Wearable device-measured moderate to vigorous physical activity and risk of degenerative aortic valve stenosis.

BACKGROUND AND AIMS: Physical activity has proven effective in preventing atherosclerotic cardiovascular disease, but its role in preventing degenerative valvular heart disease (VHD) remains uncertain. This study aimed to explore the dose-response association between moderate to vigorous physical activity (MVPA) volume and the risk of degenerative VHD among middle-aged adults. METHODS: A full week of accelerometer-derived MVPA data from 87 248 UK Biobank participants (median age 63.3, female: 56.9%) between 2013 and 2015 were used for primary analysis. Questionnaire-derived MVPA data from 361 681 UK Biobank participants (median age 57.7, female: 52.7%) between 2006 and 2010 were used for secondary analysis. The primary outcome was the diagnosis of incident degenerative VHD, including aortic valve stenosis (AS), aortic valve regurgitation (AR), and mitral valve regurgitation (MR). The secondary outcome was VHD-related intervention or mortality. RESULTS: In the accelerometer-derived MVPA cohort, 555 incident AS, 201 incident AR, and 655 incident MR occurred during a median follow-up of 8.11 years. Increased MVPA volume showed a steady decline in AS risk and subsequent AS-related intervention or mortality risk, levelling off beyond approximately 300 min/week. In contrast, its association with AR or MR incidence was less apparent. The adjusted rates of AS incidence (95% confidence interval) across MVPA quartiles (Q1-Q4) were 11.60 (10.20, 13.20), 7.82 (6.63, 9.23), 5.74 (4.67, 7.08), and 5.91 (4.73, 7.39) per 10 000 person-years. The corresponding adjusted rates of AS-related intervention or mortality were 4.37 (3.52, 5.43), 2.81 (2.13, 3.71), 1.93 (1.36, 2.75), and 2.14 (1.50, 3.06) per 10 000 person-years, respectively. Aortic valve stenosis risk reduction was also observed with questionnaire-based MVPA data [adjusted absolute difference Q4 vs. Q1: AS incidence, -1.41 (-.67, -2.14) per 10 000 person-years; AS-related intervention or mortality, -.38 (-.04, -.88) per 10 000 person-years]. The beneficial association remained consistent in high-risk populations for AS, including patients with hypertension, obesity, dyslipidaemia, and chronic kidney disease. CONCLUSIONS: Higher MVPA volume was associated with a lower risk of developing AS and subsequent AS-related intervention or mortality. Future research needs to validate these findings in diverse populations with longer durations and repeated periods of activity monitoring.

Genetically predicted biomarkers of iron homeostasis and risk of non-ischemic cardiomyopathy: A mendelian randomization study.

BACKGROUND AND AIMS: Both iron overload and iron deficiency have been associated with cardiovascular diseases in observational studies. Previous Mendelian Randomization (MR) studies discovered a protective effect of higher iron status on coronary atrial disease, while a neutral effect on all-cause heart failure. Using two-sample MR, we evaluated how genetically predicted systemic iron status affects the risk of non-ischemic cardiomyopathy and different phenotypes. METHODS AND RESULTS: Two-sample MR analyses were performed to estimate the causal effect of four biomarkers of systemic iron status on diagnosed cardiomyopathy and its subtypes in 242,607 participants from the FinnGen research project. The level of transferrin saturation was significantly associated with an increased risk of cardiomyopathy (OR, 1.17; 95% CI, 1.13-1.38) when using nine separately selected genetic instruments. An increase in genetically determined serum iron (odds ratio [OR] per standard deviation [SD], 1.25; 95% confidence interval [CI], 1.13-1.38) and ferritin (OR, 1.49; 95% CI, 1.02-2.18) were associated with an increased risk of cardiomyopathy. Total iron binding capacity, a marker of reduced iron status, was inversely linked with cardiomyopathy (OR, 0.80; 95% CI, 0.65-0.98). The risk effect of iron status was more evident in hypertrophic cardiomyopathy and related heart failure. CONCLUSIONS: These analyses support the causal effect of increased systemic iron status on a higher risk of non-ischemic cardiomyopathy. A screening test for cardiomyopathy should be considered in patients with evidence of iron overload. Future study is needed for exploring the mechanism of these causal variants on cardiomyopathy.

Implication of geriatric nutritional risk index on treatment response and long-term prognosis in patients with cardiac resynchronization therapy.

PURPOSE: Geriatric Nutritional Risk Index (GNRI) is a simple tool for assessing the nutritional status of the aging population. This study aims to explore the clinical implication of GNRI on treatment response and long-term clinical outcomes in heart failure (HF) patients receiving cardiac resynchronization therapy (CRT). METHODS: Patients who underwent CRT implantation or upgrade at our hospital were retrospectively included. The association of GNRI and its tertiles with the echocardiographic response, all-cause mortality or heart transplantation, and the first hospitalization due to HF were investigated. RESULTS: Totally, 647 patients were enrolled, with a median age of 60 [Interquartile Range (IQR): 52-67] years and mean score of GNRI at 107.9 ± 23.7. Super-response rates increased significantly among the GNRI T1, T2, and T3 groups (25.1%, 29.8% vs. 41.1%, P = 0.002). Patients with higher GNRI were more likely to have better LVEF improvement after multiple adjustments (OR = 1.13, 95% CI: 1.04-1.23, P = 0.010). Higher GNRI was independently associated with a lower risk of all-cause mortality or heart implantation (HR = 0.95, 95% CI: 0.93-0.96, P < 0.001) and HF hospitalization (HR = 0.96, 95% CI: 0.95-0.98, P < 0.001). The inclusion of GNRI enhanced the predictability of all-cause mortality based on traditional model, including sex, New York Heart Association functional class, left bundle branch block, QRS reduction, and N-terminal pro-B-type natriuretic peptide level (C statistics improved from 0.785 to 0.813, P = 0.007). CONCLUSION: Higher GNRI was associated with better treatment response and long-term prognosis in HF patients with CRT. Evaluation of nutritional status among CRT population is necessary for individualized choice of potential responders.

Association between triglyceride-glucose index and the risk of heart failure hospitalization in older diabetic patients received right ventricular pacing: a retrospective cohort study.

BACKGROUND: The prognostic value of triglyceride-glucose (TyG) index is not yet known for older diabetic patients received right ventricular pacing (RVP). We aimed to investigate the association between TyG index and the risk of heart failure hospitalization (HFH) in older diabetic patients received RVP. METHODS: This study was conducted between January 2017 and January 2018 at Fuwai Hospital, Beijing, China, and included older (age ≥ 65 years) diabetic patients that received RVP for the first time. TyG index were obtained before implantation. The primary endpoint was HFH. RESULTS: A total of 231 patients were divided into three groups according to the tertiles of TyG index: < 8.5 (T1, N = 77), 8.5-9.1 (T2, N = 77), and > 9.1 (T3, N = 77). T3 group had higher rate of HFH (Log-rank = 11.7, P = 0.003). Multivariate analyses showed that, TyG index served as an independent predictor for HFH, both as numerical variable (HR = 1.94, 95% CI 1.21-3.11, P = 0.006), and as categorical variable (HR = 2.31, 95% CI 1.09-4.89, P = 0.03). RCS demonstrated that the risk of HFH was relatively low until TyG index exceeded 8.8, beyond which the risk began to increase rapidly (P-non-linear = 0.006). CONCLUSION: Preimplantation TyG index emerges as a robust, independent predictor for HFH in older diabetic patients received RVP, and TyG index > 8.8 might be the optimal cut-off value.

The long noncoding RNA CARDINAL attenuates cardiac hypertrophy by modulating protein translation.

One of the features of pathological cardiac hypertrophy is enhanced translation and protein synthesis. Translational inhibition has been shown to be an effective means of treating cardiac hypertrophy, although system-wide side effects are common. Regulators of translation, such as cardiac-specific long noncoding RNAs (lncRNAs), could provide new, more targeted therapeutic approaches to inhibit cardiac hypertrophy. Therefore, we generated mice lacking a previously identified lncRNA named CARDINAL to examine its cardiac function. We demonstrate that CARDINAL is a cardiac-specific, ribosome-associated lncRNA and show that its expression was induced in the heart upon pathological cardiac hypertrophy and that its deletion in mice exacerbated stress-induced cardiac hypertrophy and augmented protein translation. In contrast, overexpression of CARDINAL attenuated cardiac hypertrophy in vivo and in vitro and suppressed hypertrophy-induced protein translation. Mechanistically, CARDINAL interacted with developmentally regulated GTP-binding protein 1 (DRG1) and blocked its interaction with DRG family regulatory protein 1 (DFRP1); as a result, DRG1 was downregulated, thereby modulating the rate of protein translation in the heart in response to stress. This study provides evidence for the therapeutic potential of targeting cardiac-specific lncRNAs to suppress disease-induced translational changes and to treat cardiac hypertrophy and heart failure.

Signaling cascades in the failing heart and emerging therapeutic strategies.

Chronic heart failure is the end stage of cardiac diseases. With a high prevalence and a high mortality rate worldwide, chronic heart failure is one of the heaviest health-related burdens. In addition to the standard neurohormonal blockade therapy, several medications have been developed for chronic heart failure treatment, but the population-wide improvement in chronic heart failure prognosis over time has been modest, and novel therapies are still needed. Mechanistic discovery and technical innovation are powerful driving forces for therapeutic development. On the one hand, the past decades have witnessed great progress in understanding the mechanism of chronic heart failure. It is now known that chronic heart failure is not only a matter involving cardiomyocytes. Instead, chronic heart failure involves numerous signaling pathways in noncardiomyocytes, including fibroblasts, immune cells, vascular cells, and lymphatic endothelial cells, and crosstalk among these cells. The complex regulatory network includes protein-protein, protein-RNA, and RNA-RNA interactions. These achievements in mechanistic studies provide novel insights for future therapeutic targets. On the other hand, with the development of modern biological techniques, targeting a protein pharmacologically is no longer the sole option for treating chronic heart failure. Gene therapy can directly manipulate the expression level of genes; gene editing techniques provide hope for curing hereditary cardiomyopathy; cell therapy aims to replace dysfunctional cardiomyocytes; and xenotransplantation may solve the problem of donor heart shortages. In this paper, we reviewed these two aspects in the field of failing heart signaling cascades and emerging therapeutic strategies based on modern biological techniques.

Cardiac ISL1-Interacting Protein, a Cardioprotective Factor, Inhibits the Transition From Cardiac Hypertrophy to Heart Failure.

Heart failure is characterized by the inability of the heart to pump effectively and generate proper blood circulation to meet the body's needs; it is a devastating condition that affects more than 100 million people globally. In spite of this, little is known about the mechanisms regulating the transition from cardiac hypertrophy to heart failure. Previously, we identified a cardiomyocyte-enriched gene, CIP, which regulates cardiac homeostasis under pathological stimulation. Here, we show that the cardiac transcriptional factor GATA4 binds the promotor of CIP gene and regulates its expression. We further determined that both CIP mRNA and protein decrease in diseased human hearts. In a mouse model, induced cardiac-specific overexpression of CIP after the establishment of cardiac hypertrophy protects the heart by inhibiting disease progression toward heart failure. Transcriptome analyses revealed that the IGF, mTORC2 and TGFß signaling pathways mediate the inhibitory function of CIP on pathologic cardiac remodeling. Our study demonstrates GATA4 as an upstream regulator of CIP gene expression in cardiomyocytes, as well as the clinical significance of CIP expression in human heart disease. More importantly, our investigation suggests CIP is a key regulator of the transition from cardiac hypertrophy to heart failure. The ability of CIP to intervene in the onset of heart failure suggests a novel therapeutic avenue of investigation for the prevention of heart disease progression.

Loss of m6A Methyltransferase METTL5 Promotes Cardiac Hypertrophy Through Epitranscriptomic Control of SUZ12 Expression.

Enhancement of protein synthesis from mRNA translation is one of the key steps supporting cardiomyocyte hypertrophy during cardiac remodeling. The methyltransferase-like5 (METTL5), which catalyzes m6A modification of 18S rRNA at position A1832, has been shown to regulate the efficiency of mRNA translation during the differentiation of ES cells and the growth of cancer cells. It remains unknown whether and how METTL5 regulates cardiac hypertrophy. In this study, we have generated a mouse model, METTL5-cKO, with cardiac-specific depletion of METTL5 in vivo. Loss function of METTL5 promotes pressure overload-induced cardiomyocyte hypertrophy and adverse remodeling. The regulatory function of METTL5 in hypertrophic growth of cardiomyocytes was further confirmed with both gain- and loss-of-function approaches in primary cardiomyocytes. Mechanically, METTL5 can modulate the mRNA translation of SUZ12, a core component of PRC2 complex, and further regulate the transcriptomic shift during cardiac hypertrophy. Altogether, our study may uncover an important translational regulator of cardiac hypertrophy through m6A modification.

Circle the Cardiac Remodeling With circRNAs.

Cardiac remodeling occurs after the heart is exposed to stress, which is manifested by pathological processes such as cardiomyocyte hypertrophy and apoptosis, dendritic cells activation and cytokine secretion, proliferation and activation of fibroblasts, and finally leads to heart failure. Circular RNAs (circRNAs) are recently recognized as a specific type of non-coding RNAs that are expressed in different species, in different stages of development, and in different pathological conditions. Growing evidences have implicated that circRNAs play important regulatory roles in the pathogenesis of a variety of cardiovascular diseases. In this review, we summarize the biological origin, characteristics, functional classification of circRNAs and their regulatory functions in cardiomyocytes, endothelial cells, fibroblasts, immune cells, and exosomes in the pathogenesis of cardiac remodeling.

A Roadmap for Fixing the Heart: RNA Regulatory Networks in Cardiac Disease.

With the continuous development of RNA biology and massive genome-wide transcriptome analysis, more and more RNA molecules and their functions have been explored in the last decade. Increasing evidence has demonstrated that RNA-related regulatory networks play an important role in a variety of human diseases, including cardiovascular diseases. In this review, we focus on RNA regulatory networks in heart disease, most of which are devastating conditions with no known cure. We systemically summarize recent discoveries of important new components of RNA regulatory networks, including microRNAs, long non-coding RNAs, and circular RNAs, as well as multiple regulators that affect the activity of these networks in cardiac physiology and pathology. In addition, this review covers emerging micropeptides, which represent short open reading frames (sORFs) in long non-coding RNA transcripts that may modulate cardiac physiology. Based on the current knowledge of RNA regulatory networks, we think that ongoing discoveries will not only provide us a better understanding of the molecular mechanisms that underlie heart disease, but will also identify novel biomarkers and therapeutic targets for the diagnosis and treatment of cardiac disease.