David J. Maron

BACKGROUND: In the ISCHEMIA-CKD trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches–Chronic Kidney Disease), at a median follow-up of 2.2 years, the primary composite outcome of death or nonfatal myocardial infarction was similar between an initial invasive strategy (INV) compared with an initial conservative strategy (CON) in patients with moderate or severe myocardial ischemia and advanced chronic kidney disease. However, the long-term outcomes comparing the 2 strategies are unknown. METHODS: Participants in the ISCHEMIA-CKD trial were randomly assigned to either INV, involving coronary angiography and revascularization when feasible, added to guideline-directed medical therapy or to CON with guideline-directed medical therapy alone and invasive procedures reserved for failure of guideline-directed medical therapy. After the active intervention trial phase, long-term vital status follow-up was conducted through participant contact by participating sites and by health record and centralized death database searches. The primary outcome for the extended follow-up phase was all-cause mortality. Secondary outcomes were cause-specific mortality, including cardiovascular and noncardiovascular mortality. RESULTS: Among the 777 participants randomized (388 to INV and 389 to CON), over a median of 8 years of follow-up, vital status retention among survivors was 95%. There was a total of 429 deaths (55%). Cumulative all-cause mortality (57.4% versus 56.8%; adjusted hazard ratio, 1.05 [95% CI, 0.87–1.28]) or cardiovascular mortality (40.3% versus 38.4%; adjusted hazard ratio, 1.06 [95% CI, 0.84–1.34]) at 8 years did not differ between INV and CON. The restricted mean survival time was 1941 days (1834–2047 days) for INV versus 1990 days (1885–2094 days) for CON, with an adjusted estimated difference of −99 days (−245 to 46). The posterior probability of at least a 1 percentage point lower or higher death with INV at the 8-year median follow-up was 28% and 52%, respectively. Similarly, the posterior probability of at least a 1 percentage point lower or higher cardiovascular mortality with INV was 23% and 56%, respectively. CONCLUSIONS: In patients with at least moderate ischemia and advanced chronic kidney disease, there was no significant long-term benefit of an initial INV at reducing the risk of all-cause or cardiovascular mortality compared with an initial conservative strategy. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01985360

Background: Data from National Health and Nutrition Examination Survey (NHANES) cycles 1988–1994 and 1999–2004 show a declining trend in the adherence to Dietary Approaches to Stop Hypertension (DASH) among adults. Since then, DASH evidence, dietary guidelines, and public-facing dietary resources have advanced, but whether national DASH adherence has improved is uncertain. Methods: We extended the Mellen et al. NHANES analysis among 14,163 adults with self-reported hypertension (N=6,914, 2003–2010, N=7,249, 2011–2018). DASH score included 9 nutrient components: total fat, saturated fat, protein, cholesterol, fiber, calcium, magnesium, potassium, and sodium, with adherence defined as a score ≥4.5. Survey-weighted multivariable models compared DASH score, adherence, and nutrient-threshold attainment across periods. Results: In 2011–2018, U.S. adults with self-reported hypertension represented 76.2 million individuals (33.8%). Multivariable-adjusted DASH adherence declined from 22.1% in 2003-2010 to 18.6% in 2011-2018 (p=0.003), and mean DASH score declined from 2.98 to 2.85 (p=0.007). Adjusted odds of adherence were lower in 2011–2018 compared with 2003–2010 (OR, 0.78; 95% CI, 0.67–0.91; p=0.002). Adherence was lower among non-Hispanic Black adults (OR, 0.70; 95% CI, 0.59–0.84), adults with BMI ≥30 kg/m² (OR, 0.61; 95% CI, 0.51– 0.73), and adults with prior stroke (OR, 0.71; 95% CI, 0.56–0.89). Total fat and sodium threshold attainment declined from 20.9% to 18.7% and 13.8% to 11.8%, respectively. Conclusions: DASH adherence among U.S. adults with self-reported hypertension declined from 2003-2011 to 2011-2018. Implementation strategies should identify barriers to adoption and address the full DASH dietary pattern.

BACKGROUND: Patient-centered prognostic assessment in chronic coronary disease is vital for treatment optimization. Although the Seattle Angina Questionnaire Summary Score (SAQ-SS) correlates with clinical outcomes, clinicians lack guidance on how to weigh prior, current, or changes in scores, and whether prognostic significance varies by revascularization strategy. METHODS: The ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches; 2012–2019) was a global, multicenter, randomized controlled trial. This secondary analysis evaluated the prognostic value of serial SAQ-SS assessments. The SAQ-SS ranges from 0 to 100, with higher scores indicating better health status. To simulate routine clinical care, the follow-up in ISCHEMIA was equated to outpatient clinic visits—we defined the 3-month SAQ-SS as the prior score and the 6-month assessment as the current score in the clinic. Analyses were stratified by treatment strategy: conservative management and invasive management with revascularization. Cox proportional hazards models assessed the association of the prior score, the current score, and the change in scores with ISCHEMIA’s primary composite end point (cardiovascular death, myocardial infarction, hospitalization for unstable angina, heart failure, and resuscitated cardiac arrest), adjusting for 17 clinical covariates. RESULTS: This analysis included 3405 participants (1965 in conservative management: 77.4% male, mean age 64.3 years±9.5; 1440 in invasive management: 77.6% male, mean age 64.0 years±9.4). Over a median follow-up of 3.2 years, 215 (11.0%) and 96 (6.7%) participants in the conservative and invasive cohorts, respectively, experienced the primary composite end point. Higher prior, current, and change SAQ-SS were each independently associated with a lower risk of cardiovascular events. In the conservative cohort, each 5-point increase in the current SAQ-SS was associated with a 7% lower risk of the primary end point (hazard ratio, 0.93 [95% CI, 0.90–0.96]); in the invasive cohort, the association was 9% (hazard ratio, 0.91 [95% CI, 0.86–0.96]). CONCLUSIONS: In patients with chronic coronary disease, the most recent SAQ-SS is the strongest health status predictor of future cardiovascular events. Serial SAQ-SS assessments provide a practical, dynamic, and patient-centered approach for updating prognosis in chronic coronary disease management. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01471522.

The role of myocardial revascularization in heart failure (HF) patients with coronary artery disease by either percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) is controversial. For patients with HFrEF, prior to the advances in pharmacological heart failure therapy over the last 10 years, evidence suggests a modest, long-term benefit of CABG over guideline-recommended medical therapy. In the era of modern medical therapy, revascularization had no benefit in HFrEF. Whether a patient with HF and CAD should be advised to have revascularization and, if so, which procedure remains unclear and should be discussed by the heart team given the limited and conflicting evidence. Evidence for viability or ischaemia-guided selection strategies is controversial. In all cases with HF, establishing and optimizing guideline-directed medical therapy (GDMT) and device therapy is required. When HF symptoms dominate despite GDMT, additional invasive procedures are not indicated. When angina persists despite GDMT and device therapy, revascularization should be considered. The choice of revascularization procedure should be discussed in the heart team, considering symptoms and ischaemic burden, surgical risk, coronary complexity, and the applicable HF treatment.

BACKGROUND: Cardiac stress testing is a cornerstone of risk stratification and management in patients with chronic coronary disease, yet the consistency and accuracy of its interpretation remain poorly defined. This analysis evaluated variation in the interpretation of myocardial ischemia between enrollment sites and core laboratories in the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches). METHODS: ISCHEMIA was a global (37 countries, 2012–2018) randomized trial of an initial invasive versus conservative strategy in patients with chronic coronary disease and moderate or severe ischemia. This analysis included participants with site-interpreted qualifying stress tests—nuclear, echocardiography (echo), cardiac magnetic resonance, or exercise tolerance test—and independent core laboratory adjudication. Core laboratories, serving as the reference standard, reinterpreted tests blinded to site results. A trinary outcome variable (site underestimation, concordance, or overestimation) was defined by comparing site-determined ischemia levels to standardized core lab assessments. Adjusted mixed-effects logistic regression models with random site intercepts assessed variability. RESULTS: Among 6971 participants (mean age, 62.8 years; 73% men), site interpretations showed 0% no/mild (by design), 43% moderate, and 57% severe ischemia. Core labs reclassified these as 8% none, 11% mild, 30% moderate, and 51% severe ischemia. For the imaging modalities, median site-core lab agreement rates were ≈55%; nearly 25% of site-classified moderate/severe cases were downgraded to no or mild ischemia by core labs. Adjusted median odds ratios for site overestimation were 2.36 (95% CI, 2.02–2.82; nuclear), 1.98 (95% CI, 1.62–2.60; echo), 1.89 (95% CI, 1.0–5.41; cardiac magnetic resonance), and 2.15 (95% CI, 1.76–2.79; exercise tolerance test). Adjusted median odds ratios for underestimation ranged from 1.25 to 1.77. CONCLUSIONS: In ISCHEMIA, enrollment sites frequently overestimated or underestimated the severity of myocardial ischemia compared with core laboratory assessments, highlighting the need for strategies to improve the consistency and accuracy of stress testing interpretation in patients with chronic coronary disease. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01471522.

Chronic coronary disease (CCD) remains a leading cause of morbidity and mortality worldwide. However, current clinical assessments, including tests of inducible ischemia or coronary artery disease severity poorly discriminate risk for future cardiovascular (CV) disease events among this population with established CCD. To address this gap, our study leverages high-dimensional molecular data from the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) Trials biorepository to molecularly characterize patients with CCD. By integrating transcriptomic (N = 646) and methylomic (N = 732) data with core-lab confirmed clinical phenotyping, we describe molecular signatures associated with disease severity and identify distinct whole-blood molecular subtypes of CCD. These subtypes demonstrate differential risks of CV events, independent of traditional clinical risk scores, and have distinct molecular and immune profiles. Validation of the transcriptomic and methylomic subtypes in two independent external cohorts confirms the clinical relevance and generalizability of our findings. These findings underscore the potential of blood-based multi-omic approaches to refine risk stratification, improve personalized treatment strategies and advance secondary prevention in CCD. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT01471522; https://clinicaltrials.gov/ct2/show/NCT01471522.

Background: The American Heart Association Predicting Risk of Cardiovascular Disease Events risk scores estimate cardiovascular disease (CVD) risk, including heart failure (HF) and atherosclerotic CVD (ASCVD) events. Whether they associate with subclinical CVD in an asymptomatic community population is unknown. Methods: We analyzed 1138 participants from the multicenter PBHS (Project Baseline Health Study) cohort, who underwent echocardiography and coronary artery calcium scoring and were free of known CVD. Subclinical CVD was defined as the presence of subclinical HF or subclinical coronary artery disease. Subclinical HF included left ventricular diastolic dysfunction, left ventricular hypertrophy, or low ejection fraction (0. Predicting Risk of CVD Events 10‐year risk score associations with subclinical CVD were assessed using logistic regression and area under the receiver operating characteristic curve analysis. Results: Median age was 52 (41–64) years; 64% were White; and 57% were women. Subclinical HF was found in 182 (16%) participants, predominantly with left ventricular diastolic dysfunction (14%). Diastolic dysfunction prevalence increased from 5.8% in low‐risk HF groups to 44.1% in intermediate‐/high‐risk HF groups. Each unit increase in 10‐year HF risk corresponded to 2.67‐fold higher odds of diastolic dysfunction (95% CI, 2.25–3.18; area under the curve, 0.81). Subclinical coronary artery disease was present in 466 (41%) participants, with prevalence increasing from 28.5% in low‐risk ASCVD groups to 79.3% in intermediate‐/high‐risk ASCVD groups. Each unit increase in 10‐year ASCVD risk was associated with 2.91‐fold higher odds of any coronary calcification (95% CI, 2.54–3.35; area under the curve, 0.80), increasing to 4.76‐fold for coronary artery calcium >100 (95% CI, 3.70–6.12; area under the curve, 0.86) and 5.60‐fold for coronary artery calcium >300 (95% CI, 3.89–8.05; area under the curve, 0.87). Conclusions: In an asymptomatic CVD‐free community sample, subclinical CVD was increasingly associated with higher 10‐year HF and ASCVD risks calculated by the Predicting Risk of CVD Events equations.