BACKGROUND: Class III cardiovascular device premarket approval (PMA) studies often fail to fully represent the intended-use population (IUP) owing to low enrollment of racial and ethnic minority subjects and women. The i...BACKGROUND: Class III cardiovascular device premarket approval (PMA) studies often fail to fully represent the intended-use population (IUP) owing to low enrollment of racial and ethnic minority subjects and women. The impact of research site selection on this is unknown. OBJECTIVES: In this study, we sought to determine if site characteristics predict enrollment of demographic minority and female participants in coronary stent PMA trials and evaluate if site selection could improve representation of the IUP. METHODS: We pooled data from 8,859 U.S. participants enrolled in 9 pivotal coronary stent PMA studies (2003-2018) across 196 sites. Site characteristics included U.S. region, surrounding county demographics, teaching status, Veterans Administration affiliation, trial volume, female principal investigator (PI) involvement, and number of acute hospital beds. Multivariable regression identified predictors of minority and female enrollment. Participant-to-prevalence ratios (PPRs) were modeled under varying site selection scenarios. RESULTS: Minority participants (12%; PPR = 0.48) and women (30%; PPR = 0.77) were underrepresented. Minority enrollment varied markedly across sites and was predicted by West and South regions, county minority population, population density, and per-capita income (R = 0.50; P < 0.001). Modeling estimated that reallocating enrollment from low to high minority-enrolling sites could normalize Black and Hispanic representation (PPRs ≥0.80) without compromising that of non-Hispanic Whites (PPR = 1.00). Female enrollment showed less variation and was poorly predicted by research site characteristics and site PI gender (non-VA status only; R = 0.095; P < 0.001); however there were few female PIs (<6%), limiting correlation. CONCLUSIONS: Coronary stent PMA studies do not fully reflect the IUP, owing to marked underrepresentation of minority participants and modest underrepresentation of women. Because minority enrollment is influenced by site characteristics, targeted site selection could improve representation; however, improving female enrollment requires alternative strategies. These insights have implications on the planning and design of future cardiovascular device trials.
Salazar JW, Nakasuka K, Connolly AJ
… +2 more, Moffatt E, Tseng ZH
J Am Coll Cardiol
· 2026 Mar · PMID 42029360
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BACKGROUND: Sudden cardiac death (SCD) prevention focuses on individuals with diagnosed disease (ie, conventional SCD risk factors [RFs]) such as reduced ejection fraction and myocardial infarction (MI). The burden of oc...BACKGROUND: Sudden cardiac death (SCD) prevention focuses on individuals with diagnosed disease (ie, conventional SCD risk factors [RFs]) such as reduced ejection fraction and myocardial infarction (MI). The burden of occult disease among community SCDs without diagnosed RFs is unknown and represents a target for prevention through increased detection. OBJECTIVES: This study sought to determine the sensitivity of diagnosed RFs for community sudden deaths and identify cardiac pathology, including occult MI and dilated cardiomyopathy (DCM), among community sudden deaths without diagnosed RFs. METHODS: The POST SCD (POstmortem Systematic invesTigation of Sudden Cardiac Death) is a prospective countywide study using autopsy to adjudicate arrhythmic (potentially rescuable with defibrillator) or nonarrhythmic (eg, tamponade, overdose) deaths among presumed SCDs meeting World Health Organization criteria. We assessed prevalence ("sensitivity") of diagnosed RFs (ejection fraction ≤35%, heart failure, prior MI, syncope) among arrhythmic, nonarrhythmic, and reference trauma deaths. Among arrhythmic deaths without diagnosed RFs, we assessed occult cardiac pathologies including DCM (short-axis diameter ≥3.5 cm and heart weight 1 SD more than expected based on sex, age, height, and weight; Z-score =1) and healed MI (histopathological evidence of healed MI). RESULTS: Of 877 presumed SCDs, 513 (58%) were autopsy-defined arrhythmic deaths, of which 166 subjects (32%) had diagnosed RFs (mean age: 64.3 years; 77% men); therefore, sensitivity of RFs for arrhythmic death was 32%. Another 159 subjects (31%) had occult MI or DCM with similar demographics (mean age: 62.6 years; 80% men) and cardiac pathologies as those with RFs, including fibrosis and coronary disease. The remaining 185 arrhythmic deaths (36%) were subjects who were younger (mean age: 56.9 years) with less cardiac pathology than arrhythmic deaths with occult MI or DCM but still had increased heart weight (Z-score: 0.9 vs 0.0), larger left ventricular diameter (2.5 cm vs 1.9 cm), and more significant coronary disease (52% vs 13%, all P < 0.001) but similar fibrosis (6.7% vs 6.3%) and left ventricular hypertrophy burden (57% vs 55%) than trauma deaths. CONCLUSIONS: In this 12-year countywide postmortem study, two-thirds of community arrhythmic SCDs occurred in individuals without diagnosed disease despite substantial cardiac pathology; half of these "silent" arrhythmic deaths had occult MI or DCM. Improved detection of occult cardiac disease is a critical priority to reduce community sudden deaths.
Kapur NK, Mangner N, Aghili N
… +39 more, Faraz H, McElwee S, Nazir R, Chieffo A, Jolly S, Bieniarz M, Cuculi F, George Z, Katopodis J, Manly D, Metzger C, Noel T, Polzin A, Rana G, Rengifo-Moreno P, Westenfeld R, Bossard M, Nordbeck P, Reddy N, Woitek F, Yau R, Facemire C, Parikh A, Gao Y, Awad H, Moretz J, Christanday G, Sood P, Bilazarian S, Simonton CA, Han Y, Marx SO, Burkhoff D, Udelson J, Moses J, Kimmelstiel C, Karas R, Stone GW, O'Neill W
J Am Coll Cardiol
· 2026 Mar · PMID 42029358
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BACKGROUND: Despite rapid percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI), large infarcts contribute to heart failure and mortality. Left ventricular (LV) wall tension and...BACKGROUND: Despite rapid percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI), large infarcts contribute to heart failure and mortality. Left ventricular (LV) wall tension and load are major determinants of infarct size. Preclinical studies identified that delaying reperfusion to permit LV unloading with a transvalvular microaxial flow pump (TV-mAFP) reduces infarct size. We tested whether this combination reduces infarct size compared with reperfusion alone in patients with anterior STEMI without cardiogenic shock. OBJECTIVES: The STEMI-Door to Unload (DTU) pivotal trial tested the central hypothesis that the combination of mechanical LV unloading plus a 30-minute delay before PCI reduces infarct size compared with immediate PCI alone in patients with anterior STEMI without cardiogenic shock. METHODS: We conducted an open-label, randomized controlled trial at 55 hospitals in the United States, Germany, Italy, United Kingdom, Switzerland, and Canada. Adults aged 18 to 85 years with no prior myocardial infarction and presenting with acute anterior STEMI within 1 to 6 hours of symptom onset before hospital arrival were eligible for inclusion. Patients were randomly assigned (1:1) by study site personnel to either LV unloading with a TV-mAFP for 30 minutes before PCI (treatment group) or PCI alone (control group). The primary outcome was infarct size normalized to LV mass (IS/LVM) evaluated by cardiac magnetic resonance imaging 3 to 5 days after PCI and was evaluated in all randomized patients. The trial is closed to new participants. RESULTS: Between December 12, 2019 and September 3, 2024, 527 patients were randomized; 262 patients were assigned to the treatment group and 265 to the control group. Mean patient age was 61 ± 11 years, and 417 patients (79.1%) were men. Total ischemic time was longer in the treatment arm. IS/LVM was 30.8% ± 16.2% in the treatment group and 31.9% ± 16.9% in the control group (mean difference: -1.1%; 95% CI: -4.2 to 2.0; P = 0.50). Major bleeding or vascular complications at 30-day follow-up occurred more frequently in the treatment group when compared with either a prespecified performance goal or the control group. CONCLUSIONS: Combination of a TV-mAFP plus delayed PCI did not reduce infarct size in patients with anterior STEMI without cardiogenic shock compared with PCI alone. (Primary Unloading and Delayed Reperfusion in ST-Elevation Myocardial Infarction: The STEMI-DTU Trial [DTU-STEMI]; NCT03947619).
BACKGROUND: Right ventricular pacing (RVP) is associated with an increased risk of pacing-induced cardiomyopathy (PICM) in patients with a high pacing burden. Left bundle branch pacing (LBBP), a more physiological pacing...BACKGROUND: Right ventricular pacing (RVP) is associated with an increased risk of pacing-induced cardiomyopathy (PICM) in patients with a high pacing burden. Left bundle branch pacing (LBBP), a more physiological pacing modality, may better preserve cardiac function. OBJECTIVES: This randomized trial aimed to evaluate the clinical outcomes of LBBP vs RVP in patients with a high pacing burden with high risk of cardiac dysfunction. METHODS: In this prospective, multicenter, randomized controlled trial, 160 patients with a high pacing burden with high risk of cardiac dysfunction were randomly assigned in a 1:1 ratio to either LBBP or RVP. The primary endpoint was a composite of all-cause mortality, heart failure hospitalization, or PICM. Secondary endpoints were the individual components of the primary endpoints, echocardiographic parameters, and NYHA functional class. RESULTS: During a median follow-up duration of 36 months, the primary endpoint occurred in 9 patients in the LBBP group and in 25 patients in the RVP group (11.6% vs 33.9%; HR: 0.310; 95% CI: 0.145-0.664; P = 0.001), mainly driven by PICM (6.5% vs 18.2%; subdistribution HR: 0.324; 95% CI: 0.119-0.883; P = 0.028). No significant differences were observed in all-cause mortality (P = 0.391) and heart failure hospitalization (P = 0.100) between 2 groups. LBBP showed superior improvements over RVP in left ventricular ejection fraction (mean difference: 5.34; 95% CI: 3.18-7.50; P < 0.001), left ventricular end-diastolic diameter (mean difference: -3.06; 95% CI: -4.38 to -1.73; P < 0.001), and left ventricular end-systolic diameter (mean difference: -3.74; 95% CI: -5.07 to -2.41; P < 0.001) from baseline to 36 months. Patients in the LBBP group also showed favored NYHA functional class compared with those in the RVP group at the 36-month follow-up (1.66 ± 0.60 vs 1.90 ± 0.56, P = 0.014). CONCLUSIONS: In patients with a high pacing burden with high risk of cardiac dysfunction, LBBP significantly reduced the risk of the composite outcome, driven primarily by a decreased risk of PICM, and is associated with better echocardiographic improvements and clinical function. (A multicenter, prospective, randomized, controlled trial of left bundle branch pacing and right ventricular pacing in preventing deterioration of cardiac function in patients with ventricular pacing dependence [LBBP-FAVOUR]; ChiCTR2000036553).
J Am Coll Cardiol
· 2026 Mar · PMID 42024048
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BACKGROUND: The total burden of community sudden cardiac deaths (SCDs) attributable to myocardial infarction (MI), including myocardial infarction with nonobstructive coronary arteries (MINOCA), is unclear. OBJECTIVES: T...BACKGROUND: The total burden of community sudden cardiac deaths (SCDs) attributable to myocardial infarction (MI), including myocardial infarction with nonobstructive coronary arteries (MINOCA), is unclear. OBJECTIVES: The study sought to determine the burden of community SCD due to MI by histopathologic examination. METHODS: The POST SCD (Postmortem Systematic Investigation of Sudden Cardiac Death) study is a prospective countywide study using autopsy to adjudicate presumed SCDs as cardiac (arrhythmic or nonarrhythmic) or noncardiac causes, with trauma deaths as reference control deaths. We defined a case as "SCD due to MI" if histopathological findings of MI without other lethal cause were found, and defined obstructive coronary artery disease as ≥50% stenosis in ≥1 coronary artery. RESULTS: Of 943 presumed SCDs from February 1, 2011, to March 31, 2023, 360 (38%) had noncardiac cause and 583 (62%) were autopsy-confirmed SCDs, of which 237 (41%) were due to MI (MI SCD): 214 (90%) were acute or healed myocardial infarction with obstructive coronary artery disease (MI-CAD) and 23 (10%) were acute MINOCA (highest proportion among Black patients; P < 0.05). Among 173 coronary lesions in acute MI-CAD SCDs (n = 95), the left anterior descending artery (n = 66 [38%]) and right coronary artery (n = 59 [35%]) were most commonly affected, and the right coronary artery was the most common culprit (43%). Nonarrhythmic causes were more common in MINOCA than acute MI-CAD SCDs (35% vs 15%; P = 0.037), with a trend toward being the highest in Asian patients (P = 0.1). The total fibrosis burden was similar in MINOCA and acute MI-CAD SCDs (P = 0.6). CONCLUSIONS: In this 12-year countywide study, one-fourth of all sudden deaths and 41% of autopsy-confirmed SCDs were attributable to MI, with significant racial differences. The left anterior descending artery and right coronary artery were most commonly affected among SCDs due to MI-CAD. Nonarrhythmic causes were twice as common in MINOCA SCDs than acute MI-CAD.
BACKGROUND: Unblinded studies have demonstrated superior procedural and clinical outcomes of percutaneous coronary intervention (PCI) in focal compared with diffuse coronary artery disease. However, data from the first p...BACKGROUND: Unblinded studies have demonstrated superior procedural and clinical outcomes of percutaneous coronary intervention (PCI) in focal compared with diffuse coronary artery disease. However, data from the first placebo-controlled study did not demonstrate a differential impact of disease pattern on symptom endpoints. OBJECTIVES: The study sought to test the ability of pattern of coronary artery disease to predict the placebo-controlled efficacy of PCI. METHOD: In the ORBITA-2 (Objective Randomised Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina-2) randomized placebo-controlled trial of angioplasty for stable angina, patients underwent prerandomization nonhyperemic pressure wire pullback assessments. Seven blinded interventional cardiologists independently reviewed each pullback trace to categorize disease patterns as focal, diffuse, or mixed. These were assigned numerical values of 1, 0, and 0.5, respectively. Overall disease pattern score was determined by the mean. A score >0.5 was considered focal and ≤0.5 was considered diffuse. Bayesian proportional odds modeling was used. RESULTS: A total of 245 patients with 300 target vessel pullbacks were analyzed. With adjustment for prerandomization nonhyperemic pressure ratio, PCI in focal compared with diffuse disease resulted in greater improvement in angina symptom score (OR: 1.80; 95% credible interval [CrI]: 1.48-2.18; Pr[Benefit] > 99.9%) and daily episodes of angina (OR: 1.55; 95% CrI: 1.26-1.89; Pr[Benefit] > 99.9%). Focal disease also predicted greater placebo-controlled benefit in exercise treadmill time (Pr[Interaction] > 99.9%), Canadian Cardiovascular Society class (Pr[Interaction] = 99.0%), EuroQol Group 5-Dimensions 5-Level questionnaire (Pr[Interaction] = 95.1%), and Seattle Angina Questionnaire angina frequency (Pr[Interaction] = 99.5%). There was weaker evidence of interaction between disease pattern and the placebo-controlled impact of PCI on improvement in dobutamine stress echocardiography score (Pr[Interaction] = 83%). CONCLUSIONS: In focal disease, PCI resulted in greater placebo-controlled improvement of symptoms compared with diffuse disease. Physiological patterns of disease may be useful to guide treatment decision making with PCI for symptom relief.
BACKGROUND: Higher cardiorespiratory fitness (CRF) is associated with a lower risk for chronic disease and death, but its relation to healthy aging more broadly remains understudied. OBJECTIVES: The aim of this study was...BACKGROUND: Higher cardiorespiratory fitness (CRF) is associated with a lower risk for chronic disease and death, but its relation to healthy aging more broadly remains understudied. OBJECTIVES: The aim of this study was to examine the associations between midlife CRF and later life health span (years without major chronic disease), disease burden, and lifespan among adults who remained apparently healthy through 65 years of age. METHODS: This cohort study included 24,576 participants (25% women) from the CCLS (Cooper Center Longitudinal Study) (1971-2017) linked to Medicare administrative claims (1999-2019). CRF was estimated using a maximal treadmill test at a preventive medicine clinic visit before age 65 years. Eleven major chronic conditions were identified from the Medicare Chronic Conditions Data Warehouse and used to define disease as: 1) any of the 11 conditions (composite); 2) any condition within a clinical group (cardiovascular, cardiovascular-kidney-metabolic, cancer); or 3) an individual condition. Multivariable illness-death models estimated the likelihood of transitioning between health, disease, and death by CRF level (low, moderate, or high). Model parameters were used to calculate adjusted Aalen-Johansen probabilities and expected times in each state of health, disease, and death; these were then used to calculate expected health span, number of diseases, disease-years, and lifespan by CRF. RESULTS: When disease was defined as any of 11 major chronic conditions, high-fit men had a 2% (95% CI: 1%-2%) longer health span, 9% (95% CI: 1%-17%) fewer diseases, and a 3% (95% CI: 2%-4%) longer lifespan compared with low-fit men, with similar patterns among women. When disease was clinically grouped, higher fit men and women generally had a later onset of cardiovascular, cardiovascular-kidney-metabolic, and cancer outcomes and developed fewer conditions within each group. On average, the onset of each of the 11 chronic conditions occurred at least 1.5 years later among high-fit men and women compared with low-fit individuals. Results were consistent across clinical subgroups defined by clinic visit year (before or after 1990), age (younger or older than 45 years), smoking status (current smoking, nonsmoking, or missing smoking), and weight status according to body mass index (healthy weight and overweight or obese). CONCLUSIONS: Higher midlife CRF was associated with longer health span, lower multimorbidity, and longer lifespan among men and women.
Sunderland N, Asselin G, Henry A
… +55 more, Nelson CP, Lemieux Perreault LP, Asselbergs FW, Boersma E, Cappola TP, Chazara O, Chutkow W, Cyr MC, Gkatzionis A, Gui H, Haefliger C, Hedman ÅK, Hillege H, Hyde CL, Kamanu FK, Kardys I, Koekemoer AL, Kraus WE, Lang CC, Malarstig A, Margulies KB, Marston NA, Melloni GEM, Morley MP, O'Donoghue ML, Owens AT, Paul DS, Tilling K, van der Harst P, van Setten J, van Vugt M, Verweij N, Veluchamy A, Wallentin L, Wang X, Xing H, Yang Y, White HD, Zannad F, Smith JG, Brunner-La Rocca HP, Lanfear DE, Mann DL, de Denus S, Tardif JC, Voors AA, Samani NJ, Ellinor PT, Ruff CT, Sabatine MS, Sattar N, McMurray JJV, Paternoster L, Dubé MP, Lumbers RT
J Am Coll Cardiol
· 2026 Jun · PMID 42017882
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BACKGROUND: Excess adiposity, most commonly indexed through body mass index (BMI), is strongly associated with the development of heart failure (HF). Weight loss therapies improve outcomes in patients with obesity and HF...BACKGROUND: Excess adiposity, most commonly indexed through body mass index (BMI), is strongly associated with the development of heart failure (HF). Weight loss therapies improve outcomes in patients with obesity and HF with preserved left ventricular ejection fraction (LVEF), but their effects in HF with reduced LVEF remain unclear. OBJECTIVES: The aim of this work is to determine whether higher BMI is associated with adverse clinical outcomes in patients with HF and whether there is effect modification by LVEF subgroup. METHODS: Two-sample Mendelian randomization (MR) was used, with genome-wide significant loci associated with BMI as instrumental variables and outcome data from a genome-wide association study (GWAS) of time-to-event clinical outcomes in patients with HF. A total of 50,636 individuals of European ancestry with established HF from 22 cohorts were included in the genetic analysis: 12 HF trials, 1 prospective case-cohort study, 9 cohorts nested within non-HF cardiovascular trials, and 1 population-based cohort derived from the UK Biobank. The exposure was genetically predicted BMI and the outcome measures were all-cause mortality and a composite of cardiovascular mortality or HF hospitalization. Genetic associations for the outcomes were derived from our GWAS and MR was used to estimate the unbiased association of genetically predicted BMI with these clinical outcomes. RESULTS: The mean BMI was 29.2 ± 5.8 kg/m. Over a median follow-up of 27.0 months, all-cause mortality occurred in 11,454 patients (23%), and 11,360 participants (22%) experienced the composite endpoint. Genetically predicted BMI was associated with an increased rate of both all-cause mortality (HR per SD [4.8 BMI units] 1.21; 95% CI: 1.13-1.29; P = 9 × 10) and the composite outcome (HR 1.29; 95% CI: 1.20-1.38; P = 8 × 10). Associations were consistent across LVEF ≤40% and >40%: for all-cause mortality, HR: 1.16 (95% CI: 0.99-1.37) and 1.20 (95% CI: 0.94-1.53); and for the composite outcome, HR: 1.30 (95% CI: 1.15-1.48) and 1.57 (95% CI: 1.29-1.91), respectively. CONCLUSIONS: Among patients with HF, higher BMI was associated with increased all-cause mortality and cardiovascular death or HF hospitalization, supporting the potential role of weight-management strategies across the ejection fraction spectrum.
Johansson Bartolini I, Joseph P, Islam S
… +34 more, Ramachan SP, Rosengren A, Kruger IM, Mazapuspavina YM, Chifamba J, Yusuf R, Palileo-Villanueva LM, Bahonar A, Yusufali A, Wang B, Huang Y, Bo H, Felix C, Zaidi NZ, Davletov K, Khatib R, Lopez-Lopez JP, Mir H, Zatońska K, Mirrakhimov E, Lanas F, Alhabib KF, Rammohan K, Teo KK, Mohan V, Temizhan A, Kontsevaya A, Diaz ML, Avezum Á, Yeates K, Gupta R, Rangarajan S, Yusuf S, PURE Investigators
J Am Coll Cardiol
· 2026 Jun · PMID 42017880
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BACKGROUND: Most population studies examining heart failure (HF) have been conducted in Western high-income countries (HICs), with limited comparable data from lower-income settings. OBJECTIVES: The aims of this study we...BACKGROUND: Most population studies examining heart failure (HF) have been conducted in Western high-income countries (HICs), with limited comparable data from lower-income settings. OBJECTIVES: The aims of this study were to describe differences in HF incidence and 30-day, 1-year, and 5-year case fatality rates among HF patients from countries at different income levels and in different global regions and to examine the impact of common and potentially modifiable risk factors for incident HF. METHODS: This analysis of the PURE (Prospective Urban Rural Epidemiology) study included 172,653 individuals from 25 HICs, upper middle-income countries (UMICs), lower middle-income countries (LMICs), and low-income countries (LICs) and 8 geographic regions of the world, followed for a median of 15 years. Age- and sex-standardized HF incidence, as well as 30-day, 1-year, and 5-year HF case fatality, were compared by income group and by geographic region. The population attributable fractions (PAFs) for incident HF related to 13 cardiometabolic, lifestyle, socioeconomic, environmental, and psychosocial risk factors were also estimated. RESULTS: The standardized rate of incident HF was 0.39 (95% CI: 0.36-0.41) per 1,000 person-years overall; the rate was highest in UMICs (0.58; 95% CI: 0.52-0.64), followed by HICs (0.36; 95% CI: 0.30-0.43), then LMICs (0.34; 95% CI: 0.30-0.38), and then LICs (0.26; 95% CI: 0.22-0.30). Among regions, the highest HF incidence was in sub-Saharan Africa (1.18; 95% CI: 0.95- 1.41) and Europe and Central Asia (0.86; 95% CI: 0.72-1.00) and lowest in South Asia (0.19; 95% CI: 0.15-0.22). Thirty-day case fatality was highest in LICs (59%) and lowest in HICs (11%); it was highest in South Asia (63%) and sub-Saharan Africa (63%) and lowest in North America (12%). Five-year case fatality after HF diagnosis was highest in LICs (77%) and lowest in HICs (28%); it was highest in South Asia (81%) and sub-Saharan Africa (75%) and lowest in North America (25%). More than 71% of the PAF for HF was attributable to the 13 modifiable risk factors studied, the largest being hypertension (PAF = 25%). CONCLUSIONS: HF incidence and associated mortality vary substantially across countries at different levels of economic development and by geographic region. Hypertension is the largest population-level risk factor for HF globally. Preventive measures, early diagnosis, and access to guideline-directed medical therapy should be prioritized to reduce global disparities in HF incidence and mortality.