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 MMSE 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.

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.

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.

Impact of Vitamin D3 Versus Placebo on Cardiac Structure and Function: A Randomized Clinical Trial.

Background Vitamin D supplementation leads to regression of left ventricular (LV) hypertrophy and improves LV function in animal models. However, limited data exist from prospective human studies. We examined whether vitamin D supplementation improved cardiac structure and function in midlife/older individuals in a large randomized trial. Methods and Results The VITAL (Vitamin D and OmegA-3 Trial) was a nationwide double-blind, placebo-controlled randomized trial that tested the effects of vitamin D3 (2000 IU/d) and n-3 fatty acids (1 g/d) on cardiovascular and cancer risk in 25 871 individuals aged ≥50 years. We conducted a substudy of VITAL in which participants underwent echocardiography at baseline and 2 years. Images were interpreted by a blinded investigator at a central core laboratory. The primary end point was change in LV mass. Among 1054 Greater Boston-area participants attending in-clinic visits, we enrolled 1025 into this study. Seventy-nine percent returned for follow-up and had analyzable echocardiograms at both visits. At baseline, the median age was 64 years (interquartile range, 60-69 years), 52% were men, and 43% had hypertension. After 2 years, the change in LV mass did not significantly differ between the vitamin D and placebo arms (median +1.4 g versus +2.6 g, respectively; P=0.32). Changes in systolic and diastolic LV function also did not differ significantly between arms. There were no significant changes in cardiac structure and function between the n-3 fatty acids and placebo arms. Conclusions Among adults aged ≥50 years, neither vitamin D3 nor n-3 fatty acids supplementation had significant effects on cardiac structure and function after 2 years. Registration URL: https://clinicaltrials.gov/; Unique identifiers: NCT01169259 (VITAL) and NCT01630213 (VITAL-Echo).

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.

Gender Differences in Diagnosis, Prevention, and Treatment of Cardiotoxicity in Cardio-Oncology.

Gender differences exist throughout the medical field and significant progress has been made in understanding the effects of gender in many aspects of healthcare. The field of cardio-oncology is diverse and dynamic with new oncologic and cardiovascular therapies approved each year; however, there is limited knowledge regarding the effects of gender within cardio-oncology, particularly the impact of gender on cardiotoxicities. The relationship between gender and cardio-oncology is unique in that gender likely affects not only the biological underpinnings of cancer susceptibility, but also the response to both oncologic and cardiovascular therapies. Furthermore, gender has significant socioeconomic and psychosocial implications which may impact cancer and cardiovascular risk factor profiles, cancer susceptibility, and the delivery of healthcare. In this review, we summarize the effects of gender on susceptibility of cancer, response to cardiovascular and cancer therapies, delivery of healthcare, and highlight the need for further gender specific studies regarding the cardiovascular effects of current and future oncological treatments.

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.

Electronic Health Records-Based Cardio-Oncology Registry for Care Gap Identification and Pragmatic Research: Procedure and Observational Study.

BACKGROUND: Professional society guidelines are emerging for cardiovascular care in cancer patients. However, it is not yet clear how effectively the cancer survivor population is screened and treated for cardiomyopathy in contemporary clinical practice. As electronic health records (EHRs) are now widely used in clinical practice, we tested the hypothesis that an EHR-based cardio-oncology registry can address these questions. OBJECTIVE: The aim of this study was to develop an EHR-based pragmatic cardio-oncology registry and, as proof of principle, to investigate care gaps in the cardiovascular care of cancer patients. METHODS: We generated a programmatically deidentified, real-time EHR-based cardio-oncology registry from all patients in our institutional Cancer Population Registry (N=8275, 2011-2017). We investigated: (1) left ventricular ejection fraction (LVEF) assessment before and after treatment with potentially cardiotoxic agents; and (2) guideline-directed medical therapy (GDMT) for left ventricular dysfunction (LVD), defined as LVEF<50%, and symptomatic heart failure with reduced LVEF (HFrEF), defined as LVEF<50% and Problem List documentation of systolic congestive heart failure or dilated cardiomyopathy. RESULTS: Rapid development of an EHR-based cardio-oncology registry was feasible. Identification of tests and outcomes was similar using the EHR-based cardio-oncology registry and manual chart abstraction (100% sensitivity and 83% specificity for LVD). LVEF was documented prior to initiation of cancer therapy in 19.8% of patients. Prevalence of postchemotherapy LVD and HFrEF was relatively low (9.4% and 2.5%, respectively). Among patients with postchemotherapy LVD or HFrEF, those referred to cardiology had a significantly higher prescription rate of a GDMT. CONCLUSIONS: EHR data can efficiently populate a real-time, pragmatic cardio-oncology registry as a byproduct of clinical care for health care delivery investigations.

Longitudinal Associations Between Income Changes and Incident Cardiovascular Disease: The Atherosclerosis Risk in Communities Study.

Importance: Higher income is associated with lower incident cardiovascular disease (CVD). However, there is limited research on the association between changes in income and incident CVD. Objective: To examine the association between change in household income and subsequent risk of CVD. Design, Setting, and Participants: The Atherosclerosis Risk In Communities (ARIC) study is an ongoing, prospective cohort of 15 792 community-dwelling men and women, of mostly black or white race, from 4 centers in the United States (Jackson, Mississippi; Washington County, Maryland; suburbs of Minneapolis, Minnesota; and Forsyth County, North Carolina), beginning in 1987. For our analysis, participants were followed up until December 31, 2016. Exposures: Participants were categorized based on whether their household income dropped by more than 50% (income drop), remained unchanged/changed less than 50% (income unchanged), or increased by more than 50% (income rise) over a mean (SD) period of approximately 6 (0.3) years between ARIC visit 1 (1987-1989) and visit 3 (1993-1995). Main Outcomes and Measures: Our primary outcome was incidence of CVD after ARIC visit 3, including myocardial infarction (MI), fatal coronary heart disease, heart failure (HF), or stroke during a mean (SD) of 17 (7) years. Analyses were adjusted for sociodemographic variables, health behaviors, and CVD biomarkers. Results: Of the 8989 included participants (mean [SD] age at enrollment was 53 [6] years, 1820 participants were black [20%], and 3835 participants were men [43%]), 900 participants (10%) experienced an income drop, 6284 participants (70%) had incomes that remained relatively unchanged, and 1805 participants (20%) experienced an income rise. After full adjustment, those with an income drop experienced significantly higher risk of incident CVD compared with those whose incomes remained relatively unchanged (hazard ratio, 1.17; 95% CI, 1.03-1.32). Those with an income rise experienced significantly lower risk of incident CVD compared with those whose incomes remained relatively unchanged (hazard ratio, 0.86; 95% CI, 0.77-0.96). Conclusions and Relevance: Income drop over 6 years was associated with higher risk of subsequent incident CVD over 17 years, while income rise over 6 years was associated with lower risk of subsequent incident CVD over 17 years. Health professionals should have greater awareness of the influence of income change on the health of their patients.

Efficacy of Neurohormonal Therapies in Preventing Cardiotoxicity in Patients with Cancer Undergoing Chemotherapy.

BACKGROUND: Various cardioprotective approaches have been evaluated to prevent chemotherapy-related cardiotoxicity; however, their overall utility remains uncertain. OBJECTIVES: To assess the effects of neurohormonal therapies in preventing cardiotoxicity in patients receiving chemotherapy. METHODS: This meta-analysis included randomized clinical trials of adult patients that underwent chemotherapy and neurohormonal therapies (beta-blockers, mineralocorticoid receptor antagonists, or ACE inhibitors/ARBs) vs. placebo with follow-up ≥4 weeks. The primary outcome was change in left ventricular ejection fraction (LVEF) from baseline to the end of trial. Other outcomes of interest were measures of LV size, strain, and diastolic function. Pooled estimates for each outcome were reported as standardized mean difference (SMD) and weighted mean difference (WMD) between the neurohormonal therapy and placebo groups using random effects models. RESULTS: We included 17 trials, collectively enrolling 1,984 participants. In pooled analysis, neurohormonal therapy (vs. placebo) was associated with significantly higher LVEF on follow-up [SMD(95% CI): +1.04(0.57 to 1.50)] but with significant heterogeneity in the pooled estimate (I2 = 96%). Compared with placebo-treated patients, those randomized to neurohormonal therapies experienced a 3.96% (95%CI: 2.9% to 5.0%) less decline in LVEF estimated by WMD, but with significant heterogeneity (I2 = 98%). There was a trend towards lower adverse clinical events with neurohormonal therapy (vs. placebo) without statistical significance [risk ratio(95%CI): 0.80(0.53-1.20) I2 = 71%]. CONCLUSIONS: Neurohormonal therapies are associated with higher LVEF in follow-up among cancer patients receiving chemotherapy, although absolute changes in LVEF are small and may be within inter-test variability. Furthermore, significant heterogeneity is observed in the treatment effects across studies highlighting the need for larger trials of cardioprotective strategies.

Self-Assembly of Hierarchical Structures Using Cyclotriphosphazene-Containing Poly(substituted methylene) Block Copolymers.

The cyclotriphosphazene-substituted diazoacetate homopolymer (polyPNDA') (PNDA' = hexaphenoxy-substituted phosphazene-containing methylene) and a novel poly(substituted methylene) block copolymer, polyPNDA'-block-poly(hexyloxycarbonylmethylene) (polyPNDA'-b-polyHDA'), were synthesized, and the self-assembly behavior of these polymers was studied in detail. A hexagonally packed aggregated structure was observed in the self-assembled structure of polyPNDA', whereas a lamellar structure was observed in the microphase-separated nanoassembly of polyPNDA'-b-polyHDA'. These results indicate that a hierarchical structure composed of highly regular polyPNDA' nanoaggregates and the long-range microphase-separated polyPNDA' and polyHDA' domains had formed.

The relationship of body mass and fat distribution with incident hypertension: observations from the Dallas Heart Study.

BACKGROUND: Obesity has been linked to the development of hypertension, but whether total adiposity or site-specific fat accumulation underpins this relationship is unclear. OBJECTIVES: This study sought to determine the relationship between adipose tissue distribution and incident hypertension. METHODS: Normotensive participants enrolled in the Dallas Heart Study were followed for a median of 7 years for the development of hypertension (systolic blood pressure [SBP] ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of blood pressure medications). Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) was quantified by magnetic resonance imaging and proton-spectroscopic imaging, and lower body fat (LBF) was imaged by dual-energy x-ray absorptiometry. Multivariable relative risk regression was performed to test the association between individual fat depots and incident hypertension, adjusting for age, sex, race/ethnicity, diabetes, smoking, SBP, and body mass index (BMI). RESULTS: Among 903 participants (median age, 40 years; 57% women; 60% nonwhite; median BMI 27.5 kg/m(2)), 230 (25%) developed incident hypertension. In multivariable analyses, higher BMI was significantly associated with incident hypertension (relative risk: 1.24; 95% confidence interval: 1.12 to 1.36, per 1-SD increase). However, when VAT, SAT, and LBF were added to the model, only VAT remained independently associated with incident hypertension (relative risk: 1.22; 95% confidence interval: 1.06 to 1.39, per 1-SD increase). CONCLUSIONS: Increased visceral adiposity, but not total or subcutaneous adiposity, was robustly associated with incident hypertension. Additional studies will be needed to elucidate the mechanisms behind this association.