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Heart failure is a serious global health challenge, affecting more than 6.2 million people in the United States and is projected to reach over 8 million by 2030. Independent of etiology, failing hearts share common features, including defective calcium (Ca 2+ ) handling, mitochondrial Ca 2+ overload, and oxidative stress. In cardiomyocytes, Ca 2+ not only regulates excitation-contraction coupling, but also mitochondrial metabolism and oxidative stress signaling, thereby controlling the function and actual destiny of the cell. Understanding the mechanisms of mitochondrial Ca 2+ uptake and the molecular pathways involved in the regulation of increased mitochondrial Ca 2+ influx is an ongoing challenge in order to identify novel therapeutic targets to alleviate the burden of heart failure. In this review, we discuss the mechanisms underlying altered mitochondrial Ca 2+ handling in heart failure and the potential therapeutic strategies.

Background: Cardiac fibrosis represents a key element in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), a condition highly prevalent amongst geriatric patients, especially if diabetic. The microRNA 181c (miR-181c) has been shown to be associated with the response to exercise training in HFpEF patients and has been also linked to diabetic cardiovascular complications. However, the underlying mechanisms have not been fully elucidated., Objective: To measure circulating miR-181c in elderly patients with HFpEF and diabetes mellitus (DM) and identify gene targets pathophysiologically relevant in HFpEF., Methods: We quantified circulating miR-181c in frail older adults with a confirmed diagnosis of HFpEF and DM, and, as control, we enrolled age-matched subjects without HFpEF and without DM. We validated in human cardiac fibroblasts the molecular mechanisms linking miR-181c to a pro-fibrotic response., Results: 51 frail patients were included :34 patients with DM and HFpEF and 17 age-matched controls. We observed that miR-181c was significantly upregulated (p < 0.0001) in HFpEF patients vs controls. We confirmed in vitro that miR-181c is targeting PRKN and SMAD7., Conclusions: We demonstrate that miR-181c levels are significantly increased in frail elderly adults with DM and HFpEF and that miR-181c targets PRKN and SMAD7 in human cardiac fibroblasts., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Growing evidence correlate the accrual of the sphingolipid ceramide in plasma and cardiac tissue with heart failure (HF). Regulation of sphingolipid metabolism in the heart and the pathological impact of its derangement remain poorly understood. Recently, we discovered that Nogo-B, a membrane protein of endoplasmic reticulum, abundant in the vascular wall, down-regulates the sphingolipid de novo biosynthesis via serine palmitoyltransferase (SPT), first and rate liming enzyme, to impact vascular functions and blood pressure. Nogo-A, a splice isoform of Nogo, is transiently expressed in cardiomyocyte (CM) following pressure overload. Cardiac Nogo is up-regulated in dilated and ischaemic cardiomyopathies in animals and humans. However, its biological function in the heart remains unknown., Methods and Results: We discovered that Nogo-A is a negative regulator of SPT activity and refrains ceramide de novo biosynthesis in CM exposed to haemodynamic stress, hence limiting ceramide accrual. At 7 days following transverse aortic constriction (TAC), SPT activity was significantly up-regulated in CM lacking Nogo-A and correlated with ceramide accrual, particularly very long-chain ceramides, which are the most abundant in CM, resulting in the suppression of 'beneficial' autophagy. At 3 months post-TAC, mice lacking Nogo-A in CM showed worse pathological cardiac hypertrophy and dysfunction, with ca. 50% mortality rate., Conclusion: Mechanistically, Nogo-A refrains ceramides from accrual, therefore preserves the 'beneficial' autophagy, mitochondrial function, and metabolic gene expression, limiting the progression to HF under sustained stress., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Endothelial dysfunction (ED) causes worse prognoses in heart failure (HF) patients treated with cardiac resynchronization therapy (CRTd). ED triggers the downregulation of microRNA-130 (miR-130a-5p), which targets endothelin-1 (ET-1). Thus, we evaluated ED and the response to CRTd by assessing miR-130a-5p and ET-1 serum levels. We designed a prospective multi-center study with a 1-year follow-up to evaluate ED, ET-1, and miR-130a-5p in CRTd patients with ED (ED-CRTd) vs. patients without ED (NED-CRTd). Clinical outcomes were CRTd response, HF hospitalization, cardiac death, and all-cause death. At 1-year follow-up, NED-CRTd (n = 541) vs. ED-CRTd (n = 326) patients showed better clinical statuses, lower serum values of B type natriuretic peptide (BNP: 266.25 ± 10.8 vs. 297.43 ± 16.22 pg/mL; p < 0.05) and ET-1 (4.57 ± 0.17 vs. 5.41 ± 0.24 pmol/L; p < 0.05), and higher values of miR-130a-5p (0.51 ± 0.029 vs. 0.41 ± 0.034 A.U; p < 0.05). Compared with NED-CRTd patients, ED-CRTd patients were less likely to be CRTd responders (189 (58%) vs. 380 (70.2%); p < 0.05) and had higher rates of HF hospitalization (115 (35.3%) vs. 154 (28.5%); p < 0.05) and cardiac deaths (30 (9.2%) vs. 21 (3.9%); p < 0.05). Higher miR-130a-5p levels (HR 1.490, CI 95% [1.014−2.188]) significantly predicted CRTd response; the presence of hypertension (HR 0.818, CI 95% [0.669−0.999]), and displaying higher levels of ET-1 (HR 0.859, CI 98% [0.839−0.979]), lymphocytes (HR 0.820, CI 95% [0.758−0.987]), LVEF (HR 0.876, CI 95% [0.760−0.992]), and ED (HR 0.751, CI 95% [0.624−0.905]) predicted CRTd non-response. Higher serum miR-130a-5p levels (HR 0.332, CI 95% [0.347−0.804]) and use of ARNI (HR 0.319, CI 95% [0.310−0.572]) predicted lower risk of HF hospitalization, whereas hypertension (HR 1.818, CI 95% [1.720−2.907]), higher BNP levels (HR 1.210, CI 95% [1.000−1.401]), and presence of ED (HR 1.905, CI 95% [1.238−2.241]) predicted a higher risk of HF hospitalization. Hence, serum miR-130a-5p could identify different stages of ED and independently predict CRTd response, therefore representing a novel prognostic HF biomarker.

Endothelial dysfunction represents a key mechanism underlying heart failure with preserved ejection fraction (HFpEF), diabetes mellitus (DM), and frailty. However, reliable biomarkers to monitor endothelial dysfunction in these patients are lacking. In this study, we evaluated the expression of a panel of circulating microRNAs (miRs) involved in the regulation of endothelial function in a population of frail older adults with HFpEF and DM treated for 3 months with empagliflozin, metformin, or insulin. We identified a distinctive pattern of miRs that were significantly regulated in HFpEF patients compared to healthy controls and to HFpEF patients treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin. Three miRs were significantly downregulated (miR-126, miR-342-3p, and miR-638) and two were significantly upregulated (miR-21 and miR-92) in HFpEF patients compared to healthy controls. Strikingly, two of these miRs (miR-21 and miR-92) were significantly reduced in HFpEF patients after the 3-month treatment with empagliflozin, whereas no significant differences in the profile of endothelial miRs were detected in patients treated with metformin or insulin. Taken together, our findings demonstrate for the first time that specific circulating miRs involved in the regulation of endothelial function are significantly regulated in frail HFpEF patients with DM and in response to SGLT2 inhibition. SIGNIFICANCE STATEMENT: We have identified a novel microRNA signature functionally involved in the regulation of endothelial function that is significantly regulated in frail patients with HFpEF and diabetes. Moreover, the treatment with the SGLT2 inhibitor empagliflozin caused a modification of some of these microRNAs in a direction that was opposite to what observed in HFpEF patients, indicating a rescue of endothelial function. Our findings are relevant for clinical practice inasmuch as we were able to establish novel biomarkers of disease and response to therapy., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: To assess whether the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improves cognitive impairment in frail older adults with diabetes and heart failure with preserved ejection fraction (HFpEF)., Research Design and Methods: We designed a prospective study to assess cognitive and physical function in consecutive frail older adults with diabetes and HFpEF, comparing the effects of empagliflozin, metformin, and insulin., Results: A total of 162 frail older adults with HFpEF and diabetes successfully completed the study. Montreal Cognitive Assessment scores at baseline and after 1 month were 19.80 ± 3.77 vs. 22.25 ± 3.27 (P < 0.001) in the empagliflozin group, 19.95 ± 3.81 vs. 20.71 ± 3.56 (P = 0.26) in the metformin group, and 19.00 ± 3.71 vs. 19.1 ± 3.56 (P = 0.81) in the insulin group. A multivariable regression analysis confirmed the beneficial effects of empagliflozin. Additionally, we observed a marked amelioration of physical impairment, assessed by the 5-m gait speed test, in the empagliflozin and metformin groups but not in the insulin group., Conclusions: This study is the first to show significant beneficial effects of the SGLT2 inhibitor empagliflozin on cognitive and physical impairment in frail older adults with diabetes and HFpEF., (© 2022 by the American Diabetes Association.)

Finding reliable parameters to identify patients with heart failure (HF) that will respond to cardiac resynchronization therapy (CRT) represents a major challenge. We and others have observed post-translational modifications of Ryanodine Receptor (RyR) in several tissues (including skeletal muscle and circulating lymphocytes) of patients with advanced HF. We designed a prospective study to test the hypothesis that RyR1 glycation in circulating lymphocytes could predict CRT responsiveness in patients with non-ischemic HF. We enrolled 94 patients who underwent CRT and 30 individuals without HF, examining RyR1 glycation in peripheral lymphocytes at enrollment and after 1 year. We found that baseline RyR1 glycation independently predicts CRT response at 1 year after adjusting for age, diabetes, QRS duration and morphology, echocardiographic dyssynchrony, and hypertension. Moreover, RyR1 glycation in circulating lymphocytes significantly correlated with pathologic intracellular calcium leak. Taken together, our data show for the first time that RyR1 glycation in circulating lymphocytes represents a novel biomarker to predict CRT responsiveness., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Patients with heart failure (HF) have augmented vascular tone, which increases cardiac workload, impairing ventricular output and promoting further myocardial dysfunction. The molecular mechanisms underlying the maladaptive vascular responses observed in HF are not fully understood. Vascular smooth muscle cells (VSMCs) control vasoconstriction via a Ca2+-dependent process, in which the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) on the sarcoplasmic reticulum (SR) plays a major role. To dissect the mechanistic contribution of intracellular Ca2+ release to the increased vascular tone observed in HF, we analyzed the remodeling of IP3R1 in aortic tissues from patients with HF and from controls. VSMC IP3R1 channels from patients with HF and HF mice were hyperphosphorylated by both serine and tyrosine kinases. VSMCs isolated from IP3R1VSMC-/- mice exhibited blunted Ca2+ responses to angiotensin II (ATII) and norepinephrine compared with control VSMCs. IP3R1VSMC-/- mice displayed significantly reduced responses to ATII, both in vivo and ex vivo. HF IP3R1VSMC-/- mice developed significantly less afterload compared with HF IP3R1fl/fl mice and exhibited significantly attenuated progression toward decompensated HF and reduced interstitial fibrosis. Ca2+-dependent phosphorylation of the MLC by MLCK activated VSMC contraction. MLC phosphorylation was markedly increased in VSMCs from patients with HF and HF mice but reduced in VSMCs from HF IP3R1VSMC-/- mice and HF WT mice treated with ML-7. Taken together, our data indicate that VSMC IP3R1 is a major effector of increased vascular tone, which contributes to increased cardiac afterload and decompensation in HF.

Heart failure and cardiovascular disorders represent the leading cause of death in diabetic patients. Here we present a systematic review of the main mechanisms underlying the development of diabetic cardiomyopathy. We also provide an excursus on the relative contribution of cardiomyocytes, fibroblasts, endothelial and smooth muscle cells to the pathophysiology of heart failure in diabetes. After having described the preclinical tools currently available to dissect the mechanisms of this complex disease, we conclude with a section on the most recent updates of the literature on clinical management., Competing Interests: Declaration of competing interest Nothing to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We previously demonstrated that the selective retinoic acid receptor (RAR) β agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. We hypothesized that by decreasing oxidative stress and consequent fibrogenesis, AC261066 could attenuate the development of contractile dysfunction in post-ischemic heart failure (HF). We tested this hypothesis in vivo using an established murine model of myocardial infarction (MI), obtained by permanent occlusion of the left anterior descending coronary artery. Treating mice with AC261066 in drinking water significantly attenuated the post-MI deterioration of echocardiographic indices of cardiac function, diminished remodeling, and reduced oxidative stress, as evidenced by a decrease in malondialdehyde level and p38 mitogen-activated protein kinase expression in cardiomyocytes. The effects of AC261066 were also associated with a decrease in interstitial fibrosis, as shown by a marked reduction in collagen deposition and 2 agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. We hypothesized that by decreasing oxidative stress and consequent fibrogenesis, AC261066 could attenuate the development of contractile dysfunction in post-ischemic heart failure (HF). We tested this hypothesis in vivo using an established murine model of myocardial infarction (MI), obtained by permanent occlusion of the left anterior descending coronary artery. Treating mice with AC261066 in drinking water significantly attenuated the post-MI deterioration of echocardiographic indices of cardiac function, diminished remodeling, and reduced oxidative stress, as evidenced by a decrease in malondialdehyde level and p38 mitogen-activated protein kinase expression in cardiomyocytes. The effects of AC261066 were also associated with a decrease in interstitial fibrosis, as shown by a marked reduction in collagen deposition and α -smooth muscle actin expression. In cardiac murine fibroblasts subjected to hypoxia, AC261066 reversed hypoxia-induced decreases in superoxide dismutase 2 and angiopoietin-like 4 transcriptional levels as well as the increase in NADPH oxidase 2 mRNA, demonstrating that the post-MI cardioprotective effects of AC261066 are associated with an action at the fibroblast level. Thus, AC261066 alleviates post-MI cardiac dysfunction by modulating a set of genes involved in the oxidant/antioxidant balance. These AC261066 responsive genes diminish interstitial fibrogenesis and remodeling. Since MI is a recognized major cause of HF, our data identify RAR β agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. This study shows that AC261066 attenuates the development of contractile dysfunction and maladaptive remodeling in post-ischemic heart failure (HF) by modulating a set of genes involved in oxidant/antioxidant balance. Since myocardial infarction is a recognized major cause of HF, these data identify RAR 2 as a potential pharmacological target in the treatment of HF. SIGNIFICANCE STATEMENT: A previous report showed that the selective retinoic acid receptor (RAR) β 2 agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. This study shows that AC261066 attenuates the development of contractile dysfunction and maladaptive remodeling in post-ischemic heart failure (HF) by modulating a set of genes involved in oxidant/antioxidant balance. Since myocardial infarction is a recognized major cause of HF, these data identify RAR β 2 as a potential pharmacological target in the treatment of HF., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Source Citation: Kozhuharov N, Goudev A, Flores D, et al. Effect of a strategy of comprehensive vasodilation vs usual care on mortality and heart failure rehospitalization among patients with acute heart failure: the GALACTIC randomized clinical trial. JAMA. 2019;322:2292-302. 31846016.

Adding rivaroxaban to standard therapy in patients with heart failure and no atrial fibrillation did not show any beneficial effect on death risk.

Background: Advances in congestive heart failure (CHF) management depend on biomarkers for monitoring disease progression and therapeutic response. During systole, intracellular Ca 2+ is released from the sarcoplasmic reticulum into the cytoplasm through type-2 ryanodine receptor/Ca 2+ release channels. In CHF, chronically elevated circulating catecholamine levels cause pathological remodeling of type-2 ryanodine receptor/Ca 2+ release channels resulting in diastolic sarcoplasmic reticulum Ca 2+ leak and decreased myocardial contractility. Similarly, skeletal muscle contraction requires sarcoplasmic reticulum Ca 2+ release through type-1 ryanodine receptors (RyR1), and chronically elevated catecholamine levels in CHF cause RyR1-mediated sarcoplasmic reticulum Ca 2+ leak, contributing to myopathy and weakness. Circulating B-lymphocytes express RyR1 and catecholamine-responsive signaling cascades, making them a potential surrogate for defects in intracellular Ca 2+ handling because of leaky RyR channels in CHF., Methods: Whole blood was collected from patients with CHF, CHF following left-ventricular assist device implant, and controls. Blood was also collected from mice with ischemic CHF, ischemic CHF+S107 (a drug that specifically reduces RyR channel Ca 2+ leak), and wild-type controls. Channel macromolecular complex was assessed by immunostaining RyR1 immunoprecipitated from lymphocyte-enriched preparations. RyR1 Ca 2+ leak was assessed using flow cytometry to measure Ca 2+ fluorescence in B-lymphocytes in the absence and presence of RyR1 agonists that empty RyR1 Ca 2+ stores within the endoplasmic reticulum., Results: Circulating B-lymphocytes from humans and mice with CHF exhibited remodeled RyR1 and decreased endoplasmic reticulum Ca 2+ stores, consistent with chronic intracellular Ca 2+ leak. This Ca 2+ leak correlated with circulating catecholamine levels. The intracellular Ca 2+ leak was significantly reduced in mice treated with the Rycal S107. Patients with CHF treated with left-ventricular assist devices exhibited a heterogeneous response., Conclusions: In CHF, B-lymphocytes exhibit remodeled leaky RyR1 channels and decreased endoplasmic reticulum Ca 2+ stores consistent with chronic intracellular Ca 2+ leak. RyR1-mediated Ca 2+ leak in B-lymphocytes assessed using flow cytometry provides a surrogate measure of intracellular Ca 2+ handling and systemic sympathetic burden, presenting a novel biomarker for monitoring response to pharmacological and mechanical CHF therapy.

Activation of autophagy improves post-infarction myocardial function in mice.

Both cardiovascular disease and aging are associated with changes in the sympathetic nervous system. Indeed, mounting evidence indicates that adrenergic receptors are functionally involved in numerous processes underlying both aging and cardiovascular disorders, in particular heart failure. This article will review the pathophysiological role of the sympathetic nervous system in heart failure and cardiovascular aging., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Calcium (Ca2+) released from the sarcoplasmic reticulum (SR) is crucial for excitation-contraction (E-C) coupling. Mitochondria, the major source of energy, in the form of ATP, required for cardiac contractility, are closely interconnected with the SR, and Ca2+ is essential for optimal function of these organelles. However, Ca2+ accumulation can impair mitochondrial function, leading to reduced ATP production and increased release of reactive oxygen species (ROS). Oxidative stress contributes to heart failure (HF), but whether mitochondrial Ca2+ plays a mechanistic role in HF remains unresolved. Here, we show for the first time, to our knowledge, that diastolic SR Ca2+ leak causes mitochondrial Ca2+ overload and dysfunction in a murine model of postmyocardial infarction HF. There are two forms of Ca2+ release channels on cardiac SR: type 2 ryanodine receptors (RyR2s) and type 2 inositol 1,4,5-trisphosphate receptors (IP3R2s). Using murine models harboring RyR2 mutations that either cause or inhibit SR Ca2+ leak, we found that leaky RyR2 channels result in mitochondrial Ca2+ overload, dysmorphology, and malfunction. In contrast, cardiac-specific deletion of IP3R2 had no major effect on mitochondrial fitness in HF. Moreover, genetic enhancement of mitochondrial antioxidant activity improved mitochondrial function and reduced posttranslational modifications of RyR2 macromolecular complex. Our data demonstrate that leaky RyR2, but not IP3R2, channels cause mitochondrial Ca2+ overload and dysfunction in HF.

Heart failure (HF) disease progression is related to numerous adaptive processes including cardiac fibrosis, hypertrophy and apoptosis by activation of the 'fetal' gene program and downregulation of mRNA signatures, suggesting the importance of molecular mechanisms that suppress mRNA steady-state levels. miRNAs (miRs) are small, noncoding RNAs that bind mRNAs at their 3'-UTRs, leading to mRNA degradation or inhibition of protein translation. Several miRs are unregulated in response to cellular stress and can modify cellular functions such as proliferation, differentiation and programmed death; these miRs are also regulated in cardiac disease. Cardiac resynchronization therapy improves cardiac performance and myocardial mechanical efficiency. In this updated critical appraisal we report on the main miRs that play a key role in response to cardiac resynchronization therapy (i.e., responder vs nonresponder HF patients), focusing on the miR-mediated modulation of cardiac angiogenesis, apoptosis, fibrosis and membrane ionic currents.

Heart failure (HF) and type 2 diabetes mellitus (T2DM) exhibit a well-established interrelationship and a growing prevalence, in particular in elderly people. Cardiac resynchronization therapy (CRT) has been shown to improve myocardial function in patients with HF and cardiac dyssynchrony. However, reports on CRT in diabetic elderly patients are limited and controversial. Therefore, the aim of the present study was to investigate the functional role of T2DM on the effectiveness of CRT at advanced age. In this single-center prospective study, we enrolled 72 HF patients over 75 years old with and without T2DM who underwent CRT implant. Detailed clinical and instrumental data, including cardiac ultrasound analysis, 6-min walk test, and quality-of-life evaluation, were collected at baseline and at 1-year follow-up. At the time of implantation, 44.4 % of patients had T2DM, of which 62.5 % were well controlled with diet and hypoglycemic drugs and 37.5 % were treated by insulin therapy. After 1 year, CRT improved myocardial ventricular geometry and functional capacity in a comparable proportion of diabetic and non-diabetic patients alongside with a similar amelioration in the functional status. Taken together, our findings demonstrate that diabetic patients >75 years old exhibit a response to CRT that is comparable to non-diabetic subjects.

Current therapeutic strategies for acute heart failure (AHF) are based on traditional inotropic agents that are often associated with untoward effects; therefore, finding new effective approaches with a safer profile is dramatically needed. Istaroxime is a novel compound, chemically unrelated to cardiac glycosides, that is currently being studied for the treatment of AHF. Its effects are essentially related to its inotropic and lusitropic positive properties exerted through a dual mechanism of action: activation of the sarcoplasmic reticulum Ca2+ ATPase isoform 2a (SERCA2a) and inhibition of the Na+/K+-ATPase (NKA) activity. The advantages of istaroxime over the available inotropic agents include its lower arrhythmogenic action combined with its capability of increasing systolic blood pressure without augmenting heart rate. However, it has a limited half-life (1 hour) and is associated with adverse effects including pain at the injection site and gastrointestinal issues. Herein, we describe the main mechanism of action of istaroxime and we present a systematic overview of both clinical and preclinical trials testing this drug, underlining the latest insights regarding its adoption in clinical practice for AHF. [ABSTRACT FROM AUTHOR]

microRNAs (miRNA, miRs) play crucial roles in cardiovascular disease regulating numerous processes, including inflammation, cell proliferation, angiogenesis, and cell death. Herein, we present an updated and comprehensive overview of the functional involvement of miRs in the regulation of cardiomyocyte death, a central event in acute myocardial infarction, ischemia/reperfusion, and heart failure. Specifically, in this systematic review we are focusing on necrosis, apoptosis, and autophagy. [ABSTRACT FROM AUTHOR]

Background: Despite primary percutaneous coronary intervention (PPCI) is generally considered the best therapy in older frail adults with ST-segment elevation myocardial infarction (STEMI), the incidence of re-hospitalization for cardiovascular diseases remains significant in these patients. Aims: We hypothesized that thrombus aspiration (TA) before PPCI could be a useful treatment for reducing mortality and rehospitalizations in frail patients undergoing PPCI for STEMI. Methods: We conducted a study comparing PPCI alone vs TA + PPCI in frail STEMI patients. We examined a cohort of consecutive frail patients aged ≥ 65 years with first STEMI treated with PPCI between February 2008 and July 2015 at the Department of Cardiology of the "Cardarelli" Hospital in Naples, Italy. Results: The study was completed by 389 patients (PPCI: 195, TA + PPCI: 194). At 1-month follow-up, the rate of death from any cause was 7.0% in patients treated with PPCI alone vs 3.0% in patients treated with TA + PPCI (p 0.036), whereas death from cardiovascular causes was 6.0% in the PPCI group vs 3.0% in the TA + PPCI group (p 0.028). Equally important, the rate of re-hospitalization due to heart failure was 7.5% in the PPCI group vs 4.0% in TA + PPCI group (p 0.025) and the rate of re-hospitalization due to acute coronary syndrome was 10.0% in the PPCI group vs 4.5% in the TA + PPCI group (p 0.016). Conclusion: These results indicate the importance of TA in the treatment of STEMI in a group of high-risk patients such as elderly with frailty. [ABSTRACT FROM AUTHOR]

Background: Advances in congestive heart failure (CHF) management depend on biomarkers for monitoring disease progression and therapeutic response. During systole, intracellular Ca2+ is released from the sarcoplasmic reticulum into the cytoplasm through type-2 ryanodine receptor/Ca2+ release channels. In CHF, chronically elevated circulating catecholamine levels cause pathological remodeling of type-2 ryanodine receptor/Ca2+ release channels resulting in diastolic sarcoplasmic reticulum Ca2+ leak and decreased myocardial contractility. Similarly, skeletal muscle contraction requires sarcoplasmic reticulum Ca2+ release through type-1 ryanodine receptors (RyR1), and chronically elevated catecholamine levels in CHF cause RyR1-mediated sarcoplasmic reticulum Ca2+ leak, contributing to myopathy and weakness. Circulating B-lymphocytes express RyR1 and catecholamine-responsive signaling cascades, making them a potential surrogate for defects in intracellular Ca2+ handling because of leaky RyR channels in CHF.Methods: Whole blood was collected from patients with CHF, CHF following left-ventricular assist device implant, and controls. Blood was also collected from mice with ischemic CHF, ischemic CHF+S107 (a drug that specifically reduces RyR channel Ca2+ leak), and wild-type controls. Channel macromolecular complex was assessed by immunostaining RyR1 immunoprecipitated from lymphocyte-enriched preparations. RyR1 Ca2+ leak was assessed using flow cytometry to measure Ca2+ fluorescence in B-lymphocytes in the absence and presence of RyR1 agonists that empty RyR1 Ca2+ stores within the endoplasmic reticulum.Results: Circulating B-lymphocytes from humans and mice with CHF exhibited remodeled RyR1 and decreased endoplasmic reticulum Ca2+ stores, consistent with chronic intracellular Ca2+ leak. This Ca2+ leak correlated with circulating catecholamine levels. The intracellular Ca2+ leak was significantly reduced in mice treated with the Rycal S107. Patients with CHF treated with left-ventricular assist devices exhibited a heterogeneous response.Conclusions: In CHF, B-lymphocytes exhibit remodeled leaky RyR1 channels and decreased endoplasmic reticulum Ca2+ stores consistent with chronic intracellular Ca2+ leak. RyR1-mediated Ca2+ leak in B-lymphocytes assessed using flow cytometry provides a surrogate measure of intracellular Ca2+ handling and systemic sympathetic burden, presenting a novel biomarker for monitoring response to pharmacological and mechanical CHF therapy. [ABSTRACT FROM AUTHOR]

Class I phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases activated by cell membrane receptors, either receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs), to catalyze the production of the lipid second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3). These enzymes engage multiple downstream intracellular signaling pathways controlling cell proliferation, survival and migration. In the cardiovascular system, the four class I PI3K isoforms, PI3Ka, PI3Kb, PI3Kd, and PI3Kg are differentially expressed in distinct cell subsets which include cardiomyocytes, fibroblasts, endothelial, and vascular smooth muscle cells as well as leukocytes, suggesting specific functions for distinct PI3K isoenzymes. During the last decades, genetic disruption studies targeting different PI3K genes have elucidated the contribution of specific isoenzymes to cardiac and vascular function regulation, highlighting both beneficial and maladaptive roles. New layers of complexity in the function of PI3Ks have recently emerged, indicating that distinct PI3K isoforms are interconnected by various crosstalk events and can function not only as kinases, but also as scaffold proteins coordinating key signalosomes in cardiovascular health and disease. In this review, we will summarize major breakthroughs in the comprehension of detrimental and beneficial actions of PI3K signaling in cardiovascular homeostasis, and we will discuss recently unraveled cross-talk and scaffold mechanisms as well as the role of the less characterized class II and III PI3K isoforms. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a major cause of death in the developed countries (Murray and Lopez, 1996; Koitabashi and Kass, 2012). Adverse cardiac remodeling that precedes heart muscle dysfunction is characterized by a myriad of molecular changes affecting the cardiomyocyte. Among these, alterations in protein kinase pathways play often an important mediator role since they link upstream pathologic stress signaling with downstream regulatory programs and thus affect both the structural and functional integrity of the heart muscle. In the context of cardiac disease, a profound understanding for the overriding mechanisms that regulate protein kinase activity (protein-protein interactions, post-translational modifications, or targeting via anchoring proteins) is crucial for the development of specific and effective pharmacological treatment strategies targeting the failing myocardium. In this review, we focus on several mechanisms of upstream regulation of Ca2+-calmodulin-dependent protein kinase II that play a relevant pathophysiological role in the development and progression of cardiovascular disease; precise targeting of these mechanisms might therefore represent novel and promising tools for prevention and treatment of HF. [ABSTRACT FROM AUTHOR]

Reversible phosphorylation of amino acid side chains in proteins is a frequently used mechanism in cellular signal transduction and alterations of such phosphorylation patterns are very common in cardiovascular diseases. They reflect changes in the activities of the protein kinases and phosphatases involving signaling pathways. Phosphorylation of serine, threonine, and tyrosine residues has been extensively investigated in vertebrates, whereas reversible histidine phosphorylation, a well-known regulatory signal in lower organisms, has been largely neglected as it has been generally assumed that histidine phosphorylation is of minor importance in vertebrates. More recently, it has become evident that the nucleoside diphosphate kinase isoform B (NDPK-B), an ubiquitously expressed enzyme involved in nucleotide metabolism, and a highly specific phosphohistidine phosphatase (PHP) form a regulatory histidine protein kinase/phosphatase system in mammals. At least three well defined substrates of NDPK-B are known: The β-subunit of heterotrimeric G-proteins (Gb), the intermediate conductance potassium channel SK4 and the Ca2+ conducting TRP channel family member, TRPV5. In each of these proteins the phosphorylation of a specific histidine residue regulates cellular signal transduction or channel activity. This article will therefore summarize our current knowledge on protein histidine phosphorylation and highlight its relevance for cardiovascular physiology and pathophysiology. [ABSTRACT FROM AUTHOR]

This minireview discusses the evidence that the inhibition of p38 mitogen-activated protein kinases (p38 MAPKs) maybe of therapeutic value in heart failure. Most previous experimental studies, as well as past and ongoing clinical trials, have focussed on the role of p38 MAPKs in myocardial infarction and acute coronary syndromes. There is now growing evidence that these kinases are activated within the myocardium of the failing human heart and in the heart and blood vessels of animal models of heart failure. Furthermore, from a philosophical viewpoint the chronic activation of the adaptive stress pathways that lead to the activation of p38 MAPKs in heart failure is analogous to the chronic activation of the sympathetic, renin-aldosterone-angiotensin and neprilysin systems. These have provided some of the most effective therapies for heart failure. This minireview questions whether similar and synergistic advantages would follow the inhibition of p38 MAPKs. [ABSTRACT FROM AUTHOR]

Activation of the adrenergic system has a profound effects on metabolism. Increased circulating catecholamine and activation of the different adrenergic receptors deployed in the various organs produce important metabolic responses which include: (1) increased lipolysis and elevated levels of fatty acids in plasma, (2) increased gluconeogenesis by the liver to provide substrate for the brain, and (3) moderate inhibition of insulin release by the pancreas to conserve glucose and to shift fuel metabolism of muscle in the direction of fatty acid oxidation. These physiological responses, typical of the stress conditions, are demonstrated to be detrimental for the functioning of different organs like the cardiac muscle when they become chronic. Indeed, a common feature of many pathological conditions involving over-activation of the adrenergic system is the development of metabolic alterations which can include insulin resistance, altered glucose and lipid metabolism and mitochondrial dysfunction. These patterns are involved with a variably extent among the different pathologies, however, they are in general strictly correlated to the level of activation of the adrenergic system. Here we will review the effects of the different adrenergic receptors subtypes on the metabolic variation observed in important disease like Heart Failure. [ABSTRACT FROM AUTHOR]

Aging is a complex process characterized by a gradual decline in organ functional reserves, which eventually reduces the ability to maintain homeostasis. An exquisite feature of elderly subjects, which constitute a growing proportion of the world population, is the high prevalence of cardiovascular disorders, which negatively affect both the quality of life and the life expectancy. It is widely acknowledged that physical activity represents one of the foremost interventions capable in reducing the health burden of cardiovascular disease. Interestingly, the benefits of moderate-intensity physical activity have been established both in young and elderly subjects. Herein we provide a systematic and updated appraisal of the literature exploring the pathophysiological mechanisms evoked by physical activity in the elderly, focusing on the functional role of the β adrenergic system. [ABSTRACT FROM AUTHOR]

Lymphocyte G protein–coupled receptor kinase 2 (GRK2) levels are increased in patients with chronic heart failure, and in this condition, they correlate with cardiac function. The aim of this study was to assess the prognostic role of GRK2 during acute cardiac dysfunction in humans. A study was designed to investigate the role of GRK2 levels in patients with acute coronary syndromes. Lymphocyte GRK2 levels were examined at admission and after 24 and 48 hours in 42 patients with acute coronary syndromes, 32 with ST-segment elevation myocardial infarction and 10 with unstable angina as a control group. Echocardiographic parameters of systolic and diastolic function and left ventricular remodeling were evaluated at admission and after 2 years. GRK2 levels increased during ST-segment elevation myocardial infarction and were associated with worse systolic and diastolic function. This association held at 2-year follow-up, when GRK2 was correlated with the ejection fraction and end-systolic volume, indicating a prognostic value for GRK2 levels during acute ST-segment elevation myocardial infarction. In conclusion, lymphocyte GRK2 levels increase during acute myocardial infarction and are associated with worse cardiac function. Taken together, these data indicate that GRK2 could be predictive of ventricular remodeling after myocardial infarction and could facilitate the tailoring of appropriate therapy for high-risk patients. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T-cells (CAR-T) are improving outcomes in pediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukemias and subtypes of non-Hodgkin Lymphoma. As this treatment is being increasingly utilized, a better understanding of the unique toxicities associated with this therapy is warranted. While there is growing knowledge on the diagnosis and treatment of cytokine release syndrome (CRS), relatively little is known about the associated cardiac events that occur with CRS that may result in prolonged length of hospital stay, admission to the intensive care unit for pressor support, or cardiac death. This review focuses on the various manifestations of cardiotoxicity, potential risk factors, real world and clinical trial data on prevalence of reported cardiotoxicity events, and treatment recommendations. [ABSTRACT FROM AUTHOR]

The potential beneficial effects of the antioxidant properties of vitamin C have been investigated in a number of pathological conditions. In this review, we assess both clinical and preclinical studies evaluating the role of vitamin C in cardiac and vascular disorders, including coronary heart disease, heart failure, hypertension, and cerebrovascular diseases. Pitfalls and controversies in investigations on vitamin C and cardiovascular disorders are also discussed. [ABSTRACT FROM AUTHOR]

Arginine (L-arginine), is an amino acid involved in a number of biological processes, including the biosynthesis of proteins, host immune response, urea cycle, and nitric oxide production. In this systematic review, we focus on the functional role of arginine in the regulation of endothelial function and vascular tone. Both clinical and preclinical studies are examined, analyzing the effects of arginine supplementation in hypertension, ischemic heart disease, aging, peripheral artery disease, and diabetes mellitus. [ABSTRACT FROM AUTHOR]