Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF.

BACKGROUND: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-ß peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). METHODS: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSEs score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. RESULTS: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07). The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P=0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. CONCLUSIONS: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Cardio-oncology imaging tools at the translational interface.

Cardiovascular imaging is an evolving component in the care of cancer patients. With improved survival following prompt cancer treatment, patients are facing increased risks of cardiovascular complications. While currently established imaging modalities are providing useful structural mechanical information, they continue to develop towards increased specificity. New modalities, emerging from basic science and oncology, are being translated, targeting earlier stages of cardiovascular disease. Besides these technical advances, matching an imaging modality with the patients' individual risk level for a specific pathological change is part of a successful imaging strategy. The choice of suitable imaging modalities and time points for specific patients will impact the cardio-oncological risk stratification during surveillance and follow-up monitoring. In addition, future imaging tools are poised to give us important insights into the underlying cardiovascular molecular pathology associated with cancer and oncological therapies. This review aims at giving an overview of the novel imaging technologies that have the potential to change cardio-oncological science and clinical practice in the near future.

Development and Validation of Machine Learning-Based Race-Specific Models to Predict 10-Year Risk of Heart Failure: A Multicohort Analysis.

BACKGROUND: Heart failure (HF) risk and the underlying risk factors vary by race. Traditional models for HF risk prediction treat race as a covariate in risk prediction and do not account for significant parameters such as cardiac biomarkers. Machine learning (ML) may offer advantages over traditional modeling techniques to develop race-specific HF risk prediction models and to elucidate important contributors of HF development across races. METHODS: We performed a retrospective analysis of 4 large, community cohort studies (ARIC [Atherosclerosis Risk in Communities], DHS [Dallas Heart Study], JHS [Jackson Heart Study], and MESA [Multi-Ethnic Study of Atherosclerosis]) with adjudicated HF events. The study included participants who were >40 years of age and free of HF at baseline. Race-specific ML models for HF risk prediction were developed in the JHS cohort (for Black race-specific model) and White adults from ARIC (for White race-specific model). The models included 39 candidate variables across demographic, anthropometric, medical history, laboratory, and electrocardiographic domains. The ML models were externally validated and compared with prior established traditional and non-race-specific ML models in race-specific subgroups of the pooled MESA/DHS cohort and Black participants of ARIC. The Harrell C-index and Greenwood-Nam-D'Agostino χ2 tests were used to assess discrimination and calibration, respectively. RESULTS: The ML models had excellent discrimination in the derivation cohorts for Black (n=4141 in JHS, C-index=0.88) and White (n=7858 in ARIC, C-index=0.89) participants. In the external validation cohorts, the race-specific ML model demonstrated adequate calibration and superior discrimination (Black individuals, C-index=0.80-0.83; White individuals, C-index=0.82) compared with established HF risk models or with non-race-specific ML models derived with race included as a covariate. Among the risk factors, natriuretic peptide levels were the most important predictor of HF risk across both races, followed by troponin levels in Black and ECG-based Cornell voltage in White individuals. Other key predictors of HF risk among Black individuals were glycemic parameters and socioeconomic factors. In contrast, prevalent cardiovascular disease and traditional cardiovascular risk factors were stronger predictors of HF risk in White adults. CONCLUSIONS: Race-specific and ML-based HF risk models that integrate clinical, laboratory, and biomarker data demonstrated superior performance compared with traditional HF risk and non-race-specific ML models. This approach identifies distinct race-specific contributors of HF.

Associations Between High-Density Lipoprotein Particles and Ischemic Events by Vascular Domain, Sex, and Ethnicity: A Pooled Cohort Analysis.

BACKGROUND: High-density lipoprotein (HDL) cholesterol concentration (HDL-C) is an established atheroprotective marker, in particular for coronary artery disease; however, HDL particle concentration (HDL-P) may better predict risk. The associations of HDL-C and HDL-P with ischemic stroke and myocardial infarction (MI) among women and Blacks have not been well studied. We hypothesized that HDL-P would consistently be associated with MI and stroke among women and Blacks compared with HDL-C. METHODS: We analyzed individual-level participant data in a pooled cohort of 4 large population studies without baseline atherosclerotic cardiovascular disease: DHS (Dallas Heart Study; n=2535), ARIC (Atherosclerosis Risk in Communities; n=1595), MESA (Multi-Ethnic Study of Atherosclerosis; n=6632), and PREVEND (Prevention of Renal and Vascular Endstage Disease; n=5022). HDL markers were analyzed in adjusted Cox proportional hazard models for MI and ischemic stroke. RESULTS: In the overall population (n=15 784), HDL-P was inversely associated with the combined outcome of MI and ischemic stroke, adjusted for cardiometabolic risk factors (hazard ratio [HR] for quartile 4 [Q4] versus quartile 1 [Q1], 0.64 [95% CI, 0.52-0.78]), as was HDL-C (HR for Q4 versus Q1, 0.76 [95% CI, 0.61-0.94]). Adjustment for HDL-C did not attenuate the inverse relationship between HDL-P and atherosclerotic cardiovascular disease, whereas adjustment for HDL-P attenuated all associations between HDL-C and events. HDL-P was inversely associated with the individual end points of MI and ischemic stroke in the overall population, including in women. HDL-P was inversely associated with MI among White participants but not among Black participants (HR for Q4 versus Q1 for Whites, 0.49 [95% CI, 0.35-0.69]; for Blacks, 1.22 [95% CI, 0.76-1.98]; Pinteraction=0.001). Similarly, HDL-C was inversely associated with MI among White participants (HR for Q4 versus Q1, 0.53 [95% CI, 0.36-0.78]) but had a weak direct association with MI among Black participants (HR for Q4 versus Q1, 1.75 [95% CI, 1.08-2.83]; Pinteraction<0.0001). CONCLUSIONS: Compared with HDL-C, HDL-P was consistently associated with MI and ischemic stroke in the overall population. Differential associations of both HDL-C and HDL-P for MI by Black ethnicity suggest that atherosclerotic cardiovascular disease risk may differ by vascular domain and ethnicity. Future studies should examine individual outcomes separately.

Regional adiposity, cardiorespiratory fitness, and left ventricular strain: an analysis from the Dallas Heart Study.

BACKGROUND: Low cardiorespiratory fitness (CRF), high body mass index, and excess visceral adiposity are each associated with impairment in left ventricular (LV) peak circumferential strain (Ecc), an intermediate phenotype that precedes the development of clinical heart failure (HF). However, the association of regional fat distribution and CRF with Ecc independent of each other and other potential confounders is not known. METHODS: Participants from the Dallas Heart Study Phase 2 who underwent dual energy X-ray absorptiometry assessment of regional fat distribution, CRF assessment by submaximal treadmill test, and Ecc quantification by tissue-tagged cardiovascular magnetic resonance were included in the analysis. The cross-sectional associations of measures of regional adiposity, namely visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and lower-body fat (LBF) with Ecc after adjustment for CRF and other potential confounders (independent variables) were assessed using multivariable linear regression analysis. RESULTS: The study included 1089 participants (55% female, 39% black). In the unadjusted analysis, higher VAT was associated with greater impairment in Ecc. After adjustment for baseline risk factors, CRF, parameters of LV structure and function, and other fat depots such as SAT and LBF, higher VAT remained associated with greater impairment in Ecc (ß: 0.19, P = 0.002). SAT and LBF were not significantly associated with Ecc, however, CRF remained associated with Ecc in the fully adjusted model including all fat depots (ß: - 0.15, P < 0.001). CONCLUSIONS: VAT and CRF are each independently associated with impairment in Ecc, suggesting that higher VAT burden and low CRF mediate pathological cardiac remodeling through distinct mechanisms.

Hypertensive coronary microvascular dysfunction: a subclinical marker of end organ damage and heart failure.

AIMS: Hypertension is a well-established heart failure (HF) risk factor, especially in the context of adverse left ventricular (LV) remodelling. We aimed to use myocardial flow reserve (MFR) and global longitudinal strain (GLS), markers of subclinical microvascular and myocardial dysfunction, to refine hypertensive HF risk assessment. METHODS AND RESULTS: Consecutive patients undergoing symptom-prompted stress cardiac positron emission tomography (PET)-computed tomography and transthoracic echocardiogram within 90 days without reduced left ventricular ejection fraction (<40%) or flow-limiting coronary artery disease (summed stress score ≥ 3) were included. Global MFR was quantified by PET, and echocardiograms were retrospectively analysed for cardiac structure and function. Patients were followed over a median 8.75 (Q1-3 4.56-10.04) years for HF hospitalization and a composite of death, HF hospitalization, MI, or stroke. Of 194 patients, 155 had adaptive LV remodelling while 39 had maladaptive remodelling, which was associated with lower MFR and impaired GLS. Across the remodelling spectrum, diastolic parameters, GLS, and N-terminal pro-B-type natriuretic peptide were independently associated with MFR. Maladaptive LV remodelling was associated with increased adjusted incidence of HF hospitalization and death. Importantly, the combination of abnormal MFR and GLS was associated with a higher rate of HF hospitalization compared to normal MFR and GLS [adjusted hazard ratio (HR) 3.21, 95% confidence interval (CI) 1.09-9.45, P = 0.034), including in the adaptive remodelling subset (adjusted HR 3.93, 95% CI 1.14-13.56, P = 0.030). CONCLUSION: We have demonstrated important associations between coronary microvascular dysfunction and myocardial mechanics that refine disease characterization and HF risk assessment of patients with hypertension based on subclinical target organ injury.

Chemically tailored high-χ block copolymers for perpendicular lamellae via thermal annealing.

A chemically tailored high-χ block copolymer (BCP), polystyrene-block-poly[2-hydroxy-3-(2,2,2-trifluoroethylsulfanyl)propyl methacrylate] (PS-b-PHFMA), was designed to incorporate tailored surface affinities and chemical incompatibilities for engineering perpendicular lamellae using thermal annealing. PS-b-PHFMA was synthesized via the sequential anionic polymerization of styrene and glycidyl methacrylate and the post-polymerization functionalization of the glycidyl moieties with 2,2,2-trifluoroethanethiol. The bulk studies revealed lamellae with a minimum domain spacing of 9.6 nm and a large effective Flory-Huggins interaction parameter (χeff) of 0.191 at 25 °C. Furthermore, atomic force microscopy and scanning electron microscopy showed perpendicular lamellae of the PS-b-PHFMA prepared on thermally-annealed thin films. The introduction of hydrophobic trifluoroethyl moieties onto the hydrophilic glycidyl moieties successfully balanced the surface affinity of the PHFMA block relative to PS, while simultaneously increasing the strength of segregation. Thus, χeff of the chemically tailored BCP increased, and a perpendicular orientation was facilitated on the thin films using thermal annealing.

The role of advanced lipid testing in the prediction of cardiovascular disease.

Advanced lipid testing has been suggested by some experts to identify patients with substantial residual risk for more aggressive targeting of lifestyle and pharmacologic therapies. It measures the subpopulation of lipoproteins and apolipoproteins, which include lipoprotein (a), apolipoprotein A-I, and apolipoprotein B, and measures of lipoprotein particle composition such as LDL particle (LPL-P) and HDL particle (HDL-P) number and size. Obesity is associated with smaller LDL-P and HDL-P sizes. Moderate weight loss via fasting/calorie restriction is associated with LDL-P size increase, whereas moderate weight loss via endurance exercise is associated with HDL-P size increase. Diets high in carbohydrates are associated with a more atherogenic advanced lipoprotein profile characterized by smaller LDL-P and HDL-P sizes. In summary, lifestyle changes such as weight loss, exercise, and dietary modification correlate with improvement in the profile of advanced lipoproteins. Regrettably, therapies targeting HDL and HDL composition have been disappointing to date.

Association of Beta-Blocker Use With Exercise Capacity in Participants With Heart Failure With Preserved Ejection Fraction: A Post Hoc Analysis of the RELAX Trial.

Patients with heart failure with preserved ejection fraction (HFpEF) often receive ß-blocker (BB) therapy for management of co-morbidities. However, the association of BB therapy with exercise capacity and health-related quality of life (HRQL) in HFpEF is not well-studied. In this post hoc analysis of the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF (RELAX) trial, which included patients with chronic stable HFpEF with peak exercise capacity assessment at baseline and at 12 and 24 weeks of follow-up, we evaluated the association of BB use with the measures of exercise capacity (peak exercise oxygen uptake), anaerobic threshold, and HRQL (Minnesota living with heart failure questionnaire). Separate linear mixed-effect models were constructed for each outcome with adjustment for treatment arm, demographics, medical history, left ventricular ejection fraction, and duration of heart failure. Of the 216 study participants (median age 69 years, 48.2% women), 76% reported BB use at baseline. Participants with (vs without) BB therapy were older (70 vs 63.5 years, p = 0.001) and had a higher prevalence of ischemic heart disease (44% vs 23%, p = 0.01). In the adjusted linear mixed model, BB use over time was not associated with peak exercise oxygen uptake (ß 95% confidence interval [CI] 0.2 (-0.31 to 0.7), p = 0.5) and 6-minute walk distance (ß 95% CI 14.69 [-14.25 to 43.63], p = 0.3). However, BB use was associated with a higher anaerobic threshold (ß 95% CI 0.32 (0.02 to 0.62), p = 0.036) and better HRQL (lower quality of life as assessed by Minnesota living with heart failure questionnaire score) (ß 95% CI -6.68 [-10.96 to -2.4], p = 0.002). Future trials are needed to better evaluate the effects of BB on exercise capacity in patients with chronic stable HFpEF.

Association of global longitudinal strain by feature tracking cardiac magnetic resonance imaging with adverse outcomes among community-dwelling adults without cardiovascular disease: The Dallas Heart Study.

AIM: Left ventricular (LV) global longitudinal strain (GLS) may detect subtle abnormalities in myocardial contractility among individuals with normal LV ejection fraction (LVEF). However, the prognostic implications of GLS among healthy, community-dwelling adults is not well-established. METHODS AND RESULTS: Overall, 2234 community-dwelling adults (56% women, 47% Black) with LVEF ≥50% without a history of cardiovascular disease (CVD) from the Dallas Heart Study who underwent cardiac magnetic resonance (CMR) with GLS assessed by feature tracking CMR (FT-CMR) were included. The association of GLS with the risk of incident major adverse cardiovascular events (MACE; composite of incident myocardial infarction, incident heart failure [HF], hospitalization for atrial fibrillation, coronary revascularization, and all-cause death), and incident HF or death were assessed with adjusted Cox proportional hazards models. A total of 309 participants (13.8%) had MACE during a median follow-up duration of 17 years. Participants with the worst GLS (Q4) were more likely male and of the Black race with a history of tobacco use and diabetes with lower LVEF, higher LV end-diastolic volume, and higher LV mass index. Cumulative incidence of MACE was higher among participants with worse (Q4 vs. Q1) GLS (20.4% vs. 9.0%). In multivariable-adjusted Cox models that included clinical characteristics, cardiac biomarkers and baseline LVEF, worse GLS (Q4 vs. Q1) was associated with a significantly higher risk of MACE (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.07-2.24, p = 0.02) and incident HF or death (HR 1.57, 95% CI 1.03-2.38, p = 0.04). CONCLUSIONS: Impaired LV GLS assessed by FT-CMR among adults free of cardiovascular disease is associated with a higher risk of incident MACE and incident HF or death independent of cardiovascular risk factors, cardiac biomarkers and LVEF.

Temporal trends and racial/ethnic- and sex-differences in LDL cholesterol control among US adults with self-reported atherosclerotic cardiovascular disease.

Objective: Current guidelines for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend targeting a low-density lipoprotein cholesterol (LDL-C) of < 70 mg/dL. However, temporal trends and racial/ethnic- and sex-differences in achievement of LDL-C targets are not well described. We assessed trends and racial/ethnic- and sex-differences in achievement of LDL-C < 70 mg/dL using data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2008 to 2017-March 2020. Methods: We combined NHANES cycles into 4 periods: 2005-2008, 2009-2012, 2013-2016, and 2017-March 2020 and included participants ≥ 40 years with self-reported ASCVD. We estimated LDL-C < 70 mg/dL prevalence over time and further stratified by sex and race/ethnicity. We used multivariable logistic regression adjusted for social determinants of health and clinical covariates to model LDL-C target attainment. Results: Among 1,826 NHANES participants representing 7,161,221 US adults with self-reported ASCVD (59.6% ≥ 65 years, 56.4% male, 74.8% White), LDL-C target attainment increased from 19.0% (95% CI, 15.3%-23.3%) in 2005-2008 to 26.3% (95% CI, 20.4%-33.1%) in 2017-March 2020 (P = 0.012 for trend). Achievement of LDL-C < 70 mg/dL significantly rose among men from19.5% (95% CI, 15.1%-24.8%) to 29.4% (95% CI, 20.7%-29.9%) without significant change in women (from 18.3% [95% CI, 13.6%-24.2%] to 22.5% [95% CI, 13.0%-35.9%]; P = 0.241 for trend). Improvement in LDL-C target attainment was similar among White, Black, and Hispanic individuals (∼5-7% increase) and was greatest among individuals of other (non-White, Hispanic, or Black) race/ethnicity (23.1% increase). In our multivariable analysis, comorbid diabetes and ages 65-75 and > 75 years were associated with LDL-C target attainment. Conclusion: LDL-C control modestly improved between 2005 and 2008 and 2017-March 2020; however, only ∼1/4 of individuals met guideline-directed LDL-C treatment targets by 2017-March 2020. Women had lower LDL-C control and lesser magnitude of improvement in LDL-C control than men, highlighting a need for targeted interventions to improve lipid-lowering therapy utilization in this population.

Cardiac Abnormalities in Hispanic/Latina Women With Prior De Novo Hypertensive Disorders of Pregnancy.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are associated with long-term maternal risks for cardiovascular disease for reasons that remain incompletely understood. METHODS: The HCHS/SOL (Hispanic Community Health Study/Study of Latinos), a multi-center community-based cohort of Hispanic/Latino adults recruited 2008 to 2011, was used to evaluate the associations of history of de novo HDP (gestational hypertension, preeclampsia, eclampsia) with echocardiographic measures of cardiac structure and function in Hispanic/Latina women with ≥1 prior pregnancy and the proportion of association mediated by current hypertension (>140/90 mm Hg or antihypertensive therapy). RESULTS.: The study cohort included 5168 Hispanic/Latina women with an average age (SD) of 58.7 (9.7) years at time of echocardiogram. Prior de novo HDP was reported by 724 (14%) of the women studied and was associated with lower left ventricle (LV) ejection fraction -0.66 (95% confidence interval [CI], -1.21 to -0.11), higher LV relative wall thickness 0.09 (95% CI, 0-0.18), and 1.39 (95% CI, 1.02-1.89) higher risk of abnormal LV geometry after adjusting for blood pressure and other confounders. The proportion of the association mediated by current hypertension between HDP and LV ejection fraction was 0.09 (95% CI, 0.03-0.45), LV relative wall thickness was 0.28 (95% CI, 0.16-0.51), abnormal LV geometry was 0.14 (95% CI, 0.12-0.48), concentric left ventricular hypertrophy was 0.31 (95% CI, 0.19-0.86), and abnormal LV diastolic dysfunction was 0.58 (95% CI, 0.26-0.79). CONCLUSIONS.: In a large cohort of Hispanic/Latina women those with history of de novo HDP had detectable and measurable subclinical alterations in cardiac structure and both systolic and diastolic dysfunction that were only partially mediated by current hypertension.

Impact of the Insoluble Gas Concentration on Measured Stroke Volume at Rest and Submaximal Exercise Using the Innocor Device.

INTRODUCTION: The Innocor® device uses an insoluble gas (SF 6 ) to estimate lung volume and the rate of disappearance of a soluble gas (nitrous oxide) to measure pulmonary blood flow (PBF), which approximates cardiac output assuming no shunt. We sought to identify error in the measurement of the insoluble gas in an effort to reduce variation in Innocor® measurement. METHODS: We enrolled 28 participants from the Dallas Heart Study (mean age, 63 yr; 57% men; 43% White). Stroke volume was measured at rest and at submaximal (20 and 40 W) exercise using both echocardiography (Philips iE33) and the Innocor® device. We defined a priori peak and equilibrium SF 6 measurement errors as greater or less than 20% of the mean observed value. Three Innocor measurements were obtained at rest ( n = 27) for a total of 81 measurements. Of these, 22% had SF 6 measurements that fell outside of the a priori range. RESULTS: Resting Innocor® stroke volume measures with peak SF 6 measured above a priori range (>0.12%) was associated with larger stroke volumes compared with stroke volume measures without peak SF 6 error (101.4 [26.8] vs 64.9 [8.7] mL; P = 0.006) and overestimated stroke volume when compared with stroke volume by echo (101.4 [26.8] vs 59.9 [16.3] mL; P = 0.017). A similar pattern was observed at submaximal exercise. In contrast, there was no consistent association between variation in equilibrium SF 6 concentrations and measured stroke volume. CONCLUSIONS: Variability in peak SF 6 concentration is common while using the Innocor® device and results in overestimated stroke volume. These findings have implications for research protocols using this device.

The Relationship of Alcohol Consumption and HDL Metabolism in the Multiethnic Dallas Heart Study.

BACKGROUND: Small studies have suggested that moderate alcohol consumption increases HDL cholesterol (HDL-C) levels and cholesterol efflux capacity (CEC), a main anti-atherosclerotic HDL function. OBJECTIVES: This study aimed to understand the degree to which alcohol intake is associated with various HDL markers in a large, multiethnic population cohort, the Dallas Heart Study (DHS), and whether alcohol modifies the link between HDL markers and atherosclerotic cardiovascular disease (ASCVD). METHODS: Participants of the DHS were included if they had self-reported alcohol intake and CEC measurements (N=2,919). Alcohol intake was analyzed continuously (grams/week) and as an ordered categorical variable (never, past, light, moderate, heavy, and binge drinkers). HDL-C, CEC, HDL particle number (HDL-P), HDL particle size (HDL-size), and ApoA-I were the primary HDL measures. RESULTS: After adjustment for confounding variables, increasing continuous measure of alcohol intake was associated with increased levels of all HDL markers. Moreover, as compared to moderate drinkers, light drinkers had decreased levels of the HDL markers. CONCLUSION: In a large, multiethnic cohort, increased alcohol intake was associated with increased levels of multiple markers of HDL metabolism. However, the association of HDL markers with ASCVD risk as modified by alcohol consumption is unable to be determined in this low-risk cohort.

Prevalence and Predictors of Subclinical Cardiomyopathy in Patients With Type 2 Diabetes in a Health System.

INTRODUCTION: Diabetic cardiomyopathy (DbCM) is characterized by subclinical abnormalities in cardiac structure/function and is associated with a higher risk of overt heart failure (HF). However, there are limited data on optimal strategies to identify individuals with DbCM in contemporary health systems. The aim of this study was to evaluate the prevalence of DbCM in a health system using existing data from the electronic health record (EHR). METHODS: Adult patients with type 2 diabetes mellitus free of cardiovascular disease (CVD) with available data on HF risk in a single-center EHR were included. The presence of DbCM was defined using different definitions: (1) least restrictive: ≥1 echocardiographic abnormality (left atrial enlargement, left ventricle hypertrophy, diastolic dysfunction); (2) intermediate restrictive: ≥2 echocardiographic abnormalities; (3) most restrictive: 3 echocardiographic abnormalities. DbCM prevalence was compared across age, sex, race, and ethnicity-based subgroups, with differences assessed using the chi-squared test. Adjusted logistic regression models were constructed to evaluate significant predictors of DbCM. RESULTS: Among 1921 individuals with type 2 diabetes mellitus, the prevalence of DbCM in the overall cohort was 8.7% and 64.4% in the most and least restrictive definitions, respectively. Across all definitions, older age and Hispanic ethnicity were associated with a higher proportion of DbCM. Females had a higher prevalence than males only in the most restrictive definition. In multivariable-adjusted logistic regression, higher systolic blood pressure, higher creatinine, and longer QRS duration were associated with a higher risk of DbCM across all definitions. CONCLUSIONS: In this single-center, EHR cohort, the prevalence of DbCM varies from 9% to 64%, with a higher prevalence with older age and Hispanic ethnicity.

Novel Size-Based High-Density Lipoprotein Subspecies and Incident Vascular Events.

Background High-density lipoprotein (HDL) particle concentration likely outperforms HDL cholesterol in predicting atherosclerotic cardiovascular events. Whether size-based HDL subspecies explain the atheroprotective associations of HDL particle concentration remains unknown. Our objective was to assess whether levels of specific size-based HDL subspecies associate with atherosclerotic cardiovascular disease in a multiethnic pooled cohort and improve risk prediction beyond traditional atherosclerotic cardiovascular disease risk factors. Methods and Results Seven HDL size-based subspecies were quantified by nuclear magnetic resonance (LP4 algorithm; H1=smallest; H7=largest) among participants without prior atherosclerotic cardiovascular disease in ARIC (Atherosclerosis Risk in Communities), MESA (Multi-Ethnic Study of Atherosclerosis), PREVEND (Prevention of Renal and Vascular Endstage Disease), and DHS (Dallas Heart Study) cohorts (n=15 371 people). Multivariable Cox proportional hazards models were used to evaluate the association between HDL subspecies and incident myocardial infarction (MI) or ischemic stroke at follow-up (average 8-10 years) adjusting for HDL cholesterol and risk factors. Improvement in risk prediction was assessed via discrimination and reclassification analysis. Within the pooled cohort (median age 57 years; female 54%; Black 22%) higher H1 (small) and H4 (medium) concentrations were inversely associated with incident MI (hazard ratio [HR]/SD, H1 0.88 [95% CI, 0.81-0.94]; H4 0.89 [95% CI, 0.82-0.97]). H4 but not H1 improved risk prediction indices for incident MI. Increasing H2 and H4 were inversely associated with improved risk prediction indices for composite end point of stroke, MI, and cardiovascular death (HR/SD, H2 0.94 [95% CI, 0.88-0.99]; H4 0.91 [95% CI, 0.85-0.98]). Levels of the large subspecies (H6 and H7) were not associated with any vascular end point. Conclusions Two of 7 HDL size-based subspecies modestly improved risk prediction for MI and composite vascular end points in a large multiethnic pooled cohort. These findings support assessment of precise HDL subspecies for future studies regarding clinical utility.

Association of Dapagliflozin vs Placebo With Individual Kansas City Cardiomyopathy Questionnaire Components in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Secondary Analysis of the DELIVER Trial.

Importance: Dapagliflozin has been shown to improve overall health status based on aggregate summary scores of the Kansas City Cardiomyopathy Questionnaire (KCCQ) in patients with heart failure (HF) with mildly reduced or preserved ejection fraction enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. A comprehensive understanding of the responsiveness of individual KCCQ items would allow clinicians to better inform patients on expected changes in daily living with treatment. Objective: To examine the association of dapagliflozin treatment with changes in individual components of the KCCQ. Design, Setting, and Participants: This is a post hoc exploratory analysis of DELIVER, a randomized double-blind placebo-controlled trial conducted at 353 centers in 20 countries from August 2018 to March 2022. KCCQ was administered at randomization and 1, 4, and 8 months. Scores of individual KCCQ components were scaled from 0 to 100. Eligibility criteria included symptomatic HF with left ventricular ejection fraction greater than 40%, elevated natriuretic peptide levels, and evidence of structural heart disease. Data were analyzed from November 2022 to February 2023. Main Outcomes and Measures: Changes in the 23 individual KCCQ components at 8 months. Interventions: Dapagliflozin, 10 mg, once daily or placebo. Results: Baseline KCCQ data were available for 5795 of 6263 randomized patients (92.5%) (mean [SD] age, 71.5 [9.5] years; 3344 male [57.7%] and 2451 female [42.3%]). Dapagliflozin was associated with larger improvements in almost all KCCQ components at 8 months compared with placebo. The most significant improvements with dapagliflozin were observed in frequency of lower limb edema (difference, 3.2; 95% CI, 1.6-4.8; P < .001), sleep limitation by shortness of breath (difference, 3.0; 95% CI, 1.6-4.4; P < .001), and limitation in desired activities by shortness of breath (difference, 2.8; 95% CI, 1.3-4.3; P < .001). Similar treatment patterns were observed in longitudinal analyses integrating data from months 1, 4, and 8. Higher proportions of patients treated with dapagliflozin experienced improvements, and fewer had deteriorations across most individual components. Conclusions and Relevance: In this study of patients with HF with mildly reduced or preserved ejection fraction, dapagliflozin was associated with improvement in a broad range of individual KCCQ components, with the greatest benefits in domains related to symptom frequency and physical limitations. Potential improvements in specific symptoms and activities of daily living might be more readily recognizable and easily communicated to patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03619213.

Cascading loss and loss risk multipliers amid a changing climate in the Pacific Islands.

Human society has experienced, and will continue to experience, extensive loss and damage from worsening anthropogenic climate change. Despite our natural tendencies to categorise and organise, it can be unhelpful to delineate clean boundaries and linear understandings for complex and messy concepts such as loss and damage. Drawing on the perspectives of 42 local and regional Pacific Islander stakeholders, an underexplored resource for understanding loss and damage, we explore the complexity and interconnectedness of non-economic loss and damage (NELD). According to participants, Pacific Islander worldviews, knowledge systems and cosmologies often make it difficult to separate and evaluate NELD independently, challenging the nomenclature of NELD categories developed through international mechanisms. Instead, NELD understandings are often centred on the interdependencies between losses, including the cascading flow-on effects that can occur and the nature of some losses as risk multipliers (i.e. one loss creating the risk for further losses). Most notably, losses to biodiversity, ecosystem services and land are critically linked to, and have cascading effects on, livelihoods, knowledge, ways of life, wellbeing, and culture and heritage. We argue that loss and damage is not always absolute, and that there are NELD that are arguably reparable. Concerning, however, is that biodiversity loss, as a risk multiplier, was considered the least reparable by participants. We put forward that NELD understandings must consider interconnectivity, and that biodiversity and ecosystem conservation and restoration must be the focus for interventions to prevent irreparable and cascading losses from climate change in the Pacific Islands.

Cardiovascular disease and chimeric antigen receptor cellular therapy.

Chimeric antigen receptor T-cell (CAR T) therapy is a revolutionary personalized therapy that has significantly impacted the treatment of patients with hematologic malignancies refractory to other therapies. Cytokine release syndrome (CRS) is a major side effect of CAR T therapy that can occur in 70-90% of patients, with roughly 40% of patients at grade 2 or higher. CRS can cause an intense inflammatory state leading to cardiovascular complications, including troponin elevation, arrhythmias, hemodynamic instability, and depressed left ventricular systolic function. There are currently no standardized guidelines for the management of cardiovascular complications due to CAR T therapy, but systematic practice patterns are emerging. In this review, we contextualize the history and indications of CAR T cell therapy, side effects related to this treatment, strategies to optimize the cardiovascular health prior to CAR T and the management of cardiovascular complications related to CRS. We analyze the existing data and discuss potential future approaches.