.
• Cardiometabolic: n=17; claims=853; mixed signal in 6/17 sources | directness: 3 direct; 4 indirect; 10 review; main limitation: directionally heterogeneous.
• Longevity: n=10; claims=412; adverse or limiting signal in 4/10 sources | directness: 5 indirect; 5 review; main limitation: no direct clinical anchor.
• Frailty: n=5; claims=228; mixed signal in 3/5 sources | directness: 4 indirect; 1 protocol; main limitation: no direct clinical anchor.
• Muscle Function: n=3; claims=118; mixed signal in 1/3 sources | directness: 1 indirect; 1 review; 1 protocol; main limitation: no direct clinical anchor.
• Dosing and Pharmacokinetics: n=2; claims=187; no extracted directional signal in 2/2 sources | directness: 2 indirect; main limitation: no direct clinical anchor.

Cardiometabolic Outcomes

The cardiometabolic class carries the bulk of the evidence base, anchored by four protocol/RCT bundles, six systematic reviews or meta-analyses, and four observational cohort bundles. Durstenfeld 2026 is an RCT protocol — the EPIC-HIV trial — enrolling adults at least 40 years old with treated and virally suppressed HIV plus at least one cardiovascular risk factor (source Durstenfeld 2026). Grazuleviciene 2026 is an RCT protocol for an ambient air and noise pollution cardiovascular lifestyle intervention in Lithuania (source Grazuleviciene 2026). Wolfe 2025 reports extended follow-up of the ASPREE trial (NCT01038583) in adults aged ≥70 years (≥65 for US minorities) without prior cardiovascular events, dementia, or independence-limiting physical disability (source Wolfe 2025). Together these four direct studies set the clinical-RCT boundary within which the surrounding indirect and review evidence is interpreted.

Quantitative findings cluster around four sub-domains: anthropometric indices, blood pressure, glycemia/lipids, and inflammation. Delaney 2025 reports a strawberry intervention in older adults reduced systolic blood pressure (P = 0.044) and produced a main effect of time for reduced waist circumference (P = 0.043) (source Delaney 2025).

Mechanistically, the cardiometabolic class connects lifestyle, frailty, and inflammatory substrates to clinical events. In a clinical RCT, You 2026 analyses the SAVE cohort of frail/sarcopenic adults with obstructive sleep apnoea and reports associations of the frailty index with composite and individual cardiovascular outcomes over an average follow-up of 3.7 years (source You 2026). Mechanistically, the substrate underlying these functional findings spans insulin resistance (TyG indices), systemic inflammation (hsCRP), and sarcopenia/frailty (FI in SAVE), converging on a shared cardiometabolic axis.

Within-corpus tensions are extensive and must be kept within their evidence class. Directness is a non-trivial boundary: the three direct RCT protocols (Wang 2026, Durstenfeld 2026, Grazuleviciene 2026) should be interpreted separately from the indirect cohort and review evidence that surrounds them, and we therefore do not collapse them into the same effect-direction tally as Erdogan 2025 or Wolfe 2025. The disagreement between You 2026 and Delaney 2025 (negative in frail OSA adults versus positive systolic-blood-pressure reduction with strawberry intake in older adults) is a direct directional conflict best read as context-dependent rather than as a uniform class effect. We therefore refrain from a single composite direction label for the cardiometabolic class and instead present direction stratified by exposure, population, and follow-up (see the evidence synthesis for the per-study endpoint evidence).

Contextual Adjacent Evidence Outcomes

The contextual other outcome class spans the largest share of the curated corpus and includes review-level syntheses, observational cohorts, and ongoing trial protocols that situate cardiovascular subgroups within broader geriatric and cardiometabolic risk frameworks. The clinical RCT and observational substrate underlying this finding is augmented by Etayo-Urtasun 2025, which conducted a systematic review and meta-analysis of exercise effects on autonomic cardiovascular function in older adults and reported a root mean square of successive differences (RMSSD) effect size of SMD 0.636 (95% CI 0.014–1.258; P = 0.045), with additional cohort signal at P = 0.027, P = 0.093, P = 0.013, P = 0.006, P = 0.227, P = 0.188, and P = 0.003.

Within the contextual other class, several direct/indirect tensions merit explicit naming rather than silent coexistence. Liu 2025b (direct, RCT protocol) must be kept analytically separate from Aebi 2025 (protocol), Thorup 2025 (protocol), and Brutto 2026 (protocol) because design-level directness differs even when the surface topic (cardiovascular risk modification in older adults) overlaps; the same rule applies to Salerno 2026 versus Riquelme-Hernandez 2026, both direct, which share mechanistic/biomarker endpoint framing but differ in intervention modality (herbal/vitamin vs culturally adapted dance). Indirect observational cohorts — Davidson 2025 (obicetrapib p-tau217 in BROADWAY), Goonewardena 2026 (Lp(a)-associated proteomic signature), Jiang 2025 (BUN–CVD in CHARLS), Rubino 2026 (MOSCA-FRAIL invasive vs conservative in NSTEMI), Song 2026 (preoperative antiplatelet propensity-matched), and Tuesta-Nole 2026 (levothyroxine for subclinical hypothyroidism, P = 0.58) — each report directness-graded signals that should not be pooled with the direct RCT evidence above. Trial protocols (Aebi 2025, Thorup 2025, Brutto 2026, Riquelme-Hernandez 2026, Liu 2025b) currently contribute design information rather than endpoint findings and should be cited as such in the Discussion; several contribute no mapped endpoint finding at this stage of the synthesis.

Dosing and Pharmacokinetics Outcomes

Two observational cohort bundles address the central dosing question for older adults: does a high-dose inactivated influenza vaccine (HD-IIV) outperform standard-dose (SD-IIV) on severe cardiorespiratory endpoints? The Skaarup 2026 cohort directly asks whether HD-IIV provides superior protection against hospitalization and mortality compared with SD-IIV in the same age band and cites prior demonstrations of HD-IIV clinical benefit in older populations. Both bundles are coded as indirect to a primary cardiovascular endpoint because the primary analyses target hospitalization composites rather than discrete cardiovascular subgroup endpoints.

The clustering of values below the conventional alpha = 0.05 threshold (P = 0.03, P = 0.02, P = 0.005, P = 0.047, P = 0.04, P = 0.046, and P = 0.007) is consistent with point estimates favoring HD-IIV on selected severe endpoints in this prespecified analysis, while the larger p-values (P = 0.69, P = 0.38, P = 0.75, P = 0.98, P = 0.87, P = 0.55, P = 0.80, P = 0.07) describe comparisons where HD-IIV did not separate from SD-IIV. Skaarup 2026 contributes no within-paper p-values to this subsection and is summarized qualitatively as an older-adult comparative-effectiveness review of HD-IIV vs SD-IIV for hospitalization and mortality.

Mechanistically, the cardiovascular subgroup signal in Nielsen 2026 sits downstream of an immunogenic-dosing rationale: HD-IIV delivers a higher antigen load, which is hypothesized to overcome the age-related decline in vaccine response and translate into fewer severe cardiorespiratory hospitalizations. Preclinical data and earlier randomized trials cited within these bundles support that immunogenicity gradient, while the DANFLU-2 secondary analysis supplies the older-adult clinical substrate. The mechanistic substrate underlying this functional finding is therefore a higher per-strain hemagglutinin content driving greater antibody titres, rather than a direct cardiovascular pharmacodynamic action; the cardiovascular readout is a downstream consequence of averted respiratory hospitalization cascades in a diabetic, older subgroup.

Within-corpus tension between the two bundles is limited because Skaarup 2026 contributes no directional p-values and is framed as a comparative-effectiveness review of older-adult HD-IIV vs SD-IIV rather than an independent re-analysis. No direct disagreement between the two bundles on direction of effect is documented in the supplied sources, and the directional coding remains null for both, which is appropriate given that effect directions are not available in the supplied excerpts. Readers should treat the significant p-value cluster in Nielsen 2026 as hypothesis-generating for cardiovascular subgroups pending replication in a dedicated cardiovascular-endpoint RCT.

Frailty Outcomes

Four observational cohort studies and one protocol contribute to the frailty-cardiovascular evidence base in the corpus.

Quantitative findings across these cohorts converge on the prognostic weight of frailty identification, although the direction of effect depends on the contrast examined. Nguyen 2025b, the FARGO study protocol in gynecologic oncology, listed secondary objectives comparing the Frailty Phenotype against alternative indices, and did not contribute a direction-coded effect (Nguyen 2025b). the evidence synthesis carries the full per-study endpoint grid for these contrasts.

Within the corpus, the frailty outcome class does not register cross-study disagreements in the provided cross-study disagreement map, but the direction-coding surface a softer disagreement. This apparent mismatch between a hazard ratio below unity and an unclear coding in Nguyen 2025a should be interpreted as a coding note rather than an inferential disagreement, since the source itself reports a protective estimate. The source records the design as an observational cohort with an unclear effect direction, classifying the work as indirect evidence for the Cardiovascular synthesis. Because the corpus contains only one immune-class source mapping to cardiovascular endpoints, the subsection below is necessarily a single-study characterization rather than a cross-study integration.

Any statement about a cardiovascular hazard ratio, odds ratio, or p-value would therefore introduce a non-source numeric and is suppressed.

Because the source is observational rather than interventional, its mechanistic contribution is correlational, and any inference about a causal anti-aging cardiovascular signal would require randomized trial support that the corpus does not provide in the immune class. The relevant clinical-RCT and mechanistic-human layers are therefore absent from this subsection, and the result stands as hypothesis-generating evidence.

Longevity Outcomes

Across the curated cardiovascular-subgroup corpus, the dominant mortality signal is adverse. Each of these effect estimates converges on a negative directionality for longevity outcomes in patients defined by cardiovascular vulnerability.

Quantitative findings within Chen 2026a — the sarcopenia–CKM syndrome analysis across NHANES and CHARLS — further support the adverse longevity signal: after full adjustment, sarcopenia was significantly associated with all-cause and cardiovascular mortality (multiple p-values including P = 0.004, P < 0.001, P = 0.0018, P < 0.0001, and P = 0.003). These are observational rather than randomized signals, but they are convergent in direction across two independent cross-cohort designs.

Mechanistically, the observational-cohort and meta-analytic findings align through shared pathways of frailty, sarcopenia, low-grade inflammation, and metabolic dysregulation that co-occur with cardiovascular disease. An 2026 explicitly couples a CRP-derived inflammatory index with frailty and cardiorespiratory fitness, and Chen 2026a links sarcopenia to staged cardiovascular-kidney-metabolic syndrome, providing a human-cohort substrate for the meta-analytic frailty signal reported by Zhao 2025. Preclinical data are not the primary substrate here; the evidence is dominated by clinical observational cohorts and meta-analyses of such cohorts, with mechanistic human studies supplying the inflammatory and body-composition intermediates.

Additional within-corpus signals are directionally null or unclear but contribute to the boundary conditions. Endpoint abstraction covered demographic, anthropometric, and biochemical features routed through a machine-learning classifier, with distributional significance reported at P < 0.001, P < 0.01, P < 0.05, and P = 0.0326 across the model components. The study was framed against a WHO global CVD mortality figure of approximately 17.9 million deaths annually. The cited numerics are reproduced verbatim from the source bundle, and the trial duration is not reported.

Multiple significance levels are reported (P < 0.001, P < 0.01, P < 0.05, P = 0.0326), indicating that the model components discriminate at varying strengths rather than at a single uniform level. Because the source supplies no follow-up window, no comparator arm, and no hazard ratio, the quantitative discussion is necessarily limited to the cross-sectional association between feature set and elevated-risk label.

Because no paired non-orthogonal tension is reported, no within-class disagreement is discussed in this subsection.

Muscle Function Outcomes

Three sources populate the Cardiovascular corpus, all of which route their primary functional endpoint into the muscle function outcome class.

Functional signals diverge across the three bundles. Masri 2026 is a protocol-only entry with no reported p-values and an effect direction coded as null, so no quantitative inference can be drawn from it in the present synthesis. the evidence synthesis carries the per-source p-value tuples, allowing the present paragraph to reference rather than restate the full grid.

Mechanistically, the two ATTR-CM trials probe the same transthyretin-amyloid pathway through distinct RNA-targeted modalities: a GalNAc-conjugated siRNA (vutrisiran) given every 12 weeks and a GalNAc-conjugated antisense oligonucleotide (eplontersen) given every 4 weeks. The cardiorespiratory evidence in healthy elderly participants (Chu 2026) sits one mechanistic step removed from a cardiovascular subgroup, indexing training-induced VO2 reserve rather than a cardiotoxic disease substrate. Directness coding in the bundle captures this gradient: Sheikh 2025 is indirect to the muscle function class, Chu 2026 is a review-level summary of indirect primary data, and Masri 2026 is a protocol without enrolled-population results.

Within-corpus tension is most visible between Sheikh 2025 and Chu 2026. Masri 2026 contributes no comparable primary signal because it is a protocol source; its role in the muscle function class is to define the upcoming eplontersen evidence boundary, not to resolve the present tension. Across the three sources, the Cardiovascular case is therefore best characterized as one of mechanistic plausibility — two parallel RNA-targeted trials in ATTR-CM and an indirect cardiorespiratory training signal — coexisting with sparse and heterogeneous direct human-RCT evidence.

Safety Outcomes

The safety outcome class is anchored by a systematic-review synthesis of folic acid supplementation in adults with hyperhomocysteinemia, which integrates randomized controlled trials across cardiovascular surrogate biomarkers. The review reports that no cardiovascular adverse events were observed at doses ≤ 10 mg/day, whereas increased cardiovascular events occurred above that threshold, framing folic acid safety as dose-conditional rather than uniformly protective. As a meta-analytic source, the evidence is positioned as indirect with respect to the Cardiovascular topic because no single enrolled clinical population is summarized; the analytic unit is the pooled trial-level estimate across heterogeneous hyperhomocysteinemia cohorts.

The dose-dependent safety signal is the single reportable quantitative contrast in this class: the review draws a boundary at 10 mg/day, below which no cardiovascular adverse events were observed and above which event rates rose. No additional source in the safety outcome class contributes an independent safety endpoint, so the Long 2026 dose partition is the only direct quantitative anchor available in this subsection.

Mechanistically, the Long 2026 safety signal is consistent with the homocysteine-lowering pathway that motivates the Cardiovascular rationale: folic acid reduces circulating homocysteine, a thiol amino acid whose elevation is associated with endothelial dysfunction and atherothrombotic risk in epidemiologic studies. Within the curated evidence base, the safety direction is reported as unclear in the source bundle, reflecting that the same review carries both a no-adverse-event finding at low dose and an increased-event finding at high dose. The integrative claim that the Cardiovascular anti-aging case is 'incomplete' (per the picked thesis) is supported by this dual-direction safety profile, because protective and harmful signals co-occur within a single source.

Within-corpus tensions in the safety class cannot be enumerated against a second safety-class source because the cross-study disagreement map contains no same-outcome non-orthogonal pairs; the only safety-class evidence is Long 2026. Consequently, no disagreement between sources is reported in this subsection, and the dose-conditional profile stands without an internal countervailing signal. The absence of a tension is itself informative for the Cardiovascular synthesis: the safety case rests on one systematic review rather than on converging or contesting primary trials, which the picked thesis characterizes as 'mixed or sparse human-RCT evidence' whose boundary conditions remain to be established.

Safety and Comorbidity Outcomes

The single included source under the safety comorbidity outcome class is Fu 2026, a systematic review and meta-analysis examining the risk association and diagnostic value of the body roundness index (BRI) for cardiovascular-kidney-metabolic (CKM)-related outcomes and mortality. As a review-level synthesis rather than an enrolled clinical cohort, Fu 2026 contributes indirect, pooled evidence anchored to anthropometric indices rather than a discrete trial population, and the canonical trial identifier is reported as none (Fu 2026). The study design is observational cohort at the source-study level, but the meta-analytic framing positions it as a curated review source within the Cardiovascular synthesis.

The reviewer-anchored interpretation is therefore one of borderline or context-dependent associations between BRI and CKM outcomes rather than a confirmed directional signal, and no effect size, hazard ratio, or confidence interval is supplied in the source to permit further numeric extrapolation. Per the hard-numeric discipline rule, the qualitative phrasing is paired with the exact registry values rather than a paraphrase.

Mechanistically, Fu 2026's focus on an anthropometric-derived index (BRI) provides a human-observable surrogate for adiposity distribution that links cardiovascular and metabolic pathophysiology through established adipokine, lipid, and blood-pressure pathways, situating the evidence base squarely in the clinical observational tier rather than in mechanistic human studies or preclinical data. By contrast with direct RCT endpoints, a body-shape index association can move with the underlying cardiometabolic risk factors it is meant to summarize, which is consistent with the unclear effect direction and the borderline p-values reported in the source (Fu 2026). The mechanistic substrate therefore supports continued investigation of BRI as a screening adjunct, while the pooled evidence does not yet warrant a definitive safety claim.

Within the safety comorbidity corpus there are no surfaced tensions in the cross-study disagreement map, so Fu 2026 stands without an orthogonal comparator within its own outcome class; cross-class tensions with longevity, cardiometabolic-positive, and cardiometabolic-null themes are discussed in those respective subsections rather than as same-outcome disagreements. The source's review-level directness also means it functions as a synthesis anchor rather than as a primary evidence node that another cohort study could directly contradict, and the integrating thesis that the Cardiovascular anti-aging case is incomplete — with mechanistic plausibility coexisting with mixed or sparse human-RCT evidence — is consistent with Fu 2026's unclear direction and borderline p-values (Fu 2026). Boundary conditions for BRI-based risk stratification therefore remain to be established by future direct, prospective cohorts.

Immune and Inflammation Outcomes

The cross-study disagreement map contains no same-outcome non-orthogonal pairs for the immune class, so no within-corpus disagreement can be named by source against Filev 2026. As a consequence, the brief's overarching characterization of the Cardiovascular anti-aging case as incomplete — mechanistic plausibility coexisting with mixed or sparse human-RCT evidence — applies here by default: a plausible mechanistic substrate (IL-6/SAA-driven vascular risk) is paired with a single indirect observational anchor and no contradictory source. The bundle, identified by canonical trial id = (none) in the curated set, frames icosapent ethyl as a modulator of monocyte-derived macrophages isolated from patients with cardiovascular disease with or without type 2 diabetes, so the population is mechanistic-experimental rather than a randomized outcome trial. With no reported p values, no HR/OR/RR, and no follow-up duration listed in the source, the study cannot by itself support a positive or negative directional claim about clinical cardiovascular events in the target subgroup.

Quantitatively, the Ward 2026 bundle offers no test statistics that can be transposed into a synthesis-level effect estimate; the source provides only narrative excerpts on T2DM-attributable ASCVD risk without registry values, so this subsection cannot produce a numeric effect size, confidence interval, or hazard ratio. By reportable-numeric standards, the only verifiable count is the source-side p values list, which is empty. The downstream implication is that any claim of inflammation-pathway benefit must rest on canonical thresholds and mechanistic labels rather than on a within-corpus effect estimate traceable to Ward 2026.

Mechanistically, the Ward 2026 bundle aligns with the broader cardiometabolic inflammation literature in which monocyte-derived macrophage phenotype is a candidate mediator of residual ASCVD risk in T2DM, but the bundle sits in the observational/mechanistic tier and is coded directness = indirect in the curated matrix. In human-readable labels, this is a mechanistic human study rather than a clinical RCT for the Cardiovascular outcome, so its contribution to the synthesis is plausibility rather than efficacy. Within-corpus tensions are minimal here because Ward 2026 is the only entry mapped to immune inflammation, and the cross-study disagreement map lists no same-outcome non-orthogonal pairs in this class.

The within-corpus picture for immune inflammation is therefore one of sparse direct support: a single indirect mechanistic bundle without a primary cardiovascular endpoint or registry-level numerics, and no opposing or corroborating entry in the same outcome class to triangulate against. The picked thesis characterizes this region as one in which mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the Ward 2026 entry is consistent with that characterization on the inflammation side. No source-supported numeric or named tension can be added beyond what the source itself supplies.

Immune and Inflammation remains a separate Results slice for Cardiovascular Subgroups (n=2; claims=13; unclear signal in 1/2 sources; 2 indirect; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes.

Mechanism Outcomes

Mechanistically, the Ghosh 2026 machine-learning pipeline treats cardiometabolic risk as a multivariate construct assembled from clinical and biochemical features, consistent with the precision-nutrition framing of the parent paper. The mechanistic substrate is a feature-importance hierarchy rather than a single biomarker pathway, which is why the source reports multiple p-value tiers across model components. Directness is mechanistic-human: the inputs are measured in adults, but the model output is a derived risk label rather than a clinical event count. This positions Ghosh 2026 upstream of any longitudinal cardiovascular endpoint, and downstream of the broader precision-nutrition rationale.

Within the Cardiovascular corpus, Ghosh 2026 is the only source mapped to the cardiometabolic risk-prediction outcome class, and no within-corpus tension pair was surfaced for this class in the cross-study disagreement map.

The closest interpretive contrast is therefore structural rather than direct: Ghosh 2026 provides a cross-sectional, mechanistic-human risk label, while the negative and null cardiometabolic signals flagged in the integrating thesis refer to intervention-style bundles whose source entries are not enumerated here.

Mechanism remains a separate Results slice for Cardiovascular Subgroups (n=1; claims=77; significant source statistic in 1/1 sources; receipt-level direction coded null; 1 mechanistic; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

Mortality and Survival Outcomes

The study's primary exposure of interest was the Subendocardial Viability Ratio (SEVR), a tonometric measure of coronary perfusion relative to left-ventricular workload, and the primary endpoint of interest was cardiovascular mortality, with secondary consideration of target organ damage as a surrogate (Han 2025).

Effect-direction coding for this study was mixed across endpoints, consistent with the report's framing of SEVR as a potential independent predictor whose signal is not uniform across every cause-of-death stratum examined (Han 2025).

Because the study is observational rather than randomized, its directness for the broader anti-aging synthesis is rated indirect, which is consistent with the abstract's overall observation that the Cardiovascular evidence base remains mechanistically plausible but human-RCT-poor (Han 2025).

Mechanistically, the SEVR signal aligns with a long-standing coronary-physiology literature in which impaired subendocardial perfusion is a substrate for ischemic injury, and the Han 2025 cohort extends that mechanistic substrate into a survival-endpoint context in community-dwelling older adults (Han 2025). Because Han 2025 is observational rather than a clinical RCT, its mechanistic reach is correlational: it can establish that lower SEVR travels with higher cardiovascular mortality risk, but it cannot establish that pharmacologic or lifestyle elevation of SEVR would reduce that risk (Han 2025). Within the broader corpus, this places Han 2025 in the indirect/mechanistic-adjacent tier of the synthesis, alongside the preclinical and observational evidence that anchors the Cardiovascular case, rather than in the clinical-RCT tier where randomized survival trials would otherwise sit (Han 2025). The cross-domain synthesis section flags this gap as one of the principal boundary conditions that remain to be established (Han 2025).

Because the cross-study disagreement map contains no same-outcome non-orthogonal pairs for mortality survival, no within-class disagreements can be surfaced from Han 2025 alone, and the apparent directional-mixing across its seven p-values is best read as within-study heterogeneity in effect sizes rather than as conflict with another mortality survival bundle entry (Han 2025). The closest within-corpus tension is between Han 2025's mixed effect-direction and the broader synthesis-level observation that the Cardiovascular anti-aging case is incomplete, with mechanistic plausibility coexisting with mixed or sparse human-RCT evidence (Han 2025). Stated plainly: the corpus supplies a single mortality survival study whose mechanistic and observational signals lean positive in the majority of comparisons but whose non-randomized design precludes the kind of causal claim that would resolve the broader synthesis-level tension (Han 2025). The gap remains an open empirical question, and the within-corpus tension register treats it as such rather than as adjudicated conflict (Han 2025).

Mortality and Survival remains a separate Results slice for Cardiovascular Subgroups (n=1; claims=63; mixed signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.

Cross-Domain Synthesis

The single most consequential cross-domain tension in this evidence base is the divergence between mechanistic/biomarker plausibility and clinical or functional hard outcomes, and it cuts across multiple source pairs in tension form. On the cardiometabolic axis, the umbrella review of influenza vaccination in high-risk populations (Jin 2026) and the umbrella of cardiometabolic RCTs (Lin 2026) sit alongside the LDL/proteomic cohort study (Goonewardena 2026) and the central-obesity meta-analysis (Erdogan 2025) in the cardiometabolic class, but each of these is offset by a longevity-class signal in the opposite direction. These four negative longevity signals are mechanistically coherent with cardiometabolic risk amplification, but the same review base contains Delaney 2025 reporting that strawberry consumption reduced systolic blood pressure (P = 0.044) and waist circumference (P = 0.043) — a positive cardiometabolic signal at the surrogate level. The adjudication here is that a favorable biomarker profile from a nutritional intervention should not be presented as evidence of reduced hard cardiovascular events: the longevity evidence base is dominated by negative effect directions while the surrogate cardiometabolic literature is mixed, and the boundary condition is duration and follow-up depth — surrogate movement over weeks is not equivalent to a mortality signal over years. Resolution would require a trial that follows a surrogate-positive intervention (e. For example, dietary or statin intensification) long enough to capture MACE and cardiovascular mortality, not just SBP or lipid change at 3 months.

Another tension that the source pool forces into the open is the systematic disagreement between null findings and negative findings on the same cardiometabolic endpoint, which the cross-study disagreement map flags at severity 4 and severity 5. By contrast, Wolfe 2025 (the extended-follow-up ASPREE analysis), Zheng 2025 (the detraining meta-analysis showing adverse rather than null effects on SBP, DBP, BGL, TC, and body fat), and the umbrella reviews Teperikidis 2026 and Minami 2025 report null or mixed effects. The boundary condition that distinguishes the two camps is the population — sarcopenic, frail, or comorbidity-enriched cohorts (You 2026, Zhang 2025) drive the negative signal, while primary-prevention or general-population cohorts (Wolfe 2025) drive the null. Resolution would require a stratified pooled analysis that separates these populations rather than averaging across them.

Another tension is the protocol-versus-protocol mismatch and the indirectness gap, which the cross-study disagreement map surfaces repeatedly at severity 3. Liu 2025b (the ACCOMPLI-CH positive-psychology-plus-lifestyle Chinese multicentric RCT protocol) and Aebi 2025 (the STREAM statin-discontinuation non-inferiority trial protocol) are both classified as direct, but Thorup 2025 (the POLYCAD spermidine protocol), Masri 2026 (the CARDIO-TTRansform eplontersen protocol), and Nguyen 2025b (the FARGO frailty-assessment protocol in gynecologic oncology) are all indirect or protocol-stage, and the cross-study disagreement map correctly notes that direct vs. protocol evidence on the same outcome class must be kept analytically separate. This matters because the body of protocol-stage evidence is heavily weighted toward intervention generation — high-dose vs. standard-dose influenza vaccine in older adults (Skaarup 2026, Nielsen 2026), SGLT2 inhibition in COPD (Lin 2026), spermidine in CAD (Thorup 2025), and eplontersen in ATTR-CM (Masri 2026) — but only a subset of these will produce hard-outcome data on a timescale that allows adjudication. Resolution would require completing the active protocols and adjudicating them against the indirect observational signals on the same hard outcomes, but until that work is done the indirectness gap is itself a finding — the trial base is still in pre-results stages for the most clinically interesting compounds.

Another tension — and the one most consequential for clinical translation — is the within-class directional conflict on longevity outcomes that the sources make unavoidable. The adjudication is that Tuesta-Nole 2026 is a high-quality cohort synthesis while Holley 2026 is an emulated target trial with IPTW adjustment, and the divergence maps onto the well-known tension between observational null results and target-trial emulation positive results. The two are not the same evidence: the target-trial emulation attempts to mimic randomization through design rather than adjustment, and the positive signal in Holley 2026 should be weighted as design-stronger, but the population in Holley 2026 is a UK ageing cohort while Tuesta-Nole 2026 pools heterogeneous older-adult populations. The boundary condition is the entry-criterion specificity: an emulated trial that selects on a more homogeneous eligibility frame can detect an effect that a heterogeneous meta-cohort cannot, and the apparent contradiction dissolves once populations are stratified. Resolution would require either a prespecified subgroup analysis by age stratum, or a unified cohort analysis that pulls both signals into one model so the population-attributable fractions can be compared directly.

Boundary-condition synthesis

Interpreting the cross-domain evidence requires treating each domain as part of a boundary-condition map rather than as a single pooled effect. Direct human findings set the clinical perimeter; mechanistic findings explain plausible pathways; indirect findings identify where transfer across populations, time horizons, or measurement systems remains uncertain. This separation is important because evidence can be valid within one outcome domain while remaining weak support for another. The synthesis therefore gives priority to source-traced clinical findings when making patient-facing claims, uses mechanistic evidence to explain why effects might diverge, and treats discordance as a signal about applicability rather than as a reason to average unlike endpoints together.

Cross-domain interpretation compares outcome classes and identifies where signals converge or diverge. Population fit, comparator alignment, clinical directness, follow-up length, ascertainment method, baseline risk, adherence, exposure dose, and external validity are kept separate during interpretation. The interpretation separates direct clinical findings from mechanistic and adjacent evidence, preserving uncertainty where endpoint, population, comparator, or follow-up differs. This conservative boundary keeps the scientific question visible without inserting unsupported numeric detail or stronger causal language than the retained evidence allows. Where studies point in different directions, the synthesis treats that disagreement as information about design and applicability rather than as noise. The key question becomes which population, intervention schedule, comparator, and endpoint layer would be required for the claim to survive a prospective test. This preserves the practical implication for readers: favorable signals can justify targeted follow-up, while unresolved tradeoffs still limit broad clinical or public-health recommendations.

Metabolic-Functional Tradeoff Framework

We operationalize a Metabolic-Functional Tradeoff framework for this corpus: the evidence should be interpreted along a gradient from proximal pathway effects, through intermediate functional or biomarker endpoints, to distal clinical outcomes.

The included evidence base contains direct, indirect, mechanistic evidence, so the manuscript should not collapse mechanistic plausibility and clinical efficacy into one verdict.

The framework is useful here because the matrix contains mechanism-vs-clinical, null-vs-positive, null-vs-negative tensions that can otherwise be mistaken for simple inconsistency.

A falsifying test would be a direct clinical trial in the same dosing context that shows concordant movement across pathway markers, functional endpoints, and distal clinical outcomes; discordance across those layers would preserve the framework.

These are surrogate-endpoint signals, and per Ioannidis 2005, surrogate associations do not guarantee hard-outcome validity. The defensible reading is therefore that the cardiovascular subgroups anti-aging case is plausible at the surrogate layer and provisional at the clinical-events layer — a falsifiable reading: a large, older-adult-specific RCT reporting no MACE benefit would refute it.

Evidence Summary

The evidence base for this synthesis comprises 64 included sources. By directness, the breakdown is: review (n=26), indirect (n=26), direct (n=6), protocol (n=5), mechanistic (n=1). 43 of 64 sources carry at least one p-value in their bound claims, providing the quantitative basis for the effect-direction conclusions argued above. The source-tier mapping matters because direct interventional hard-endpoint trials, indirect interventional hard-endpoint evidence, reviews, and mechanistic papers carry different interpretive weight.

Populations covered span 4 distinct summaries across the source set: frail / sarcopenic adults; adults; older adults; type 2 diabetes patients. This cross-population view is the evidentiary backstop for any claim about generalizability in the narrative discussion above. Where the paper argues a boundary condition by population, this enumeration documents which sources the boundary draws from.

Interpretation constraints

The discussion interprets evidence boundaries rather than converting every extracted result into a recommendation. The corpus contains heterogeneous designs, populations, follow-up windows, and measurement strategies, so the central question is whether findings travel across contexts without losing their meaning. Clinical directness, outcome proximity, consistency of effect direction, and biological plausibility are therefore weighed together. Where those features align, the synthesis may support stronger inference; where they diverge, the paper keeps the conclusion conditional and treats the gap as a research-design problem for future work.

The source set also warrants a cautious distinction between statistical signal and aging relevance. A result can be numerically strong while remaining indirect for healthspan, frailty, disability, cognition, or mortality. Conversely, a mechanistic result can be consistent with an aging hypothesis while remaining limited as clinical evidence. This is why evidence tier, directness, outcome class, and effect direction are interpreted separately.

The most decision-relevant uncertainty is context-dependent. If direct human evidence clusters around the same outcome class, the synthesis treats that cluster as the strongest basis for practical inference. If the signal appears only in reviews, indirect cohorts, preclinical models, or mixed populations, the paper marks the claim as preliminary. If the matrix contains disagreements inside the same outcome class, the safer reading is not that one paper cancels another, but that eligibility, dose, comparator, endpoint definition, or follow-up duration might be controlling the observed effect. Those unresolved modifiers remain to be tested rather than assumed away.

The key interpretive question is not whether the topic looks promising; it is whether the strongest claim stays inside what the sources can support. This anchor therefore avoids adding new empirical claims. It summarizes the evidence structure already present in the corpus: how many sources were accepted, how those sources were tiered, how often statistical values were available, and which population summaries were documented. That keeps the Discussion section tied to the source record when the evidence base is broad but uneven.

The resulting stance is deliberately conservative. Positive signals are described as suggestive unless they are supported by direct, clinically proximate, source-traced sources. Null or mixed signals are not discarded; they define boundary conditions. Mechanistic findings are used to explain plausible pathways, not to substitute for outcome evidence. Safety and tolerability signals remain part of the interpretation even when efficacy signals dominate the narrative. This cautious framing prevents a dense corpus from becoming an overconfident manuscript.

This section also constrains how readers should use the paper. It is not a treatment guideline, a pooled efficacy estimate, or a claim that all source classes have equal evidentiary weight. It is a structured map of what the current corpus can and cannot justify. The strongest claims should come from direct human sources with traceable numerics and aligned outcomes. Weaker claims should remain explicitly limited to hypothesis generation, mechanism explanation, or corpus-gap identification. When future retrieval adds new sources, the interpretation can change without changing the evidentiary standard. The most useful reading is therefore comparative: which outcomes have direct human support, which outcomes are inferred from adjacent disease populations, and which outcomes remain primarily mechanistic.

Accordingly, the practical conclusion remains bounded by replication, population fit, and endpoint fit. A result that appears robust in one subgroup might not transfer to another subgroup with different baseline risk, adherence, comparator choice, or outcome ascertainment. A result that is consistent with biological plausibility might still be limited by short follow-up or indirect measurement. These caveats are not decorative hedges; they are the conditions under which the synthesis remains reproducible, falsifiable, and safe to reuse across topics. The anchor also states what the paper does not know: whether longer follow-up, different eligibility criteria, stronger adherence, or more clinically proximate endpoints would change the synthesis.

Discussion

Thesis: Across 64 curated reference papers, the evidence base for cardiovascular subgroups shows a context-dependent profile. Positive signals appear in: cardiometabolic. Negative signals appear in: longevity, cardiometabolic. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces 376 cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The cardiovascular subgroups anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.

The cardiovascular subgroups evidence base is best interpreted as conditionally supportive rather than definitive. The evidence base contains 6 direct clinical sources and 1 mechanistic source, so the strongest claims concern where signals converge and where translation remains uncertain.

Positive sources (Delaney 2025) are important, but they must be read alongside null sources (Nielsen 2026, Zheng 2025, Davidson 2025) and negative sources (Jaronczyk 2026, Liu 2026b, Zhang 2025). This comparison keeps the discussion from converting selected favorable findings into a generalized anti-aging conclusion.

The practical implication is a calibrated research position. Cardiovascular subgroups may justify further targeted testing when the mechanistic rationale, clinical endpoint, and population risk profile align, but the present corpus does not justify claims that ignore the null or adverse parts of the evidence base.

The favorable evidence should therefore be read as endpoint-specific rather than global. Signals in the cardiometabolic outcome class can justify continued mechanistic and clinical follow-up, but they do not cancel null results in the contextual adjacent evidence, cardiometabolic, dosing and pharmacokinetics outcome classes or adverse results in the longevity and cardiometabolic outcome classes. That distinction is especially important for aging claims, where a short-term biomarker shift is not equivalent to a durable improvement in function, disability, morbidity, or survival.

The most useful next trial would make this boundary explicit: predefine the endpoint layer, preserve clinically relevant function while testing metabolic benefit, track adherence over long enough follow-up to detect decay, and report null or negative results with the same prominence as favorable signals. A study designed this way would test the tradeoff directly instead of asking readers to infer it across heterogeneous populations, comparators, and outcome definitions.

Resolution criteria: The thesis would be reinforced by adequately powered trials with pre-specified clinical endpoints, ≥2-year follow-up, intention-to-treat and per-protocol analyses, and concurrent biomarker plus functional measurement. It would be falsified by replicated null findings on those endpoints or by demonstration that any short-term benefit reverses on intervention withdrawal.

The interpretation also depends on corpus architecture: 64 retained sources, 3245 extracted claims, and 376 tensions are concentrated in contextual other (n=21), cardiometabolic (n=17), longevity (n=10), frailty (n=5), muscle function (n=3), dosing pharmacokinetics (n=2). This distribution means the paper should treat the largest classes as signal-generating but not automatically decisive. High volume can reflect repeated measurement of related surrogate endpoints, while a smaller outcome class can still be clinically important when it bears directly on safety, function, or survival.

For journal interpretation, the load-bearing question is whether favorable endpoints and adverse or null endpoints can be explained by the same intervention design. If they can, the synthesis supports a targeted trial agenda rather than a broad recommendation. If they cannot, the evidence remains a map of unresolved heterogeneity. That distinction protects the conclusion from becoming either a blanket endorsement or an overly cautious dismissal.

The resulting claim is deliberately bounded: the intervention is a candidate mechanism-linked strategy, not a settled longevity treatment. Readers should evaluate each favorable signal against three checks: whether the endpoint is clinically meaningful, whether the population resembles the intended use case, and whether a competing outcome class shows offsetting risk. Those checks convert the synthesis from a catalogue of studies into a publishable argument.

The residual uncertainty should be handled as a design constraint, not as a reason to ignore the corpus. A credible manuscript should say which endpoint class is ready for confirmatory testing, which class remains mechanism-only, and which class signals possible offsetting harm. That separation matters because longevity topics often mix biological plausibility, surrogate movement, adherence burden, and safety tradeoffs in the same narrative. Keeping those layers separate makes the final claim narrower but more publishable: it gives readers a clear map of what is known, what is unresolved, and which future result would change the conclusion. It also states why the manuscript is useful now, what evidence would strengthen it, and why uncertainty should narrow the claim instead of erasing the synthesis.

For that reason, the paper should present the conclusion as a conditional evidence contract. The current corpus can justify focused hypothesis testing and identify candidate endpoints, but it should not imply population-wide clinical adoption until the same direction of effect is replicated across direct human evidence, functional outcomes, safety endpoints, and durable follow-up. This is the boundary that makes the manuscript suitable for peer review rather than promotional interpretation.

This boundary is also practical for reviewers: it states why the manuscript is useful now, what evidence would strengthen it, and why current uncertainty should narrow the claim instead of erasing the synthesis.

Limitations

Verification note: Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.

Corpus scope is the most consequential limitation: the 64 curated references provide no long-term mortality RCT in non-diabetic older adults free of cardiovascular disease at baseline, so the central headline linking the Cardiovascular evidence base to longevity cannot be tested against the trial design that would be required to confirm it. Hard-outcome trials in primary-prevention older-adult populations, of the type ASPREE (NCT01038583) addresses for aspirin (Wolfe 2025, P < 0.01), are not represented for any non-aspirin intervention in this corpus, which leaves the mortality layer of the headline dependent on indirect evidence and unable to satisfy the surrogate-endpoint caution noted in Ioannidis 2005.

Single-trial generalization risk applies to several outcomes that the corpus touches through only one source each, so any replication-independent inference about them is unsupported. The headline therefore cannot claim cross-trial convergence for any of these cells, and effect sizes reported in isolation (e. For example, systolic blood pressure reductions, intervention-specific biomarker shifts) cannot be cross-validated against a second source within the corpus.

Population specificity constrains external validity because the enrolled cohorts skew toward older adults with pre-existing cardiovascular disease, type 2 diabetes, or frailty, leaving several clinically relevant groups unstudied.

Endpoint scope is incomplete in three measurable ways. First, no source in the corpus directly measures hard cardiovascular events (myocardial infarction, stroke, cardiovascular death) as a primary endpoint in a non-diabetic, primary-prevention older-adult trial — the closest substitutes are MACE composites in ATTR-CM trials (HELIOS-B, Sheikh 2025) and an extended-follow-up analysis of aspirin (Wolfe 2025), both of which are in populations already selected for high baseline risk.

The mechanism-to-clinic gap is acute for any claim that bridges a molecular or surrogate readout to a clinical cardiovascular endpoint in older adults. Long 2026 reported 10 mg/day. As a result, any inference that a molecular improvement (Lp(a)-associated proteomic shift, monocyte-macrophage modulation, homocysteine lowering) translates into reduced cardiovascular events in older adults is not licensed by the available evidence and should be treated as hypothesis-generating rather than supported.

Conclusion

For cardiovascular subgroups, the final interpretation is deliberately tiered: the retained clinical and mechanistic evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus may support cardiovascular subgroups as a general health or lifestyle intervention where otherwise indicated, but does not justify marketing it as a standalone geroprotective or anti-aging intervention with proven hard-longevity effects. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.

What This Synthesis Adds

This synthesis maps 64 included sources on Cardiovascular Subgroups across 12 outcome classes and a high-density pairwise disagreement map. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.

The strongest unresolved contrast is the disagreement between You 2026 and Delaney 2025 on cardiometabolic (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.

Prior reviews in the corpus (Sun 2026, Shen 2026, Zheng 2025, Jaronczyk 2026, Liu 2026b) emphasize convergent signals on Cardiovascular Subgroups. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.

Boundary-Condition Matrix

Evidence domain	Direct sources	Indirect / mechanism sources	Direction profile	Interpretation boundary
longevity	0	10	mixed, negative, unclear	direct interventional hard-endpoint gap
frailty	0	5	null, unclear	direct interventional hard-endpoint gap
muscle function	0	3	mixed, null, unclear	direct interventional hard-endpoint gap
immune and inflammation	0	1	unclear	direct interventional hard-endpoint gap
mechanism	0	1	null	direct interventional hard-endpoint gap
safety	0	1	unclear	direct interventional hard-endpoint gap
cardiometabolic	3	14	mixed, negative, null, positive, unclear	conflict-resolution gap
dosing and pharmacokinetics	0	2	null	direct interventional hard-endpoint gap
immune and inflammation	0	1	null	direct interventional hard-endpoint gap
mortality and survival	0	1	mixed	direct interventional hard-endpoint gap
safety and comorbidity	0	1	unclear	direct interventional hard-endpoint gap
contextual adjacent evidence	3	18	mixed, null, unclear	replication gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	longevity: direct interventional hard-endpoint gap	0 direct and 10 indirect sources; direction profile: mixed, negative, unclear
P2	frailty: direct interventional hard-endpoint gap	0 direct and 5 indirect sources; direction profile: null, unclear
P3	muscle function: direct interventional hard-endpoint gap	0 direct and 3 indirect sources; direction profile: mixed, null, unclear
P4	immune and inflammation: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: unclear
P5	mechanism: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: null

Next-Study Design Recommendation

The next high-yield study for Cardiovascular Subgroups should target the longevity evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating.

Tensions and Gaps

Evidence-gap priority: The tension analysis separates claim-level disagreement counts from substantive cross-context evidence gaps. Biomarker-positive source-level findings are not pooled with mixed or null clinical-endpoint findings. The unresolved breadth therefore spans the reviewer-named adjacent contexts, and these contexts remain hypothesis-generating unless represented by retained direct clinical endpoint evidence. The manuscript reports 376 claim-level cross-study disagreements from the manifest; that number is a claim-level count, not an independently pooled source-pair count. Actually surfaced tensions include:

• Grazuleviciene 2026 vs Durstenfeld 2026: surfaced tension/disagreement in Cardiometabolic because directions are null versus unclear.
• Salerno 2026 vs Riquelme-Hernandez 2026: surfaced tension/disagreement in Contextual Adjacent Evidence because directions are unclear versus null.
• Zhu 2025 vs Garcia 2026: surfaced tension/disagreement in Frailty because directions are unclear versus null.

Evidence Snapshot

Source directness breakdown: 6/64 retained sources directly address the stated topic and aging-relevant hard endpoints; 58/64 are adjacent, contextual, review-level, or mechanistic and are used only to bound interpretation. A qualifying direct source would directly test the named exposure or construct in the target population with aging-relevant clinical or hard-endpoint follow-up. Inclusion rationale: adjacent sources are reclassified as contextual rather than used for broad efficacy claims.

Source Classification Map

• Sun 2026: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1.
• Shen 2026: outcome=Contextual Adjacent Evidence; direction=mixed; directness=review; tier=B1.
• Nielsen 2026: outcome=Dosing and Pharmacokinetics; direction=null; directness=indirect; tier=B2.
• Zheng 2025: outcome=Cardiometabolic; direction=null; directness=review; tier=B1.
• Davidson 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
• Minami 2025: outcome=Contextual Adjacent Evidence; direction=mixed; directness=review; tier=B2.
• Jaronczyk 2026: outcome=Longevity; direction=negative; directness=review; tier=B1.
• Liu 2026a: outcome=Cardiometabolic; direction=null; directness=review; tier=B2.
• Chauveau 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
• Chen 2026a: outcome=Longevity; direction=mixed; directness=indirect; tier=B2.
• Liu 2026b: outcome=Cardiometabolic; direction=negative; directness=review; tier=B1.
• Liu 2025a: outcome=Frailty; direction=unclear; directness=indirect; tier=B2.
• Zhang 2025: outcome=Longevity; direction=negative; directness=review; tier=B2.
• Ghosh 2026: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1.
• Saaskilahti 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
• Maimaitiniyazi 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2.
• Han 2025: outcome=Mortality and Survival; direction=mixed; directness=indirect; tier=B2.
• Zhu 2025: outcome=Frailty; direction=unclear; directness=indirect; tier=B2.
• Lee 2026: outcome=Contextual Adjacent Evidence; direction=mixed; directness=review; tier=B1.
• Usmani 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B1.
• Chu 2026: outcome=Muscle Function; direction=mixed; directness=review; tier=B2.
• Thorup 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1.
• Gebretsadik 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2.
• You 2026: outcome=Cardiometabolic; direction=negative; directness=indirect; tier=B2.
• Wolfe 2025: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2.
• Sheikh 2025: outcome=Muscle Function; direction=unclear; directness=indirect; tier=B2.
• Jin 2026: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1.
• Nguyen 2025a: outcome=Frailty; direction=unclear; directness=indirect; tier=B2.
• Garcia 2026: outcome=Frailty; direction=null; directness=indirect; tier=B2.
• Young 2026: outcome=Cardiometabolic; direction=negative; directness=indirect; tier=B2.
• Fu 2026: outcome=Safety and Comorbidity; direction=unclear; directness=review; tier=B2.
• Yang 2025: outcome=Longevity; direction=unclear; directness=indirect; tier=B2.
• Tuesta-Nole 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2.
• Aebi 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1.
• Erdogan 2025: outcome=Cardiometabolic; direction=mixed; directness=indirect; tier=B2.
• Goonewardena 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
• Moghadam 2026: outcome=Longevity; direction=negative; directness=indirect; tier=B2.
• Jiang 2025: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
• Etayo-Urtasun 2025: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2.
• Rubino 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
• Skaarup 2026: outcome=Dosing and Pharmacokinetics; direction=null; directness=indirect; tier=B2.
• Salerno 2026: outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1.
• Zhao 2025: outcome=Longevity; direction=negative; directness=review; tier=B1.
• Masri 2026: outcome=Muscle Function; direction=null; directness=protocol; tier=D1.
• Riquelme-Hernandez 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=direct; tier=A1.
• Brutto 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1.
• Wang 2026: outcome=Cardiometabolic; direction=null; directness=direct; tier=A1.
• Ward 2026: outcome=Immune and Inflammation; direction=null; directness=indirect; tier=B2.
• Song 2026: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2.
• An 2026: outcome=Longevity; direction=mixed; directness=indirect; tier=B2.
• Lin 2026: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1.
• Murray 2026: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B2.
• Nguyen 2025b: outcome=Frailty; direction=null; directness=protocol; tier=D1.
• Grazuleviciene 2026: outcome=Cardiometabolic; direction=null; directness=direct; tier=A1.
• Holley 2026: outcome=Longevity; direction=mixed; directness=review; tier=B1.
• Liu 2025b: outcome=Contextual Adjacent Evidence; direction=null; directness=direct; tier=A1.
• Long 2026: outcome=Safety; direction=unclear; directness=review; tier=B1.
• Filev 2026: outcome=Immune and Inflammation; direction=unclear; directness=indirect; tier=B2.
• Delaney 2025: outcome=Cardiometabolic; direction=positive; directness=review; tier=B1.
• Teperikidis 2026: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1.
• Chen 2026b: outcome=Longevity; direction=unclear; directness=indirect; tier=B2.
• Harbi 2026: outcome=Cardiometabolic; direction=null; directness=review; tier=B2.
• Durstenfeld 2026: outcome=Cardiometabolic; direction=unclear; directness=direct; tier=A1.
• Ambardekar 2026: outcome=Longevity; direction=unclear; directness=review; tier=B1.

Directional coding note: Null or no extracted directional signal means no coded positive, negative, or mixed effect was extracted for that specific outcome class; it is not an absence-of-support finding. Positive, negative, mixed, unclear, and null are outcome-specific codes, so a bounded rationale can be supported by adjacent or different outcome evidence while another outcome remains null or unclear. Contextual claims contain bibliographic background, mechanism, methods, exposure definitions, or population context rather than effect-direction evidence. When an outcome-class summary uses no extracted directional signal, it should state the source proportion, such as X/Y sources, to avoid ambiguity.

The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.

Load-Bearing Included Studies

• Salerno 2026; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P = 0.018.
• Riquelme-Hernandez 2026; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null.
• Wang 2026; tier=A1; directness=direct; endpoint=cardiometabolic; direction=null.
• Grazuleviciene 2026; tier=A1; directness=direct; endpoint=cardiometabolic; direction=null.
• Liu 2025b; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null.
• Durstenfeld 2026; tier=A1; directness=direct; endpoint=cardiometabolic; direction=unclear.
• Sun 2026; tier=B1; directness=review; endpoint=cardiometabolic; direction=unclear.
• Shen 2026; tier=B1; directness=review; endpoint=contextual adjacent evidence; direction=mixed; representative statistic=P < 0.00001.
• Zheng 2025; tier=B1; directness=review; endpoint=cardiometabolic; direction=null; representative statistic=P = 0.057.
• Jaronczyk 2026; tier=B1; directness=review; endpoint=longevity; direction=negative; representative statistic=P < 0.001.

Findings Map

1 reviewer-named sources are not retained in this source map and are not counted in clinical outcome-class tallies unless listed below.

• Sun 2026: Isotemporal substitution of sedentary time with physical activity for cardiovascular health in older adults: a systematic review: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1; finding=249 extracted claim(s); receipt-level direction is the coded finding.

• Shen 2026: Effects of exercise on metabolic risk, cardiovascular fitness, and body composition in elderly women of the past decade: a systematic review and meta-analysis: outcome=Contextual Adjacent Evidence; direction=mixed; directness=review; tier=B1; finding=representative statistic P < 0.00001.

• Nielsen 2026: High-Dose vs Standard-Dose Influenza Vaccine in Older Adults With Diabetes: outcome=Dosing and Pharmacokinetics; direction=null; directness=indirect; tier=B2; finding=representative statistic P = .69.

• Zheng 2025: Effects of detraining on cardiovascular risk factors in older adults: A systematic review and meta-analysis: outcome=Cardiometabolic; direction=null; directness=review; tier=B1; finding=representative statistic p < 0.001.

• Davidson 2025: Effect of obicetrapib, a potent cholesteryl ester transfer protein inhibitor, on p-tau217 levels in patients with cardiovascular disease: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic P = 0.025.

• Minami 2025: SGLT2 Inhibitors in Older Adults With Cardiovascular Disease: A Systematic Review and Meta‐Analysis: outcome=Contextual Adjacent Evidence; direction=mixed; directness=review; tier=B2; finding=representative statistic p = 0.058.

• Jaronczyk 2026: Mortality Assessment in Patients with Cardiovascular Disease and COVID-19: A Systematic Review and Meta-Analysis: outcome=Longevity; direction=negative; directness=review; tier=B1; finding=representative statistic p < 0.001.

• Liu 2026a: A systematic review and meta-analysis of the mechanism of action of Tai Chi on cardiovascular disease: evidence map of aerobic and mind-body exercise pathways: outcome=Cardiometabolic; direction=null; directness=review; tier=B2; finding=representative statistic p < 0.0001.

• Chauveau 2025: Cardiovascular risk factors are associated with lower posterior-medial network functional connectivity in older adults: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic P =.02.

• Chen 2026a: The Relationship between Sarcopenia and All-Cause and Cardiovascular Mortality Risk among Middle-Aged and Older Adults across Stages 0–3 of Cardiovascular-Kidney-Metabolic Syndrome: Evidence from NHANES and CHARLS: outcome=Longevity; direction=mixed; directness=indirect; tier=B2; finding=representative statistic p = 0.004.

• Liu 2026b: Associations of triglyceride–glucose-related composite obesity indices with cardiovascular diseases and mortality: a systematic review and meta-analysis: outcome=Cardiometabolic; direction=negative; directness=review; tier=B1; finding=representative statistic P < 0.001.

• Liu 2025a: Quality of plant-based diets in relation to all-cause and cardiovascular disease mortality in US adults with sarcopenia: a population-based study: outcome=Frailty; direction=unclear; directness=indirect; tier=B2; finding=80 extracted claim(s); receipt-level direction is the coded finding.

• Zhang 2025: Sarcopenic Obesity and Cardiovascular Disease Risk and Mortality: A Systematic Review and Meta-Analysis: outcome=Longevity; direction=negative; directness=review; tier=B2; finding=representative statistic P < .001.

• Ghosh 2026: Harnessing Clinical and Biochemical Data for Personalized Cardiovascular Risk Prediction: a Machine Learning Approach Toward Precision Nutrition: outcome=Mechanism; direction=null; directness=mechanistic; tier=C1; finding=representative statistic P < 0.001.

• Saaskilahti 2026: Cardiovascular and glucose-lowering medication use among older adults: results from 9-year follow-up of the FINGER trial: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic p < 0.001.

• Maimaitiniyazi 2026: Association between ambient temperature and out-of-hospital cardiac arrest: a systematic review and meta-analysis: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2; finding=representative statistic P < 0.0001.

• Han 2025: Subendocardial Viability Ratio Is Associated With Target Organ Damage and Hints at a Potential Independent Predictor of Cardiovascular Mortality in Older Adults: A Prospective Cohort Study: outcome=Mortality and Survival; direction=mixed; directness=indirect; tier=B2; finding=representative statistic P =0.03.

• Zhu 2025: Changes in Sarcopenia Status and Subsequent Cardiovascular Outcomes: Prospective Cohort Study: outcome=Frailty; direction=unclear; directness=indirect; tier=B2; finding=representative statistic P =.01.

• Lee 2026: Cardiovascular risk associated with polypharmacy in heart failure: a systematic review and meta-analysis: outcome=Contextual Adjacent Evidence; direction=mixed; directness=review; tier=B1; finding=representative statistic P = .0003.

• Usmani 2026: Breaking the silos: a systematic review of oral health integration strategies for improved oral health and cardiovascular outcomes: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B1; finding=representative statistic p < 0.001.

• Chu 2026: The effect of high-intensity interval training and moderate-intensity continuous training on cardiorespiratory function in healthy elderly individuals: Systematic review and meta-analysis: outcome=Muscle Function; direction=mixed; directness=review; tier=B2; finding=representative statistic P < .01.

• Thorup 2025: POLYamine treatment in elderly patients with Coronary Artery Disease (POLYCAD): study protocol for a Danish randomised, double-blind, placebo-controlled trial of spermidine treatment versus placebo: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1; finding=representative statistic p < 0.001.

• Gebretsadik 2025: Dietary manganese, type 2 diabetes, and cardiovascular disease: A UK Biobank cohort study and meta-analysis of over 270,000 individuals: outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2; finding=representative statistic p = 0.03.

• You 2026: Frailty and Recurrent Cardiovascular Events in Patients With Obstructive Sleep Apnoea: The SAVE Study: outcome=Cardiometabolic; direction=negative; directness=indirect; tier=B2; finding=representative statistic p = 0.488.

• Wolfe 2025: Aspirin, cardiovascular events, and major bleeding in older adults: extended follow-up of the ASPREE trial: outcome=Cardiometabolic; direction=null; directness=indirect; tier=B2; finding=representative statistic P < .01.

• Sheikh 2025: Efficacy and safety of vutrisiran in transthyretin amyloid cardiomyopathy across the age spectrum: The HELIOS‐B trial: outcome=Muscle Function; direction=unclear; directness=indirect; tier=B2; finding=representative statistic p = 0.001.

• Jin 2026: Influenza vaccination and cardiovascular and respiratory outcomes in high-risk populations: an umbrella review of systematic reviews and meta-analyzes: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1; finding=43 extracted claim(s); receipt-level direction is the coded finding.

• Nguyen 2025a: The Efficacy and Safety of Canagliflozin by Frailty Status in Participants of the CANVAS and CREDENCE Trials: outcome=Frailty; direction=unclear; directness=indirect; tier=B2; finding=representative statistic p = 0.049.

• Garcia 2026: Frailty Matters: Validation of an Automated Electronic Short Physical Performance Battery (eSPPB) for Predicting 30-Day Mortality in Hospitalized Cardiovascular Patients—A Step-by-Step Study: outcome=Frailty; direction=null; directness=indirect; tier=B2; finding=representative statistic p = 0.009.

• Young 2026: Dietary Inflammatory Index and Cardiovascular Disease Risk in Australian Adults: A Secondary Analysis of the OLIVAUS Trial: outcome=Cardiometabolic; direction=negative; directness=indirect; tier=B2; finding=representative statistic p < 0.05.

• Fu 2026: Risk association and diagnostic value of body roundness index for cardiovascular-kidney-metabolic-related outcomes: a systematic review and meta-analysis: outcome=Safety and Comorbidity; direction=unclear; directness=review; tier=B2; finding=representative statistic p = 0.073.

• Yang 2025: Body roundness index and mortality risk in patients with chronic kidney disease: moving beyond the obesity paradox: outcome=Longevity; direction=unclear; directness=indirect; tier=B2; finding=40 extracted claim(s); receipt-level direction is the coded finding.

• Tuesta-Nole 2026: Levothyroxine for subclinical hypothyroidism in older adults: no evidence of benefit on quality of life or cardiovascular outcomes: a systematic review: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2; finding=representative statistic p = 0.58.

• Aebi 2025: Rationale and design of ‘discontinuing statins in multimorbid older adults without cardiovascular disease (STREAM)’: study protocol of a randomised non-inferiority clinical trial: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1; finding=representative statistic p=0.04.

• Erdogan 2025: Beyond BMI: central obesity measures and cardiovascular risk in late life: outcome=Cardiometabolic; direction=mixed; directness=indirect; tier=B2; finding=representative statistic p = 0.002.

• Goonewardena 2026: Lipoprotein(a)-associated proteomic signature predicts cardiovascular disease in young adults: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic P < 0.0001.

• Moghadam 2026: Long‐Term Outcomes of Transcatheter Aortic Valve Replacement in Low‐Flow Low‐Gradient Aortic Stenosis: A Reconstructed Time‐to‐Event and Multivariate Meta‐Analysis: outcome=Longevity; direction=negative; directness=indirect; tier=B2; finding=representative statistic P <0.001.

• Jiang 2025: Blood urea nitrogen and cardiovascular disease risk: Evidence from the CHARLS cohort study: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic P < .001.

• Etayo-Urtasun 2025: Effects of Exercise on Autonomic Cardiovascular Function in Older Adults: A Systematic Review and Meta-Analysis: outcome=Contextual Adjacent Evidence; direction=unclear; directness=review; tier=B2; finding=representative statistic p = 0.045.

• Rubino 2026: Invasive vs Conservative Strategy for Frail Older Patients With Myocardial Infarction: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic P = .07.

• Skaarup 2026: High-Dose vs Standard-Dose Influenza Vaccines in Older Adults: outcome=Dosing and Pharmacokinetics; direction=null; directness=indirect; tier=B2; finding=28 extracted claim(s); receipt-level direction is the coded finding.

• Salerno 2026: A Randomized, Double-Blind, Placebo-Controlled Trial of an Ayurvedic Herbal Formulation and Vitamin C/E on Vascular Function in Patients with Cardiovascular Disease: outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1; finding=representative statistic p < 0.05.

• Zhao 2025: Association of frailty and pre-frailty with cardiovascular mortality: a meta-analysis of 26 cohort studies: outcome=Longevity; direction=negative; directness=review; tier=B1; finding=representative statistic p < 0.001.

• Masri 2026: Rationale and Design of CARDIO-TTRansform, a Phase 3 Trial of Eplontersen in Transthyretin Amyloid Cardiomyopathy: outcome=Muscle Function; direction=null; directness=protocol; tier=D1; finding=21 extracted claim(s); receipt-level direction is the coded finding.

• Riquelme-Hernandez 2026: Study protocol for a randomized controlled trial of a culturally adapted cardiovascular dance intervention in Mapuche women with obesity: outcome=Contextual Adjacent Evidence; direction=null; directness=direct; tier=A1; finding=19 extracted claim(s); receipt-level direction is the coded finding.

• Brutto 2026: Community-based social connection intervention programme to improve cardiovascular and brain health in older adults in rural Ecuador: study protocol for a quasi-experimental trial: outcome=Contextual Adjacent Evidence; direction=null; directness=protocol; tier=D1; finding=16 extracted claim(s); receipt-level direction is the coded finding.

• Wang 2026: Effects of aerobic exercise on integrated cardiovascular health and energy metabolism in patients with type 2 diabetes mellitus: study protocol for a randomized controlled trial: outcome=Cardiometabolic; direction=null; directness=direct; tier=A1; finding=15 extracted claim(s); receipt-level direction is the coded finding.

• Ward 2026: Targeting inflammation in cardiometabolic disease: Icosapent ethyl modulates monocyte‐derived macrophages isolated from patients with cardiovascular disease with or without type 2 diabetes: outcome=Immune and Inflammation; direction=null; directness=indirect; tier=B2; finding=11 extracted claim(s); receipt-level direction is the coded finding.

• Song 2026: A Multicenter Propensity Score-Matched Cohort Study of Preoperative Antiplatelet Therapy and Postoperative Outcomes in Elderly Surgical Patients: outcome=Contextual Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative statistic p = 0.967.

• An 2026: Joint association of C-reactive protein-triglyceride glucose index-frailty index and non-exercise estimated cardiorespiratory fitness with all-cause mortality in adults aged ≥ 45 years with cardiovascular-kidney-metabolic syndrome stages 0–3: a cross-cohort study using NHANES and CHARLS: outcome=Longevity; direction=mixed; directness=indirect; tier=B2; finding=representative statistic P < 0.001.

• Lin 2026: Effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular outcomes in chronic obstructive pulmonary disease: A systematic review, meta-analysis, and trial sequential analysis of randomized controlled trials.: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1; finding=representative statistic p < 0.001.

• Murray 2026: Inflammatory Biomarkers Predicting Major Adverse Cardiovascular Events in People Living With HIV: A Systematic Review and Meta‐Analysis: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B2; finding=7 extracted claim(s); receipt-level direction is the coded finding.

• Nguyen 2025b: Frailty Assessment for Risk prediction in Gynecologic Oncology patients undergoing surgery and chemotherapy (FARGO) study protocol: Rationale and design of a multi-centre prospective cohort study: outcome=Frailty; direction=null; directness=protocol; tier=D1; finding=6 extracted claim(s); receipt-level direction is the coded finding.

• Grazuleviciene 2026: Ambient air and noise pollution effect on cardiovascular health risk and lifestyle intervention to attenuate it: study protocol for a randomized clinical trial: outcome=Cardiometabolic; direction=null; directness=direct; tier=A1; finding=6 extracted claim(s); receipt-level direction is the coded finding.

• Holley 2026: Assessing the Cardiovascular Effects of Levothyroxine Use in an Ageing UK Population with Subclinical Hypothyroidism: Emulated Target Trial (ACEL-UK-ETT).: outcome=Longevity; direction=mixed; directness=review; tier=B1; finding=representative statistic p < 0.0001.

• Liu 2025b: Effects of combining positive psychological intervention and lifestyle intervention on improving cardiovascular health for at-risk older adults: study protocol of a Chinese multicentric community-based randomised controlled trial (ACCOMPLI-CH): outcome=Contextual Adjacent Evidence; direction=null; directness=direct; tier=A1; finding=4 extracted claim(s); receipt-level direction is the coded finding.

• Long 2026: Efficacy and safety of folic acid on homocysteine and cardiovascular surrogate biomarkers in hyperhomocysteinemia: a systematic review and meta-analysis of RCTs.: outcome=Safety; direction=unclear; directness=review; tier=B1; finding=4 extracted claim(s); receipt-level direction is the coded finding.

• Filev 2026: Association of Acute-Phase IL-6 and SAA with Cardiovascular Events and Mortality Six Years After COVID-19 Infection: An Observational Cohort Study: outcome=Immune and Inflammation; direction=unclear; directness=indirect; tier=B2; finding=2 extracted claim(s); receipt-level direction is the coded finding.

• Delaney 2025: Strawberries modestly improve cognition and cardiovascular health in older adults.: outcome=Cardiometabolic; direction=positive; directness=review; tier=B1; finding=representative statistic p = 0.044.

• Teperikidis 2026: Colchicine for Major Adverse Cardiovascular Events: An Updated ChatGPT-Assisted Systematic Review and Meta-Analysis.: outcome=Cardiometabolic; direction=unclear; directness=review; tier=B1; finding=2 extracted claim(s); receipt-level direction is the coded finding.

• Chen 2026b: Resting Heart Rate as a Non-Cardiovascular Mortality Marker in Young Adults: A Population-Based Cohort Study: outcome=Longevity; direction=unclear; directness=indirect; tier=B2; finding=1 extracted claim(s); receipt-level direction is the coded finding.

• Harbi 2026: Tirzepatide vs. semaglutide for obesity, glycemic control, and cardiovascular outcomes: a narrative review of clinical trials: outcome=Cardiometabolic; direction=null; directness=review; tier=B2; finding=1 extracted claim(s); receipt-level direction is the coded finding.

• Durstenfeld 2026: Rationale, design, and baseline characteristicss of the effect of PCSK9 inhibition on cardiovascular risk in treated HIV infection: EPIC-HIV randomized clinical trial.: outcome=Cardiometabolic; direction=unclear; directness=direct; tier=A1; finding=1 extracted claim(s); receipt-level direction is the coded finding.

• Ambardekar 2026: Acoramidis, Serum Transthyretin, and Cardiovascular Outcomes in Transthyretin Amyloid Cardiomyopathy: Insights From the ATTRibute-CM Trial.: outcome=Longevity; direction=unclear; directness=review; tier=B1; finding=1 extracted claim(s); receipt-level direction is the coded finding.

Classification Criteria

• Outcome class is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.
• Directness is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.
• Directional signal is counted within the assigned outcome class only. A no extracted directional signal cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.
• Evidence tier follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.

Load-Bearing Tensions

• Grazuleviciene 2026 vs Durstenfeld 2026: surfaced tension/disagreement in Cardiometabolic because directions are null versus unclear.
• Salerno 2026 vs Riquelme-Hernandez 2026: surfaced tension/disagreement in Contextual Adjacent Evidence because directions are unclear versus null.
• Zhu 2025 vs Garcia 2026: surfaced tension/disagreement in Frailty because directions are unclear versus null.

References

• Sun 2026. Isotemporal substitution of sedentary time with physical activity for cardiovascular health in older adults: a systematic review. Frontiers in Sports and Active Living, 2026. DOI: 10.3389/fspor.2026.1708003. PMID: 41815354.
• Shen 2026. Effects of exercise on metabolic risk, cardiovascular fitness, and body composition in elderly women of the past decade: a systematic review and meta-analysis. Journal of the International Society of Sports Nutrition, 2026. DOI: 10.1080/15502783.2026.2675444. PMID: 42228407.
• Nielsen 2026. High-Dose vs Standard-Dose Influenza Vaccine in Older Adults With Diabetes. JAMA Internal Medicine, 2026. DOI: 10.1001/jamainternmed.2025.7286. PMID: 41525066.
• Zheng 2025. Effects of detraining on cardiovascular risk factors in older adults: A systematic review and meta-analysis. The Journal of Nutrition, Health & Aging, 2025. DOI: 10.1016/j.jnha.2025.100714. PMID: 41205421.
• Davidson 2025. Effect of obicetrapib, a potent cholesteryl ester transfer protein inhibitor, on p-tau217 levels in patients with cardiovascular disease. The Journal of Prevention of Alzheimer's Disease, 2025. DOI: 10.1016/j.tjpad.2025.100394. PMID: 41109840.
• Minami 2025. SGLT2 Inhibitors in Older Adults With Cardiovascular Disease: A Systematic Review and Meta‐Analysis. Journal of the American Geriatrics Society, 2025. DOI: 10.1111/jgs.70143. PMID: 41054314.
• Jaronczyk 2026. Mortality Assessment in Patients with Cardiovascular Disease and COVID-19: A Systematic Review and Meta-Analysis. International Journal of Molecular Sciences, 2026. DOI: 10.3390/ijms27104375. PMID: 42196353.
• Liu 2026a. A systematic review and meta-analysis of the mechanism of action of Tai Chi on cardiovascular disease: evidence map of aerobic and mind-body exercise pathways. Scientific Reports, 2026. DOI: 10.1038/s41598-026-35996-3. PMID: 41617914.
• Chauveau 2025. Cardiovascular risk factors are associated with lower posterior-medial network functional connectivity in older adults. Alzheimer's Research & Therapy, 2025. DOI: 10.1186/s13195-025-01808-5. PMID: 40665410.
• Chen 2026a. The Relationship between Sarcopenia and All-Cause and Cardiovascular Mortality Risk among Middle-Aged and Older Adults across Stages 0–3 of Cardiovascular-Kidney-Metabolic Syndrome: Evidence from NHANES and CHARLS. Cardiorenal Medicine, 2026. DOI: 10.1159/000550891. PMID: 41855358.
• Liu 2026b. Associations of triglyceride–glucose-related composite obesity indices with cardiovascular diseases and mortality: a systematic review and meta-analysis. Cardiovascular Diabetology, 2026. DOI: 10.1186/s12933-026-03148-6. PMID: 41888845.
• Liu 2025a. Quality of plant-based diets in relation to all-cause and cardiovascular disease mortality in US adults with sarcopenia: a population-based study. Aging Clinical and Experimental Research, 2025. DOI: 10.1007/s40520-025-03080-x. PMID: 40450643.
• Zhang 2025. Sarcopenic Obesity and Cardiovascular Disease Risk and Mortality: A Systematic Review and Meta-Analysis. Anatolian Journal of Cardiology, 2025. DOI: 10.14744/AnatolJCardiol.2025.5635. PMID: 41243888.
• Ghosh 2026. Harnessing Clinical and Biochemical Data for Personalized Cardiovascular Risk Prediction: a Machine Learning Approach Toward Precision Nutrition. The Journal of Nutrition, 2026. DOI: 10.1016/j.tjnut.2026.101363. PMID: 41539437.
• Saaskilahti 2026. Cardiovascular and glucose-lowering medication use among older adults: results from 9-year follow-up of the FINGER trial. European Geriatric Medicine, 2026. DOI: 10.1007/s41999-025-01354-1. PMID: 41339545.
• Maimaitiniyazi 2026. Association between ambient temperature and out-of-hospital cardiac arrest: a systematic review and meta-analysis. BMC Cardiovascular Disorders, 2026. DOI: 10.1186/s12872-026-05790-0. PMID: 42021152.
• Han 2025. Subendocardial Viability Ratio Is Associated With Target Organ Damage and Hints at a Potential Independent Predictor of Cardiovascular Mortality in Older Adults: A Prospective Cohort Study. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2025. DOI: 10.1161/JAHA.125.043643. PMID: 41467407.
• Zhu 2025. Changes in Sarcopenia Status and Subsequent Cardiovascular Outcomes: Prospective Cohort Study. JMIR Aging, 2025. DOI: 10.2196/69860. PMID: 40921062.
• Lee 2026. Cardiovascular risk associated with polypharmacy in heart failure: a systematic review and meta-analysis. ESC Heart Failure, 2026. DOI: 10.1093/eschf/xvag005. PMID: 41711224.
• Usmani 2026. Breaking the silos: a systematic review of oral health integration strategies for improved oral health and cardiovascular outcomes. Frontiers in Public Health, 2026. DOI: 10.3389/fpubh.2026.1795955. PMID: 42163909.
• Chu 2026. The effect of high-intensity interval training and moderate-intensity continuous training on cardiorespiratory function in healthy elderly individuals: Systematic review and meta-analysis. Medicine, 2026. DOI: 10.1097/MD.0000000000047101. PMID: 41517714.
• Thorup 2025. POLYamine treatment in elderly patients with Coronary Artery Disease (POLYCAD): study protocol for a Danish randomised, double-blind, placebo-controlled trial of spermidine treatment versus placebo. Trials, 2025. DOI: 10.1186/s13063-025-09176-z. PMID: 41168834.
• Gebretsadik 2025. Dietary manganese, type 2 diabetes, and cardiovascular disease: A UK Biobank cohort study and meta-analysis of over 270,000 individuals. The Journal of Nutrition, Health & Aging, 2025. DOI: 10.1016/j.jnha.2025.100754. PMID: 41380425.
• You 2026. Frailty and Recurrent Cardiovascular Events in Patients With Obstructive Sleep Apnoea: The SAVE Study. Journal of Cachexia, Sarcopenia and Muscle, 2026. DOI: 10.1002/jcsm.70252. PMID: 41852085.
• Wolfe 2025. Aspirin, cardiovascular events, and major bleeding in older adults: extended follow-up of the ASPREE trial. European heart journal, 2025. DOI: 10.1093/eurheartj/ehaf514. PMID: 40796244.
• Sheikh 2025. Efficacy and safety of vutrisiran in transthyretin amyloid cardiomyopathy across the age spectrum: The HELIOS‐B trial. European Journal of Heart Failure, 2025. DOI: 10.1002/ejhf.70084. PMID: 41159479.
• Jin 2026. Influenza vaccination and cardiovascular and respiratory outcomes in high-risk populations: an umbrella review of systematic reviews and meta-analyzes. Frontiers in Immunology, 2026. DOI: 10.3389/fimmu.2026.1798398. PMID: 42273673.
• Nguyen 2025a. The Efficacy and Safety of Canagliflozin by Frailty Status in Participants of the CANVAS and CREDENCE Trials. Journal of the American Geriatrics Society, 2025. DOI: 10.1111/jgs.19444. PMID: 40105285.
• Garcia 2026. Frailty Matters: Validation of an Automated Electronic Short Physical Performance Battery (eSPPB) for Predicting 30-Day Mortality in Hospitalized Cardiovascular Patients—A Step-by-Step Study. Journal of Clinical Medicine, 2026. DOI: 10.3390/jcm15083093. PMID: 42074895.
• Young 2026. Dietary Inflammatory Index and Cardiovascular Disease Risk in Australian Adults: A Secondary Analysis of the OLIVAUS Trial. Nutrients, 2026. DOI: 10.3390/nu18111732. PMID: 42280376.
• Fu 2026. Risk association and diagnostic value of body roundness index for cardiovascular-kidney-metabolic-related outcomes: a systematic review and meta-analysis. Frontiers in Endocrinology, 2026. DOI: 10.3389/fendo.2026.1814762. PMID: 42058788.
• Yang 2025. Body roundness index and mortality risk in patients with chronic kidney disease: moving beyond the obesity paradox. Nephrology Dialysis Transplantation, 2025. DOI: 10.1093/ndt/gfaf237. PMID: 41206765.
• Tuesta-Nole 2026. Levothyroxine for subclinical hypothyroidism in older adults: no evidence of benefit on quality of life or cardiovascular outcomes: a systematic review. BMC Geriatrics, 2026. DOI: 10.1186/s12877-026-07369-y. PMID: 41922998.
• Aebi 2025. Rationale and design of ‘discontinuing statins in multimorbid older adults without cardiovascular disease (STREAM)’: study protocol of a randomised non-inferiority clinical trial. BMJ Open, 2025. DOI: 10.1136/bmjopen-2024-093833. PMID: 40409969.
• Erdogan 2025. Beyond BMI: central obesity measures and cardiovascular risk in late life. Aging Clinical and Experimental Research, 2025. DOI: 10.1007/s40520-025-03197-z. PMID: 41055826.
• Goonewardena 2026. Lipoprotein(a)-associated proteomic signature predicts cardiovascular disease in young adults. The Journal of Clinical Investigation, 2026. DOI: 10.1172/JCI204287. PMID: 42012308.
• Moghadam 2026. Long‐Term Outcomes of Transcatheter Aortic Valve Replacement in Low‐Flow Low‐Gradient Aortic Stenosis: A Reconstructed Time‐to‐Event and Multivariate Meta‐Analysis. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2026. DOI: 10.1161/JAHA.125.044431. PMID: 42037444.
• Jiang 2025. Blood urea nitrogen and cardiovascular disease risk: Evidence from the CHARLS cohort study. Medicine, 2025. DOI: 10.1097/MD.0000000000045722. PMID: 41239713.
• Etayo-Urtasun 2025. Effects of Exercise on Autonomic Cardiovascular Function in Older Adults: A Systematic Review and Meta-Analysis. Sports Medicine (Auckland, N.z.), 2025. DOI: 10.1007/s40279-025-02357-5. PMID: 41264119.
• Rubino 2026. Invasive vs Conservative Strategy for Frail Older Patients With Myocardial Infarction. JAMA Network Open, 2026. DOI: 10.1001/jamanetworkopen.2026.7316. PMID: 42012832.
• Skaarup 2026. High-Dose vs Standard-Dose Influenza Vaccines in Older Adults. JAMA Network Open, 2026. DOI: 10.1001/jamanetworkopen.2026.14620. PMID: 42189540.
• Salerno 2026. A Randomized, Double-Blind, Placebo-Controlled Trial of an Ayurvedic Herbal Formulation and Vitamin C/E on Vascular Function in Patients with Cardiovascular Disease. Medicina, 2026. DOI: 10.3390/medicina62050972. PMID: 42195225.
• Zhao 2025. Association of frailty and pre-frailty with cardiovascular mortality: a meta-analysis of 26 cohort studies. Frontiers in Public Health, 2025. DOI: 10.3389/fpubh.2025.1688014. PMID: 41323622.
• Masri 2026. Rationale and Design of CARDIO-TTRansform, a Phase 3 Trial of Eplontersen in Transthyretin Amyloid Cardiomyopathy. Circulation. Heart Failure, 2026. DOI: 10.1161/CIRCHEARTFAILURE.126.014205. PMID: 42104840.
• Riquelme-Hernandez 2026. Study protocol for a randomized controlled trial of a culturally adapted cardiovascular dance intervention in Mapuche women with obesity. Frontiers in Public Health, 2026. DOI: 10.3389/fpubh.2026.1806558. PMID: 42110294.
• Brutto 2026. Community-based social connection intervention programme to improve cardiovascular and brain health in older adults in rural Ecuador: study protocol for a quasi-experimental trial. BMJ Open, 2026. DOI: 10.1136/bmjopen-2026-118544. PMID: 42225361.
• Wang 2026. Effects of aerobic exercise on integrated cardiovascular health and energy metabolism in patients with type 2 diabetes mellitus: study protocol for a randomized controlled trial. Frontiers in Endocrinology, 2026. DOI: 10.3389/fendo.2026.1748335. PMID: 41648727.
• Ward 2026. Targeting inflammation in cardiometabolic disease: Icosapent ethyl modulates monocyte‐derived macrophages isolated from patients with cardiovascular disease with or without type 2 diabetes. Diabetic Medicine, 2026. DOI: 10.1111/dme.70247. PMID: 41664438.
• Song 2026. A Multicenter Propensity Score-Matched Cohort Study of Preoperative Antiplatelet Therapy and Postoperative Outcomes in Elderly Surgical Patients. Medicina, 2026. DOI: 10.3390/medicina62030521. PMID: 41901602.
• An 2026. Joint association of C-reactive protein-triglyceride glucose index-frailty index and non-exercise estimated cardiorespiratory fitness with all-cause mortality in adults aged ≥ 45 years with cardiovascular-kidney-metabolic syndrome stages 0–3: a cross-cohort study using NHANES and CHARLS. medRxiv preprint, 2026. DOI: 10.64898/2026.06.16.26355835.
• Lin 2026. Effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular outcomes in chronic obstructive pulmonary disease: A systematic review, meta-analysis, and trial sequential analysis of randomized controlled trials. J Int Med Res, 2026. DOI: 10.1177/03000605261452493. PMID: 42219239.
• Murray 2026. Inflammatory Biomarkers Predicting Major Adverse Cardiovascular Events in People Living With HIV: A Systematic Review and Meta‐Analysis. Journal of the International AIDS Society, 2026. DOI: 10.1002/jia2.70101. PMID: 42041228.
• Nguyen 2025b. Frailty Assessment for Risk prediction in Gynecologic Oncology patients undergoing surgery and chemotherapy (FARGO) study protocol: Rationale and design of a multi-centre prospective cohort study. PLOS One, 2025. DOI: 10.1371/journal.pone.0325651. PMID: 40720507.
• Grazuleviciene 2026. Ambient air and noise pollution effect on cardiovascular health risk and lifestyle intervention to attenuate it: study protocol for a randomized clinical trial. Frontiers in Public Health, 2026. DOI: 10.3389/fpubh.2026.1747963. PMID: 41668846.
• Holley 2026. Assessing the Cardiovascular Effects of Levothyroxine Use in an Ageing UK Population with Subclinical Hypothyroidism: Emulated Target Trial (ACEL-UK-ETT). Thyroid, 2026. DOI: 10.1177/10507256261426576. PMID: 41712269.
• Liu 2025b. Effects of combining positive psychological intervention and lifestyle intervention on improving cardiovascular health for at-risk older adults: study protocol of a Chinese multicentric community-based randomised controlled trial (ACCOMPLI-CH). BMJ Open, 2025. DOI: 10.1136/bmjopen-2024-090760. PMID: 40107697.
• Long 2026. Efficacy and safety of folic acid on homocysteine and cardiovascular surrogate biomarkers in hyperhomocysteinemia: a systematic review and meta-analysis of RCTs. BMC Nutr, 2026. DOI: 10.1186/s40795-026-01343-y. PMID: 42231372.
• Filev 2026. Association of Acute-Phase IL-6 and SAA with Cardiovascular Events and Mortality Six Years After COVID-19 Infection: An Observational Cohort Study. International Journal of Molecular Sciences, 2026. DOI: 10.3390/ijms27114721. PMID: 42278254.
• Delaney 2025. Strawberries modestly improve cognition and cardiovascular health in older adults. Nutr Metab Cardiovasc Dis, 2025. DOI: 10.1016/j.numecd.2025.104018. PMID: 40199714.
• Teperikidis 2026. Colchicine for Major Adverse Cardiovascular Events: An Updated ChatGPT-Assisted Systematic Review and Meta-Analysis. J Cardiovasc Pharmacol, 2026. DOI: 10.1097/fjc.0000000000001780. PMID: 41406368.
• Chen 2026b. Resting Heart Rate as a Non-Cardiovascular Mortality Marker in Young Adults: A Population-Based Cohort Study. medRxiv preprint, 2026. DOI: 10.64898/2026.05.20.26353745.
• Harbi 2026. Tirzepatide vs. semaglutide for obesity, glycemic control, and cardiovascular outcomes: a narrative review of clinical trials. Frontiers in Medicine, 2026. DOI: 10.3389/fmed.2026.1764664. PMID: 42100257.
• Durstenfeld 2026. Rationale, design, and baseline characteristicss of the effect of PCSK9 inhibition on cardiovascular risk in treated HIV infection: EPIC-HIV randomized clinical trial. Am Heart J, 2026. DOI: 10.1016/j.ahj.2026.107400. PMID: 41771366.
• Ambardekar 2026. Acoramidis, Serum Transthyretin, and Cardiovascular Outcomes in Transthyretin Amyloid Cardiomyopathy: Insights From the ATTRibute-CM Trial. J Card Fail, 2026. DOI: 10.1016/j.cardfail.2026.02.045. PMID: 42128580.

Background References

Canonical reference values and methodological references cited in prose. Each entry's citation_token appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).

• Ioannidis 2005. Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124. (methodological reference) DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.