Daily Cardiology Research Analysis
Analyzed 137 papers and selected 3 impactful papers.
Summary
Three impactful cardiology papers stood out today. A Nature Medicine analysis of DECLARE-TIMI 58 integrated exome sequencing to show that dapagliflozin markedly reduced heart failure hospitalization in carriers of pathogenic cardiomyopathy variants, highlighting precision prevention. A meta-analysis in European Journal of Preventive Cardiology defined non-linear, clinically actionable thresholds for visit-to-visit blood pressure variability tied to mortality. A prospective JAHA registry (J-CMD) mapped endotypes in ANOCA, supporting comprehensive invasive testing to guide targeted therapy.
Research Themes
- Genomics-enabled precision cardiometabolic therapeutics
- Actionable thresholds for visit-to-visit blood pressure variability
- Endotyping ANOCA via comprehensive invasive coronary function testing
Selected Articles
1. Effects of SGLT2 inhibition on incident heart failure in carriers of cardiomyopathy-associated genetic variants.
In a whole-exome substudy of DECLARE-TIMI 58, dapagliflozin conferred a substantially greater reduction in heart failure hospitalization among carriers of pathogenic/likely pathogenic cardiomyopathy variants than among noncarriers. Absolute risk reduction was ~13% in carriers, including those without prior HF, suggesting genomics-enabled targeting could maximize SGLT2 inhibitor benefits.
Impact: This is an early precision medicine signal linking genotype to differential therapeutic benefit from an established cardioprotective drug class in a large randomized trial dataset.
Clinical Implications: If validated, screening for pathogenic cardiomyopathy variants in high-risk patients with type 2 diabetes could identify individuals who derive outsized benefit from SGLT2 inhibitors, supporting earlier initiation for HF prevention.
Key Findings
- Among 12,685 DECLARE participants with sequencing, 121 carried pathogenic/likely pathogenic cardiomyopathy variants.
- Dapagliflozin reduced HHF more in carriers (HR 0.18) than noncarriers (HR 0.70); interaction P=0.03.
- Absolute HHF risk reduction was 13.0% in carriers vs 1.0% in noncarriers; in carriers without prior HF, ARR was 12.8%.
Methodological Strengths
- Integration of whole-exome sequencing with outcomes from a large randomized cardiovascular outcomes trial
- Prespecified high-confidence cardiomyopathy gene set and interaction testing with robust follow-up
Limitations
- Secondary, nonrandomized genetic subgroup analysis with relatively small number of variant carriers
- Generalizability limited to older, high-risk type 2 diabetes population; requires prospective validation
Future Directions: Prospective genotype-guided trials testing early SGLT2 inhibitor initiation in P/LP cardiomyopathy variant carriers without HF; exploration of variant- and gene-specific effect sizes.
Although the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibition in heart failure (HF) have been well established, it is unknown whether SGLT2 inhibition confers benefit in carriers of rare variants in cardiomyopathy-associated genes. Here we evaluated whole-exome sequencing data from the randomized DECLARE-TIMI 58 trial, in which adults with type 2 diabetes and increased cardiovascular risk were randomized to dapagliflozin or placebo treatment. Pathogenic or likely pathogenic variants (P/LP) in high-confidence cardiomyopathy genes were identified, and treatment effects on hospitalization for HF (HHF) were compared between carriers of such variants and noncarriers. Among 12,685 patients for whom sequence data were obtained, 121 carried a cardiomyopathy variant (76 dilated cardiomyopathy, 25 hypertrophic cardiomyopathy and 25 arrhythmogenic cardiomyopathy). Over a median follow-up of 4.2 years, dapagliflozin lowered the risk of HHF more strongly in carriers (hazard ratio 0.18, 95% confidence interval 0.04-0.86) than in noncarriers (hazard ratio 0.70, 95% confidence interval 0.57-0.86; P interaction 0.03). Absolute risk reduction was 13.0% in carriers and 1.0% in noncarriers (P interaction 0.03). Most carriers (82%) had no prior HF, and in carriers without prior HF, treatment with dapagliflozin reduced the absolute risk of HHF by 12.8%, compared with a reduction of 0.6% in noncarriers (P interaction 0.01). The findings from this cohort of older and high-risk patients raise the possibility that SGLT2 inhibitor treatment should be started early to prevent HF in individuals who carry P/LP cardiomyopathy variants. These results need to be confirmed in a prospective, dedicated trial of preventive HF treatments in carriers of P/LP cardiomyopathy-associated variants.
2. Visit-to-visit blood pressure variability and outcome: a traditional and a dose-response meta-analysis.
Across 50 studies and over 10 million individuals, visit-to-visit BP variability showed a non-linear association with mortality, with systolic SD thresholds around 12 mmHg and diastolic SD thresholds around 5–6 mmHg above which risk rises. At least three visits are needed to robustly assess prognostic VVBPV.
Impact: Defines pragmatic, quantitative VVBPV thresholds for risk stratification and emphasizes minimum measurement frequency, bridging evidence to practice.
Clinical Implications: Incorporate VVBPV assessment into hypertension follow-up, prioritizing patients whose systolic SD exceeds ~12 mmHg or diastolic SD exceeds ~5–6 mmHg for intensified monitoring and management; ensure ≥3 visit measurements when interpreting VVBPV.
Key Findings
- Non-linear dose-response between VVBPV and all-cause/cardiovascular mortality identified via spline meta-regression.
- Systolic SD thresholds: 11.8 mmHg (all-cause) and 12.1 mmHg (cardiovascular mortality).
- Diastolic SD thresholds: 5.8 mmHg (all-cause) and 5.25 mmHg (cardiovascular mortality).
- At least three visits are required to reliably estimate prognostic VVBPV.
Methodological Strengths
- Very large aggregated sample (n>10 million) across 50 studies
- Restricted cubic spline dose-response modeling to identify thresholds
Limitations
- Heterogeneity in BPV measurement methods and populations across included studies
- Observational nature limits causal inference; thresholds derived for SD metric may not generalize to other BPV indices
Future Directions: Prospective validation of VVBPV thresholds in diverse cohorts and testing threshold-guided treatment intensification strategies on hard outcomes.
BACKGROUND: It is not clear whether the relationship of blood pressure variability (BPV) with outcome reported in several studies is linear or becomes evident only above a given BPV threshold value. This meta-analysis was aimed at exploring the shape of the relationship between visit-to-visit BPV (VVBPV) and mortality or fatal and non-fatal cardiovascular events, also addressing whether the number of visits considered for estimation of VVBPV has an impact on this relationship. METHODS: Pooled hazard ratios and 95% confidence intervals for the association between VVBPV and outcomes were calculated by outcome type and number of visits used to estimate VVBPV. Restricted cubic spline meta-regression models were applied to explore the shape of this relationship and the presence of threshold values beyond which VVBPV significantly increases the risk of outcomes. RESULTS: The literature search identified 50 studies (n=10,624,740 individuals). The risk of all-cause and cardiovascular mortality began to increase significantly above specific VVBPV threshold values. Systolic VVBPV measured as standard deviation (SD) had a threshold of 11.8 mmHg for all-cause mortality and 12.1 mmHg for cardiovascular mortality. Diastolic VVBPV SD showed threshold values of 5.8 mmHg for all-cause mortality and 5.25 mmHg for cardiovascular mortality, the risk of these outcomes increasing significantly only when VVBPV exceed these values. Our study also provides indications that a minimum of three visits is required to reliably assess the prognostic value of VVBPV. CONCLUSIONS: This meta-analysis shows a non-linear dose-response relationship between VVBPV and outcomes, with distinct threshold values. The identification of such thresholds is vital for assessing the prognostic value of BPV in research or clinical settings. A reliable assessment of the prognostic value of VVBPV should be based on at least three visits.
3. Comprehensive Endotyping of Patients With Angina and Nonobstructive Coronary Arteries: A Report From the J-CMD.
In a 947-patient prospective multicenter registry using standardized intracoronary testing, epicardial vasospasm was most common (44.2%), followed by microvascular spasm and CMD, with frequent overlap—especially in women. The data endorse comprehensive invasive endotyping to achieve precise diagnoses and enable targeted therapy in ANOCA.
Impact: Provides large, standardized, phenotype-rich invasive data clarifying the prevalence and overlap of ANOCA endotypes, a prerequisite for precision management.
Clinical Implications: Adopt comprehensive invasive testing (ACh spasm provocation and CFR) to endotype ANOCA, recognizing frequent vasospasm–CMD overlap and sex/age patterns, to guide tailored antianginal and vasomodulatory therapy.
Key Findings
- Epicardial vasospasm was the most prevalent endotype (44.2%) among 947 ANOCA patients; microvascular spasm 16.5%; CMD with spasm 8.7%; isolated CMD 5.0%.
- Substantial overlap between vasospastic and microvascular phenotypes; women had more concurrent CMD plus any spasm (10.8% vs 6.0%).
- Standardized intracoronary testing (ACh provocation and CFR) feasibly delineates ANOCA endotypes across sexes and ages.
Methodological Strengths
- Prospective, multicenter registry with standardized invasive protocols
- Concurrent assessment of epicardial and microvascular function enabling endotype overlap analysis
Limitations
- Single-nation registry may limit generalizability outside the study setting
- Observational design without treatment randomization; long-term outcomes not detailed in abstract
Future Directions: Link invasive endotypes to treatment response and outcomes in randomized or pragmatic trials; expand to multi-ethnic cohorts to validate sex- and age-specific distributions.
BACKGROUND: Angina with nonobstructive coronary arteries (ANOCA) is frequently driven by coronary vasospasm and coronary microvascular dysfunction (CMD). Despite recommendations for comprehensive invasive testing to phenotype ANOCA, prospective data on the prevalence and interplay of these endotypes remain limited. We aimed to investigate the prevalence, clinical correlations, and overlap of epicardial vasospasm, microvascular spasm, and CMD, defined by a coronary flow reserve <2.0. METHODS: We analyzed the data from a prospective, multicenter nationwide registry of the J-CMD (Japanese Association of Coronary Microvascular Dysfunction; UMIN000047609). Patients with ANOCA underwent standardized intracoronary functional testing, including acetylcholine-based spasm provocation and coronary flow reserve assessment. The distribution of the endotypes (epicardial vasospasm, microvascular spasm, isolated CMD, and CMD with spasm) was investigated according to sex and age tertiles. RESULTS: Of 947 patients (55.6% women), epicardial vasospasm was the most common diagnosis (44.2%), followed by microvascular spasm (16.5%), CMD with spasm (8.7%), and isolated CMD (5.0%). Substantial overlap was evident; concurrent CMD and any vasospasm were more frequent in women than in men (10.8% versus 6.0%, CONCLUSIONS: Among patients with ANOCA, coronary vasospasm and CMD were prevalent and frequently coexisted, demonstrating distinct sex- and age-related patterns. These findings offer novel insights into the heterogeneous pathophysiology of ANOCA and reinforce the importance of comprehensive invasive assessment in establishing a precise diagnosis and guiding targeted therapy.