Precipitate Heart Failure Research Articles

Abstract P2110: Fibroblast-specific Smad6 Restrains Adverse Remodeling And Dysfunction Following Myocardial Infarction

Signaling induced by the Transforming Growth Factor (TGF)-β superfamily members in fibroblasts plays a central role in repair and remodeling after myocardial infarction (MI). However, TGF-b signals need to be tightly regulated, as excessive or sustained fibroblast activation after MI can accentuate fibrosis, precipitating heart failure. The inhibitory Smads, Smad6 and Smad7, function as endogenous negative regulators that restrain TGF-β and BMP signaling. We have recently demonstrated that fibroblast-specific Smad7 restrains fibrosis after MI acting through TGF-dependent and -independent pathways. However, the role of Smad6 in tissue repair and fibrosis following injury is not known. We hypothesized that Smad6 expression in infarct fibroblasts may play an important role in repair and remodeling of the heart, regulating TGF-b and BMP-mediated responses. In a mouse model of non-reperfused MI, Smad6 expression was increased in infarct fibroblasts and myofibroblasts at 7d post-infarction. To investigate the role of Smad6 in injury and repair, we used CRISPR/Cas9 to generate Smad6 loxp mice. These animals were bred with Col1a2CreER mice to generate fibroblast-specific conditional Smad6 KOs (FS6KO). 7d after MI, FS6KO mice had accentuated systolic and diastolic dysfunction (p<0.01, N=10) associated with scar expansion, accentuated fibrosis, and higher myofibroblast density in the infarct area and border zone. Fibroblast-specific Smad6 loss increased collagen denaturation in the infarct and border zone. In vitro, siRNA knockdown experiments showed that Smad6 suppresses collagen and fibronectin expression, and modulates protease and matricellular gene synthesis. Reactome analysis of RNA-Seq data suggested effects of Smad6 on pathways involved in assembly and crosslinking of collagen fibrils, collagen biosynthesis and degradation, and VEGF-dependent angiogenesis. Furthermore, Ingenuity Pathway Analysis identified signaling by Integrins, Ephrin receptors and Receptor Tyrosine Kinases as key regulators of the effects of Smad6 loss on the fibroblast transcriptome. In conclusion, fibroblast-specific Smad6 restrains adverse remodeling after MI. Ongoing studies explore the molecular mechanisms for the Smad6 effects.

Smad7 effects on TGF-β and ErbB2 restrain myofibroblast activation and protect from postinfarction heart failure.

Repair of the infarcted heart requires TGF-β/Smad3 signaling in cardiac myofibroblasts. However, TGF-β–driven myofibroblast activation needs to be tightly regulated in order to prevent excessive fibrosis and adverse remodeling that may precipitate heart failure. We hypothesized that induction of the inhibitory Smad, Smad7, may restrain infarct myofibroblast activation, and we examined the molecular mechanisms of Smad7 actions. In a mouse model of nonreperfused infarction, Smad3 activation triggered Smad7 synthesis in α-SMA+ infarct myofibroblasts, but not in α-SMA–PDGFRα+ fibroblasts. Myofibroblast-specific Smad7 loss increased heart failure–related mortality, worsened dysfunction, and accentuated fibrosis in the infarct border zone and in the papillary muscles. Smad7 attenuated myofibroblast activation and reduced synthesis of structural and matricellular extracellular matrix proteins. Smad7 effects on TGF-β cascades involved deactivation of Smad2/3 and non-Smad pathways, without any effects on TGF-β receptor activity. Unbiased transcriptomic and proteomic analysis identified receptor tyrosine kinase signaling as a major target of Smad7. Smad7 interacted with ErbB2 in a TGF-β–independent manner and restrained ErbB1/ErbB2 activation, suppressing fibroblast expression of fibrogenic proteases, integrins, and CD44. Smad7 induction in myofibroblasts serves as an endogenous TGF-β–induced negative feedback mechanism that inhibits postinfarction fibrosis by restraining Smad-dependent and Smad-independent TGF-β responses, and by suppressing TGF-β–independent fibrogenic actions of ErbB2.

Abstract MP262: Endogenous Smad7 Restrains Myofibroblast Activation And Protects From Post-infarction Heart Failure By Suppressing Tgf-beta Signaling And By Directly Inhibiting Erbb2

Repair of the infarcted heart requires TGF-β/Smad3 signaling in cardiac myofibroblasts and formation of an organized myofibroblast-populated scar. However, TGF-β-driven myofibroblast activation needs to be tightly regulated to prevent excessive fibrosis and adverse remodeling that may precipitate heart failure. We hypothesized that induction of endogenous suppressive signals, such as the inhibitory Smad7; may restrain infarct myofibroblast activation, protecting from adverse remodeling and fibrosis, and we examined the molecular mechanisms of Smad7 actions. In a mouse model of non-reperfused infarction, Smad3 activation triggered Smad7 synthesis in α-SMA+ infarct myofibroblasts, but not in α-SMA-negative fibroblasts. Mice with myofibroblast-specific Smad7 loss had increased heart failure-related mortality, worse dysfunction, and accentuated fibrosis in the infarct border zone and papillary muscles. In isolated cardiac fibroblasts, Smad7 overexpression attenuated myofibroblast conversion and reduced synthesis of structural and extracellular matrix proteins, whereas Smad7 knockdown promoted a matrix-synthetic phenotype. Smad7 actions on TGF-β cascades involved de-activation of Smad2/3 and non-Smad Erk/Akt pathways, without affecting TGF-β receptor activity. Unbiased transcriptomic analysis identified receptor tyrosine kinase (RTK) signaling as a major target of Smad7. Proteomic arrays demonstrated that the RTK Erbb2 is a target of Smad7 in cardiac fibroblasts. Western blots and co-immunoprecipitation assays showed that Smad7 interacts with Erbb2 in a TGF-independent manner and restrains Erbb1/Erbb2 activation, suppressing expression of fibrogenic proteases, integrins and CD44. In conclusion, Smad7 induction in infarct myofibroblasts serves as an endogenous TGF-β-induced negative feedback mechanism that inhibits post-infarction fibrosis by restraining Smad- dependent and Smad-independent TGF-β responses, and by suppressing TGF-independent fibrogenic actions of Erbb2. Protective effects of Smad7 in cardiac remodeling may have important therapeutic implications for heart failure patients.

ATTD 2021 Invited Speaker Abstracts.

ATTD 2021 Invited Speaker Abstracts.

Psychosocial Stress Hastens Disease Progression and Sudden Death in Mice with Arrhythmogenic Cardiomyopathy.

Physiological stressors, such as exercise, can precipitate sudden cardiac death or heart failure progression in patients with arrhythmogenic cardiomyopathy (ACM). Yet, whether and to what extent a highly prevalent and more elusive environmental factor, such as psychosocial stress (PSS), can also increase ACM disease progression is unexplored. Here, we first quantified perceived stress levels in patients with ACM and found these levels correlated with the extent of arrhythmias and cardiac dysfunction. To determine whether the observed correlation is due to causation, we inflicted PSS-via the resident-intruder (RI) paradigm—upon Desmoglein-2 mutant mice, a vigorously used mammalian model of ACM. We found that ACM mice succumbed to abnormally high in-trial, PSS mortality. Conversely, no sudden deaths occurred in wildtype (WT) counterparts. Desmoglein-2 mice that survived RI challenge manifested markedly worse cardiac dysfunction and remodeling, namely apoptosis and fibrosis. Furthermore, WT and ACM mice displayed similar behavior at baseline, but Desmoglein-2 mice exhibited heightened anxiety following RI-induced PSS. This outcome correlated with the worsening of cardiac phenotypes. Our mouse model demonstrates that in ACM-like subjects, PSS is incisive enough to deteriorate cardiac structure and function per se, i.e., in the absence of any pre-existing anxious behavior. Hence, PSS may represent a previously underappreciated risk factor in ACM disease penetrance.

APPROACH TO THE LEFT SIDED PURKINJE SYSTEM AND LEFT VENTRICLE ENDOCARDIUM DIRECTLY FROM THE RIGHT ATRIUM - POTENTIAL NEW APPROACH TO LBBAP

Right ventricular (RV) pacing-induced dyssynchrony may precipitate heart failure (HF) with impaired left ventricle (LV) systolic function in susceptible patients. LV pacing via coronary sinus or endocardially via transseptal approach has its limitations due to anatomy and requirement for long term anticoagulation respectively. His pacing is promising, as it engages the natural conduction system. However, in patients with LBBB, His pacing may be able to normalize LBBB in about 50% of patients. Pacing the LBB area via the right ventricle has rapidly evolved however engaging the LBB can be challenging due to restrictive short active fixation helix. An alternative is to engage the Purkinje network in the LV septum via the membranous septum from the right atrium (RA) to LV. We sought to determine the anatomic dimensions that could safely guide placement of this RA-LV lead bounded by COMiT (boundaries: Coronary sinus(CS), left ventricular outflow tract (LVOT), Mitral annulus (MA), Tricuspid annulus (TA)).

ASSOCIATION OF TRAUMATIC BRAIN INJURY AND HEART FAILURE: A PROPENSITY WEIGHTED ANALYSIS OF THE NATIONAL INPATIENT SAMPLE

SESSION TITLE: Critical Care Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: The most common cause of death among trauma patients is traumatic brain injury (TBI). Although the exact cause of death is not well understood, it is thought to be a result of cerebral herniation. Associated catecholamine surge commonly precipitates heart failure (HF). We attempted to better characterize the correlation, if any, between TBI and HF. METHODS: A composite database of National Inpatient Sample (NIS) for 2016 and 2017 was queried using ICD-10 codes to identify patients with acute HF among a cohort of patients with TBI. A propensity weighted logistic regression analysis was performed controlling for age, gender, and comorbidities. Propensity weighted cohorts were compared for correlation with HF by age category. RESULTS: Among a cohort of 111,280 patients with traumatic brain injury, mean age was 58.3 +/- 0.15 years, of whom 39.61% were female. A propensity weighted logistic regression model was performed controlling for age, gender, and comorbidity (presence of AICD, Pacemaker, history of chronic heart failure, diabetes, ischemic stroke, COPD, PVD, CKD, OSA, hypertension, CAD). Acute diastolic HF was found to be associated with concussion [OR 1.549, 95% CI (1.002-2.394), p=0.049)]; Takotsubo cardiomyopathy was associated with diffuse TBI [OR 1.840, 95% CI (1.037-3.263), p=0.037)], traumatic cerebral edema in patients 40 years or older [OR 2.311, 95% CI (1.387-3.851), p=0.001)], and subarachnoid hemorrhage [OR 1.510, 95% CI (1.108-2.058), p=0.009)]. CONCLUSIONS: Patients with TBI should be monitored closely for HF development. CLINICAL IMPLICATIONS: Patients with TBI should be monitored closely for HF development. DISCLOSURES: No relevant relationships by Krishna Akella, source=Web Response No relevant relationships by Charles Arcoleo, source=Web Response No relevant relationships by Akella Chendrasekhar, source=Web Response No relevant relationships by Priscilla Chow, source=Web Response No relevant relationships by Kashif Hussain, source=Web Response No relevant relationships by Samer Ibrahim, source=Web Response No relevant relationships by Gunjan Joshi, source=Web Response No relevant relationships by Ghulam Mujtaba, source=Web Response No relevant relationships by Haaris Naji, source=Web Response No relevant relationships by Rajoo Patel, source=Web Response No relevant relationships by Heidi Roppelt, source=Web Response No relevant relationships by Nandini Seshan, source=Web Response No relevant relationships by Howard Sklarek, source=Web Response No relevant relationships by Liana Tatarian, source=Web Response No relevant relationships by Daisy Young, source=Web Response

Atrial Flutter in a Newborn: a Case Report

Abstract Introduction: The incidence of cardiac arrhythmia is approximately 1% in the neonatal period and 1–3% in late pregnancy. Atrial flutter (AF), a rhythm disorder based on the mechanism of reentry, represents approximately 32% of all neonatal cardiac arrhythmias. In the majority of cases, the flutter is converted to sinus rhythm using antiarrhythmic drugs, transesophageal overdrive pacing, or synchronized electrical cardioversion. Case presentation: We present a case of a born on term, female infant who was noted to be tachycardic on the fetal monitor. Clinical examination revealed tachypnea and tachycardia with dysrhythmia, at a heart rate of 250 bpm. Electrocardiography showed AF with 2–3 : 1 atrioventricular conduction (atrial and ventricular rates were 350 bpm and 250–275 bpm, respectively). Echocardiography revealed no relevant structural disease. Therapy with amiodarone and prophylactic anticoagulant was initiated. As no control of ventricular rate was obtained and a succession of three ventricular extrasystoles was noted on the surface ECG, propranolol therapy was initiated, without success. Therefore, synchronized electrical cardioversion was applied, with conversion to sinus rhythm at a heart rate of 136 bpm. The neonate was discharged in good condition. Conclusions: AF is one of the most common high ventricular rate arrhythmias during fetal age. Uncontrolled AF may precipitate heart failure, and prompt restoration to sinus rhythm may require electrical cardioversion in cases refractory to anti-arrhythmic drugs, in order to prevent possible complications.

Impact of Sacubitril and RAAS inhibitors on p53 expression in rat-induced heart failure. A new approach for ischemic heart disease therapy

Background: p53 is a well-known protein that prevents cancer formation, which is recognized as the main protein in the adaptation to many harmful stimuli, like oxidative stress. Among actions of p53, studies have shown that it has an important role in the development of heart failure (HF), and arteriosclerosis. Several clinical studies were done to investigate the role of p53 in the progression of HF and with the intention to improve management of heart failure. Objective: The purpose of this work was to investigate the mechanisms of myocardial injury that precipitates heart failure that is mediated by both β-adrenergic signaling and p53, then compare the results with administered sacubitril and angiotensin system blockers. Methods: Thirty female albino rats were allocated into five groups; group I: served as a control group; group II: were injected with isoproterenol for HF induction; and groups III, IV, and V (HF treated groups ) whereas rats received sacubitril alone, combination of sacubitril with ramipril and combination of sacubitril with aliskiren respectively, orally on daily basis. Results: Results revealed that rats of group II (HF induced) were significantly (P = 0.002) showed more myocardial injury and higher nuclear p53 expression compared to rats of the control group. Furthermore, rats of group III, IV, V (HF treated groups) showed significantly (P = 0.037) less myocardial injury and significantly (P = 0.015) less nuclear p53 expression compared to rats of the group II. Conclusions: It was concluded that rats received either sacubitril alone or with combination of ramipril or aliskiren for HF treatment were alleviated myocardial injury and lower nuclear p53 expression. It was concluded that anti-p53 approach may provide a novel therapeutic strategy for human ischemic heart diseases and myocardial infarction.

Pro-Senescence and Anti-Senescence Mechanisms of Cardiovascular Aging: Cardiac MicroRNA Regulation of Longevity Drug-Induced Autophagy.

Chronological aging as well as biological aging accelerated by various pathologies such as diabetes and obesity contribute to cardiovascular aging, and structural and functional tissue damage of the heart and vasculature. Cardiovascular aging in humans is characterized by structural pathologic remodeling including cardiac and vascular fibrosis, hypertrophy, stiffness, micro- and macro-circulatory impairment, left ventricular diastolic dysfunction precipitating heart failure with either reduced or preserved ejection fraction, and cardiovascular cell death. Cellular senescence, an important hallmark of aging, is a critical factor that impairs repair and regeneration of damaged cells in cardiovascular tissues whereas autophagy, an intracellular catabolic process is an essential inherent mechanism that removes senescent cells throughout life time in all tissues. Several recent reviews have highlighted the fact that all longevity treatment paradigms to mitigate progression of aging-related pathologies converge in induction of autophagy, activation of AMP kinase (AMPK) and Sirtuin pathway, and inhibition of mechanistic target of rapamycin (mTOR). These longevity treatments include health style changes such as caloric restriction, and drug treatments using rapamycin, the first FDA-approved longevity drug, as well as other experimental longevity drugs such as metformin, rapamycin, aspirin, and resveratrol. However, in the heart tissue, autophagy induction has to be tightly regulated since evidence show excessive autophagy results in cardiomyopathy and heart failure. Here we discuss emerging evidence for microRNA-mediated tight regulation of autophagy in the heart in response to treatment with rapamycin, and novel approaches to monitor autophagy progression in a temporal manner to diagnose and regulate autophagy induction by longevity treatments.

Issues of Cardiovascular Risk Management in People With Diabetes in the COVID-19 Era.

People with diabetes compared with people without exhibit worse prognosis if affected by coronavirus disease 2019 (COVID-19) induced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly when compromising metabolic control and concomitant cardiovascular disorders are present. This Perspective seeks to explore newly occurring cardio-renal-pulmonary organ damage induced or aggravated by the disease process of COVID-19 and its implications for the cardiovascular risk management of people with diabetes, especially taking into account potential interactions with mechanisms of cellular intrusion of SARS-CoV-2. Severe infection with SARS-CoV-2 can precipitate myocardial infarction, myocarditis, heart failure, and arrhythmias as well as an acute respiratory distress syndrome and renal failure. They may evolve along with multiorgan failure directly due to SARS-CoV-2-infected endothelial cells and resulting endotheliitis. This complex pathology may bear challenges for the use of most diabetes medications in terms of emerging contraindications that need close monitoring of all people with diabetes diagnosed with SARS-CoV-2 infection. Whenever possible, continuous glucose monitoring should be implemented to ensure stable metabolic compensation. Patients in the intensive care unit requiring therapy for glycemic control should be handled solely by intravenous insulin using exact dosing with a perfusion device. Although not only ACE inhibitors and angiotensin 2 receptor blockers but also SGLT2 inhibitors, GLP-1 receptor agonists, pioglitazone, and probably insulin seem to increase the number of ACE2 receptors on the cells utilized by SARS-CoV-2 for penetration, no evidence presently exists that shows this might be harmful in terms of acquiring or worsening COVID-19. In conclusion, COVID-19 and related cardio-renal-pulmonary damage can profoundly affect cardiovascular risk management of people with diabetes.

Assessing Diastolic Function as an Important Tool for Clinical Decision-making in Critically Ill Patients.

Diastolic dysfunction, which is increasingly seen as being influential in precipitating heart failure and determining prognosis, is often unrecognized. In elderly patients with high rates of comorbidities, determining whether symptoms are attributable to cardiac conditions or other coexisting comorbidities can be clinically challenging. Moreover, in hemodynamically unstable patients, real-time decisions regarding fluid status are critically important. With better understanding and assessment of diastolic function, physicians should be in a better position not only to diagnose diastolic dysfunction or heart failure, but also to manage it more effectively. To optimize this approach, assessing diastolic function at the time of hemodynamic compromise or symptomatic deterioration is essential. In this review, clinical implications of assessing left ventricular diastolic function and filling pressures in critically ill patients will be reviewed with case-based discussions to emphasize how information regarding left ventricular diastolic function and filling pressure can be used for correct diagnosis and proper management of these patients.

A Rare Case of the Dilated Right Atrium in a Newborn

Aneurysms of the right atrium are extremely rare. These aneurysms can be associated with tachyarrhythmia, intracardiac thrombus formation, thromboembolism, and right ventricular compression precipitating heart failure. We report a case of a right atrial aneurysm in a newborn presenting with cardiac failure and multisystem dysfunction.

Effects of copper and temperature on heart mitochondrial hydrogen peroxide production

High energy demand for continuous mechanical work and large number of mitochondria predispose the heart to excessive reactive oxygen species (ROS) production that may precipitate oxidative stress and heart failure. While mitochondria have been proposed as a unifying cellular target and driver of adverse effects induced by diverse stressful states, there is limited understanding of how heart mitochondrial ROS homeostasis is affected by combinations of stress factors. Thus, we probed the effect of copper (Cu) and thermal stress on ROS (as hydrogen peroxide, H2O2) emission and elucidated the effects of Cu on ROS production sites in rainbow trout heart mitochondria using the Amplex UltraRed-horseradish peroxidase detection system optimized for our model. Mitochondria oxidizing malate-glutamate or succinate were incubated at 4, 11 (control) and 23 °C and exposed to a range (1–100 μM) of Cu concentrations. We found that the rates and patterns of H2O2 emission depended on substrate type, Cu concentration and temperature. In mitochondria oxidizing malate-glutamate, Cu increased the rate of H2O2 emission with a spike at 1 μM while temperature had no effect. In contrast, both temperature and Cu increased the rate of H2O2 emission in mitochondria oxidizing succinate with a prominent spike at 25 μM Cu. The rates of H2O2 emission at the three temperatures during the spike imposed by 25 μM Cu were of the order 11 > 23 > 4 °C. Interestingly, 5 μM Cu supressed H2O2 emission in mitochondria oxidizing succinate or malate-glutamate suggesting a common mechanism of action independent of substrate type. In the absence of Cu, the site-specific capacities of H2O2 emission were: complex III outer ubiquinone binding site (site IIIQo) > complex II flavin site (site IIF) ≥ complex I flavin site (site IF) > complex I ubiquinone-binding site (site IQ). Rotenone marginally increased succinate-driven H2O2 emission suggesting either the absence of reverse electron transport (RET)-driven ROS production at site IQ or masking of the expected rotenone response (reduction) by H2O2 produced from other sites. Cu acted at multiple sites in the electron transport system resulting in different site-specific H2O2 emission responses depending on the concentration. Specifically, site IF H2O2 emission was suppressed by Cu concentration-dependently while H2O2 emission by site IIF was inhibited and stimulated by low and high concentrations of Cu, respectively. Additionally, emission from site IIIQo was stimulated by low and inhibited by high Cu concentrations. Overall, our study unveiled distinctive effects and sites of modulation of mitochondrial ROS production by Cu with implications for cardiac redox signaling networks and development of mitochondria-targeted Cu-based drugs.

Heart Failure among People with HIV: Evolving Risks, Mechanisms, and Preventive Considerations.

People with HIV (PHIV) with access to modern antiretroviral therapy (ART) face a two-fold increased risk of heart failure as compared with non-HIV-infected individuals. The purpose of this review is to consider evolving risks, mechanisms, and preventive considerations pertaining to heart failure among PHIV. While unchecked HIV/AIDS has been documented to precipitate heart failure characterized by overtly reduced cardiac contractile function, ART-treated HIV may be associated with either heart failure with reduced ejection fraction (HFrEF) or with heart failure with preserved ejection fraction (HFpEF). In HFpEF, a "stiff" left ventricle cannot adequately relax in diastole-a condition known as diastolic dysfunction. Diastolic dysfunction, in turn, may result from processes including myocardial fibrosis (triggered by hypertension and/or immune activation/inflammation) and/or myocardial steatosis (triggered by metabolic dysregulation). Notably, hypertension, systemic immune activation, and metabolic dysregulation are all common conditions among even those PHIV who are well-treated with ART. Of clinical consequence, HFpEF is uniquely intransigent to conventional medical therapies and portends high morbidity and mortality. However, diastolic dysfunction is reversible-as are contributing processes of myocardial fibrosis and myocardial steatosis. Our challenges in preserving myocardial health among PHIV are two-fold. First, we must continue working to realize UNAIDS 90-90-90 goals. This achievement will reduce AIDS-related mortality, including cardiovascular deaths from AIDS-associated heart failure. Second, we must work to elucidate the detailed mechanisms continuing to predispose ART-treated PHIV to heart failure and particularly HFpEF. Such efforts will enable the development and implementation of targeted preventive strategies.

Cardiac Fibroblast to Myofibroblast Phenotype Conversion-An Unexploited Therapeutic Target.

Fibrosis occurs when the synthesis of extracellular matrix outpaces its degradation, and over time can negatively impact tissue and organ function. In the case of cardiac fibrosis, contraction and relaxation of the heart can be impaired to the point of precipitating heart failure, while at the same time fibrosis can result in arrhythmias due to altered electrical properties of the myocardium. The critical event in the evolution of cardiac fibrosis is the phenotype conversion of cardiac fibroblasts to their overly-active counterparts, myofibroblasts: cells demarked by their expression of novel markers such as periostin, by their gain of contractile activity, and by their pronounced and prolonged increase in the production of extracellular matrix components such as collagens. The phenotype change is dramatic, and can be triggered by many stimuli, including mechanical force, inflammatory cytokines, and growth factors. This review will explore fibroblast to myofibroblast transition mechanisms and will consider the therapeutic potential of targeting this process as a means to arrest or even reverse cardiac fibrosis.

Depolysulfidation of Drp1 induced by low-dose methylmercury exposure increases cardiac vulnerability to hemodynamic overload.

Chronic exposure to methylmercury (MeHg), an environmental electrophilic pollutant, reportedly increases the risk of human cardiac events. We report that exposure to a low, non-neurotoxic dose of MeHg precipitated heart failure induced by pressure overload in mice. Exposure to MeHg at 10 ppm did not induce weight loss typical of higher doses but caused mitochondrial hyperfission in myocardium through the activation of Drp1 by its guanine nucleotide exchange factor filamin-A. Treatment of neonatal rat cardiomyocytes with cilnidipine, an inhibitor of the interaction between Drp1 and filamin-A, suppressed mitochondrial hyperfission caused by low-dose MeHg exposure. Modification of cysteine residues in proteins with polysulfides is important for redox signaling and mitochondrial homeostasis in mammalian cells. We found that MeHg targeted rat Drp1 at Cys624, a redox-sensitive residue whose SH side chain forms a bulky and nucleophilic polysulfide (Cys624-S(n)H). MeHg exposure induced the depolysulfidation of Cys624-S(n)H in Drp1, which led to filamin-dependent activation of Drp1 and mitochondrial hyperfission. Treatment with NaHS, which acts as a donor for reactive polysulfides, reversed MeHg-evoked Drp1 depolysulfidation and vulnerability to mechanical load in rodent and human cardiomyocytes and mouse hearts. These results suggest that depolysulfidation of Drp1 at Cys624-S(n)H by low-dose MeHg increases cardiac fragility to mechanical load through filamin-dependent mitochondrial hyperfission.

HEART FAILURE-EXACERBATING MEDICATION USE IS COMMON BOTH BEFORE AND AFTER A HEART FAILURE HOSPITALIZATION

The American Heart Association (AHA) recently released a comprehensive list of medications that can induce or precipitate heart failure. Usage patterns of these agents at admission and discharge of a HF hospitalization are unknown. We examined adults aged ≥65 years with an adjudicated HF

Effect of Obesity on Left Atrial Strain in Persons Aged 35–55 Years (The Asklepios Study)

Obesity increases the risk of heart failure and atrial fibrillation. Left atrial (LA) dysfunction is increasingly recognized as a mediator of cardiovascular disease. Early effects of obesity on LA function have not been examined in large population samples. We quantified LA strain and strain rate (SR) through speckle tracking echocardiography in 1,531 middle-aged community-based participants enrolled in the Asklepios study. We compared LA function between individuals with body mass index (BMI) < 25 kg/m2 (n = 779), 25 to 29.9 kg/m2 (n = 618) and ≥ 30 kg/m2 (n = 134). Significant differences in reservoir longitudinal LA strain (BMI < 25 kg/m2 = 35.3%, BMI 25-29.9 kg/m2 = 33.1%, and BMI ≥ 30 kg/m2 = 30.9%; p < 0.00001) strain rate ([SR] BMI < 25 kg/m2 = 151; BMI 25 to 29.9 kg/m2 = 141; and BMI ≥ 30 kg/m2 = 135 %/s; p <0.00001) and expansion index (BMI < 25 kg/m2 = 1.6, BMI 25 to 29.9 kg/m2 = 1.4, and BMI ≥ 30 kg/m2 = 1.4; p <0.00001) were seen, indicating reduced reservoir function with increasing BMI. Obesity was also associated with impaired LA conduit function, including conduit longitudinal LA strain (BMI < 25 kg/m2 = 21.6%, BMI 25 to 29.9 kg/m2 = 18.9%, and BMI ≥ 30 kg/m2 = 16.7%; p <0.00001), SR (BMI < 25 kg/m2 = -189, BMI 25 to 29.9 kg/m2 = 166, and BMI ≥ 30 kg/m2 = 150 %/s; p <0.0001) and passive LA emptying fraction (BMI < 25 kg/m2 = 40.5, BMI 25 to 29.9 kg/m2 = 36.5, and BMI ≥ 30 kg/m2 = 36%, p <0.00001). These differences persisted after adjustment for age, gender and other potential confounders. In contrast to reservoir and conduit function, obesity was associated with increased booster pump function (active LA emptying fraction: BMI < 25 kg/m2 = 19.4%, BMI 25 to 29.9 kg/m2 = 20.5%, and BMI ≥ 30 kg/m2 = 21.5%; p <0.00001). In middle-aged adults, obesity is associated with impaired reservoir and conduit LA function and higher booster function, which may be compensatory. Loss of booster LA function, either because of more advanced LA dysfunction or atrial fibrillation, may play an important role in precipitating heart failure in obese individuals.

Abstract 16718: Electronic Cigarette Aerosols Alter Cardiac Expression of Genes Key to Electrical and Structural Remodeling in Mice

Background: Electronic cigarette (e-cig) use has mounted. Some health authorities have even proclaimed e-cigs are profoundly safer than conventional cigarettes. However, e-cigs generate several potentially cardiotoxic constituents by heating their solvent vehicles propylene glycol (PG) and vegetable glycerin (VG) into aerosols to deliver nicotine and flavors. Objectives: To investigate the effects of chronic E-cig exposures, with or without nicotine, on cardiac gene expression compared to mainstream cigarette smoke (MCS). Methods: Healthy C57BL/6J male mice were exposed chronically (12 weeks, 3 hours/day) to e-cig aerosols from an equal-ratio mixture of PG and VG (PG:VG) with nicotine (36 mg/mL) or without nicotine, or to MCS, and compared to filtered air control group (Air). Hearts (n=8/group) were assayed by quantitative PCR for expression of genes associated with electrical and structural remodeling. Results: PG:VG exposure increased gene expression for a gap junction protein (connexin 43, 1.8-fold), voltage-gated potassium and sodium channels (K v 4.3, 2.5-fold; Na v 1.5, 1.6-fold), calcium sequestration protein (sarco/endoplasmic reticulum calcium ATP-ase, 1.4-fold), cytokines (TGFβ1, 1.8-fold; TNF-α, 3.8-fold), and collagen III (3.8-fold) relative to Air (all P &lt; 0.05). Nicotine did not enhance PG:VG’s effects on gene expression relative to PG:VG-alone (all P &gt; 0.05), and cigarette smoke did not significantly affect any of the transcripts assayed (all P &gt; 0.05 vs. Air). Conclusions: E-cigs may induce cardiac electrical and structural remodeling via their primary vehicle ingredients and irrespective of nicotine or flavors. Such effects could precipitate fatal arrhythmia, stroke, and/or heart failure. Electronic nicotine delivery systems may pose cardiac risks distinct from conventional cigarettes.