Contemporary insights into the epidemiology,impact and treatment of secondary tricuspid regurgitation across the heart failure spectrum

Aim

Tricuspid regurgitation secondary to heart failure (HF) is common with considerable impact on survival and hospitalization rates. Currently, insights into epidemiology, impact, and treatment of secondary tricuspid regurgitation (sTR) across the entire HF spectrum are lacking, yet are necessary for healthcare decision-making.

Methods and results

This population-based study included data from 13 469 patients with HF and sTR from the Viennese community over a 10-year period. The primary outcome was long-term mortality. Overall, HF with preserved ejection fraction was the most frequent (57%, n = 7733) HF subtype and the burden of comorbidities was high. Severe sTR was present in 1514 patients (11%), most common among patients with HF with reduced ejection fraction (20%, n = 496). Mortality of patients with sTR was higher than expected survival of sex- and age-matched community and independent of HF subtype (moderate sTR: hazard ratio [HR] 6.32, 95% confidence interval [CI] 5.88–6.80, p < 0.001; severe sTR: HR 9.04; 95% CI 8.27–9.87, p < 0.001). In comparison to HF and no/mild sTR patients, mortality increased for moderate sTR (HR 1.58, 95% CI 1.48–1.69, p < 0.001) and for severe sTR (HR 2.19, 95% CI 2.01–2.38, p < 0.001). This effect prevailed after multivariate adjustment and was similar across all HF subtypes. In subgroup analysis, severe sTR mortality risk was more pronounced in younger patients (<70 years). Moderate and severe sTR were rarely treated (3%, n = 147), despite availability of state-of-the-art facilities and universal health care.

Conclusion

Secondary tricuspid regurgitation is frequent, increasing with age and associated with excess mortality independent of HF subtype. Nevertheless, sTR is rarely treated surgically or percutaneously. With the projected increase in HF prevalence and population ageing, the data suggest a major burden for healthcare systems that needs to be adequately addressed. Low-risk transcatheter treatment options may provide a suitable alternative.     

Multiple Plasma Biomarkers for Risk Stratification in Patients With Heart Failure and Preserved Ejection Fraction

BackgroundBetter risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF).ObjectivesThe purpose of this study was to assess the value of a targeted plasma multi-marker approach to enhance our phenotypic characterization and risk prediction in HFpEF.MethodsIn this study, the authors measured 49 plasma biomarkers from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial participants (n = 379) using a Multiplex assay. The relationship between biomarkers and the risk of all-cause death or heart failure-related hospital admission (DHFA) was assessed. A tree-based pipeline optimizer platform was used to generate a multimarker predictive model for DHFA. We validated the model in an independent cohort of HFpEF patients enrolled in the PHFS (Penn Heart Failure Study) (n = 156).ResultsTwo large, tightly related dominant biomarker clusters were found, which included biomarkers of fibrosis/tissue remodeling, inflammation, renal injury/dysfunction, and liver fibrosis. Other clusters were composed of neurohormonal regulators of mineral metabolism, intermediary metabolism, and biomarkers of myocardial injury. Multiple biomarkers predicted incident DHFA, including 2 biomarkers related to mineral metabolism/calcification (fibroblast growth factor-23 and OPG [osteoprotegerin]), 3 inflammatory biomarkers (tumor necrosis factor-alpha, sTNFRI [soluble tumor necrosis factor-receptor I], and interleukin-6), YKL-40 (related to liver injury and inflammation), 2 biomarkers related to intermediary metabolism and adipocyte biology (fatty acid binding protein-4 and growth differentiation factor-15), angiopoietin-2 (related to angiogenesis), matrix metalloproteinase-7 (related to extracellular matrix turnover), ST-2, and N-terminal pro–B-type natriuretic peptide. A machine-learning–derived model using a combination of biomarkers was strongly predictive of the risk of DHFA (standardized hazard ratio: 2.85; 95% confidence interval: 2.03 to 4.02; p < 0.0001) and markedly improved the risk prediction when added to the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure Risk Score) risk score. In an independent cohort (PHFS), the model strongly predicted the risk of DHFA (standardized hazard ratio: 2.74; 95% confidence interval: 1.93 to 3.90; p < 0.0001), which was also independent of the MAGGIC risk score.ConclusionsVarious novel circulating biomarkers in key pathophysiological domains are predictive of outcomes in HFpEF, and a multimarker approach coupled with machine-learning represents a promising strategy for enhancing risk stratification in HFpEF.     

Osteopontin Promotes Left Ventricular Diastolic Dysfunction Through a Mitochondrial Pathway

BackgroundPatients with chronic kidney disease (CKD) and coincident heart failure with preserved ejection fraction (HFpEF) may constitute a distinct HFpEF phenotype. Osteopontin (OPN) is a biomarker of HFpEF and predictive of disease outcome. We recently reported that OPN blockade reversed hypertension, mitochondrial dysfunction, and kidney failure in Col4a3^−/− mice, a model of human Alport syndrome.ObjectivesThe purpose of this study was to identify potential OPN targets in biopsies of HF patients, healthy control subjects, and human induced pluripotent stem cell–derived cardiomyocytes (hiPS-CMs), and to characterize the cardiac phenotype of Col4a3^−/− mice, relate this to HFpEF, and investigate possible causative roles for OPN in driving the cardiomyopathy.MethodsOGDHL mRNA and protein were quantified in myocardial samples from patients with HFpEF, heart failure with reduced ejection fraction, and donor control subjects. OGDHL expression was quantified in hiPS-CMs treated with or without anti-OPN antibody. Cardiac parameters were evaluated in Col4a3^−/− mice with and without global OPN knockout or AAV9-mediated delivery of 2-oxoglutarate dehydrogenase-like (Ogdhl) to the heart.ResultsOGDHL mRNA and protein displayed abnormal abundances in cardiac biopsies of HFpEF (n = 17) compared with donor control subjects (n = 12; p < 0.01) or heart failure with reduced ejection fraction patients (n = 12; p < 0.05). Blockade of OPN in hiPS-CMs conferred increased OGDHL expression. Col4a3^−/− mice demonstrated cardiomyopathy with similarities to HFpEF, including diastolic dysfunction, cardiac hypertrophy and fibrosis, pulmonary edema, and impaired mitochondrial function. The cardiomyopathy was ameliorated by Opn^−/− coincident with improved renal function and increased expression of Ogdhl. Heart-specific overexpression of Ogdhl in Col4a3^−/− mice also improved cardiac function and cardiomyocyte energy state.ConclusionsCol4a3^−/− mice present a model of HFpEF secondary to CKD wherein OPN and OGDHL are intermediates, and possibly therapeutic targets.     

Long-Term Cardiovascular Risks Associated With Adverse Pregnancy Outcomes: JACC Review Topic of the Week

Adverse pregnancy outcomes (APOs)—including pre-term birth, pre-eclampsia, and intrauterine growth restriction—are common interrelated disorders caused by placental dysfunction and maternal vascular abnormalities (endothelial activation, inflammation, and vasospasm) that occur in approximately 10% to 20% of pregnancies. Women who experience APOs are at increased risk for future cardiovascular disease (CVD). APOs are associated with increased risk of development of hypertension, left ventricular hypertrophy/dysfunction, vascular dysfunction, and renal dysfunction. The vascular abnormalities that are present during an APO also underlie common, difficult-to-treat forms of CVD in women as they age (e.g., cardiac microvascular dysfunction, heart failure with preserved ejection fraction), suggesting shared mechanistic pathways for APOs and CVD. Here, the authors synthesize the current information and knowledge gaps regarding the progression from APO to CVD. Understanding the risk factors for and pathogenesis of APO-related cardiovascular dysfunction is a critical unmet need that could inform efforts to prevent and more effectively treat CVD in women.     

Von Willebrand factor (vWF) in patients with heart failure with preserved ejection fraction (HFpEF): A retrospective observational study

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial damage and inflammation. In addition, von Willebrand factor (vWF) has been discovered as a biomarker of endothelial dysfunction. Therefore, the study aims to investigate the association between vWF level and HFpEF. Moreover, we analyzed a potential correlation between vWF and inflammatory factors, such as C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-6.We recruited altogether 272 hospitalized patients from The Fifth Affiliated Hospital of Xinjiang Medical University, 88 of whom were HFpEF patients, 88 were non-heart failure patients, and 96 were healthy controls from the medical examination center of the hospital. Enzyme-linked immunosorbent assay and double antibody sandwich immunochromatography were used for testing vWF, tissue plasminogen activator, galectin-3, nitric oxide, TNF-α, IL-6, and CRP.The HFpEF group’s levels of vWF, IL-6, TNF-α, CRP, tissue plasminogen activator, galectin-3, and nitric oxide were statistically higher than those of non-heart failure and healthy control ones (F = 403.563, 21.825, 20.678, 39.609, 35.411, 86.407, 74.605; all P = .000). the highest level of vWF was observed in class IV (New York Heart Association) of HFpEF patients and the significant difference is <.05 (P < .001). An increasing level of vWF were shown in groups (CRP: CRP >3 mg/L group and CRP ≤3 mg/L group; IL-6: IL-6 <7.0 pg/mL group and IL-6 ≥7.0 pg/mL group; TNF-α: TNF-α <5.5 pg/mL group and TNF-α ≥5.5 pg/mL group) with higher level of IL-6, TNF-α, CRP. A multiple regression analysis regarding the relationship of vWF and inflammation markers was performed among the HFpEF patients. Further, statistical significance of the analysis remained after adjusting variables such as body mass index, low-density lipoprotein cholesterol, total cholesterol, coronary artery disease, and type 2 diabetes mellitus (β = 0.406, t = 4.579, P < .001; β = 0.323, t = 3.218, P < .001; β = 0.581, t = 6.922, P < .001).Our study shows that elevated vWF levels are associated with HFpEF, and it may serve as a potential biomarker for HFpEF severity. We also found that increased vWF levels are positively correlated to IL-6, TNF-α, and CRP, which may provide a clue for further researching the pathogenesis of HFpEF.     

Risk factors for in-hospital systemic thromboembolism in myocardial infarction patients with left-ventricular thrombus: A multicenter retrospective study

Left-ventricular thrombus (LVT) is a potentially life-threatening disease. However, few studies have explored the risk factors of in-hospital systemic thromboembolism (ST) in LVT patients. In this multicenter retrospective study, we enrolled myocardial infarction patients with LVT from January 2008 to September 2021. Multivariable logistic regression analysis was applied to identify the independent risk factors for ST in LVT patients. A total number of 160 hospitalized LVT patients [median follow-up period 50 months (18.3–82.5 months)] were subjected to analysis. Of them, 54 (33.8%) patients developed acute myocardial infarction, 16 (10%) had ST, and 33 (20.6%) died. Comparable baseline characteristics were established between the ST and non-ST groups, except for the heart failure classification (P = .014). We obtained the following results from our multivariable analysis, based on the use of HFrEF as a reference: HFpEF [odd ratio (OR), 6.2; 95% confidence interval (CI), 1.4–26.3; P = .014] and HFmrEF (OR, 5.0; 95%CI, 1.1–22.2; P = .033). In conclusion, HFpEF, and HFmrEF may be independent risk factors for in-hospital ST development.     

High-Density Lipoprotein Particle Subfractions in Heart Failure With Preserved or Reduced Ejection Fraction

Background

Circulating high-density lipoprotein particle (HDL-P) subfractions impact atherogenesis, inflammation, and endothelial function, all of which are implicated in the pathobiology of heart failure (HF).

Dietary Patterns and Incident Heart Failure in U.S. Adults Without Known Coronary Disease

Background

Dietary patterns and associations with incident heart failure (HF) are not well established in the United States.

Heart Failure With Preserved Ejection Fraction and Diabetes: JACC State-of-the-Art Review

Heart failure with preserved ejection fraction (HFpEF) is now the most common form of HF, affecting over 3 million adults in the United States alone. HFpEF is a heterogenous syndrome. One important phenotype may be related to comorbid conditions, including diabetes mellitus (DM). DM has a prevalence of approximately 45% in HFpEF, but characteristics and outcomes of this population are poorly understood. In this review, the authors summarize data from several clinical trials of HFpEF therapeutics and provide original data from a large cohort using the Get With The Guidelines-HF registry, which together suggest that DM is associated with increased morbidity and long-term mortality in HFpEF. The authors then discuss several common pathological mechanisms in HFpEF and DM, including sodium retention, metabolic derangements, impaired skeletal muscle function, and potential therapeutic targets. As the understanding of comorbid HFpEF and DM improves, it is hoped clinicians will be better equipped to offer effective, patient-centered treatments.