Worsening Heart Function Research Articles

Infiltrating monocytes drive cardiac dysfunction in a cardiomyocyte-restricted mouse model of SARS-CoV-2 infection.

Cardiovascular manifestations of coronavirus disease 2019 (COVID-19) include myocardial injury, heart failure, and myocarditis and are associated with long-term disability and mortality. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antigens are found in the myocardium of COVID-19 patients, and human cardiomyocytes are susceptible to infection in cell or organoid cultures. While these observations raise the possibility that cardiomyocyte infection may contribute to the cardiac sequelae of COVID-19, a causal relationship between cardiomyocyte infection and myocardial dysfunction and pathology has not been established. Here, we generated a mouse model of cardiomyocyte-restricted infection by selectively expressing human angiotensin-converting enzyme 2 (hACE2), the SARS-CoV-2 receptor, in cardiomyocytes. Inoculation of Myh6-Cre Rosa26loxP-STOP-loxP-hACE2 mice with an ancestral, non-mouse-adapted strain of SARS-CoV-2 resulted in viral replication within the heart, accumulation of macrophages, and moderate left ventricular (LV) systolic dysfunction. Cardiac pathology in this model was transient and resolved with viral clearance. Blockade of monocyte trafficking reduced macrophage accumulation, suppressed the development of LV systolic dysfunction, and promoted viral clearance in the heart. These findings establish a mouse model of SARS-CoV-2 cardiomyocyte infection that recapitulates features of cardiac dysfunctions of COVID-19 and suggests that both viral replication and resultant innate immune responses contribute to cardiac pathology.IMPORTANCEHeart involvement after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection occurs in multiple ways and is associated with worse outcomes in coronavirus disease 2019 (COVID-19) patients. It remains unclear if cardiac disease is driven by primary infection of the heart or immune response to the virus. SARS-CoV-2 is capable of entering contractile cells of the heart in a culture dish. However, it remains unclear how such infection affects the function of the heart in the body. Here, we designed a mouse in which only heart muscle cells can be infected with a SARS-CoV-2 strain to study cardiac infection in isolation from other organ systems. In our model, infected mice show viral infection, worse function, and accumulation of immune cells in the heart. A subset of immune cells facilitates such worsening heart function. As this model shows features similar to those observed in patients, it may be useful for understanding the heart disease that occurs as a part of COVID-19.

Abstract 17705: BAG5 Plays a Critical Role in the Regulation of Cellular Oxidative Stress and Heart Function

Introduction: Molecular chaperone and co-chaperone play important roles in maintaining cardiac function by regulating cellular proteostasis and reducing oxidative stress during hypertrophy. Bcl2 binding proteinBAG5 belongs to Bcl-2 associated anthanogene (BAG) family and acts as a co-chaperone to HSP70. Genetic mutation of BAG5 induces dilated cardiomyopathy and arrhythmia. However, the molecular mechanism of BAG5 in heart function is unclear. In this study, we explore the regulatory role of BAG5 in heart function. Hypothesis: We hypothesized that BAG5 is an important Co-chaperone of cardiomyocytes and regulates heart function through the regulation of cellular proteostasis and oxidative stress. Method: We have generated adenovirus to overexpress and knockdown the BAG5 protein in cardiomyocytes. Additionally, we have generated BAG5 knockout mice to test the effect of BAG5 deficiency on cardiac function. Further, we have conducted a proteomics study to explore the role of BAG5 in heart function. Additionally, we tested the role of BAG5 in isoproterenol-induced cardiac hypertrophy. Results: Our results show that deficiency of BAG5 induces cellular hypertrophy and induction of cellular autophagy. Cardiac function analysis by echocardiography shows that the knockdown of BAG5 compromises heart function. Further, a protein interaction study shows that BAG5 participates in several critical heart signaling, including mitochondrial oxphos and glutathione-mediated regulation of oxidative stress. Additionally, we found that the knockdown of BAG5 worsens heart function during isoproterenol treatment. Conclusion: Our study shows a novel function of BAG5 and BAG5 can be exploited in treating cardiac hypertrophy and reducing oxidative stress.

Increased acylcarnitines in infant heart failure indicate fatty acid oxidation inhibition: towards therapeutic options?

Heart failure in adults is characterized by reduction of long-chain fatty acid oxidation in favour of carbohydrate metabolism. This adaptive phenomenon becomes maladaptive because energy conversion decreases and lipid toxic derivatives known to impair cardiac function are accumulating. No data are available concerning metabolic modification in heart failure in children. In order to evaluate the fatty acid oxidation in children suffering from heart failure, acylcarnitine profiles on dried blood spots were obtained from children under 16years old with dilated cardiomyopathy and clinical heart failure (DCM-HF) and control children. Nine children were included in the DCM-HF group and eight in the control group. Acylcarnitine profiles revealed a significant 3.1-fold increase of total acylcarnitines (sum of C3 to C18 acylcarnitine species) in DCM-HF children compared with controls. This result persisted considering the sum of long-chain acylcarnitines (sum of C14 to C18 species), medium-chain acylcarnitines (sum of C8 to C12 species), and short-chain acylcarnitines (sum of C3 to C6 species), respectively, 2.0-, 2.6-, and 1.9-fold increase compared with the control group. A significant linear correlation was found between left ventricular dilatation or ejection fraction and acylcarnitines accumulation. Finally, acylcarnitine ratio C16OH/C16 and C18OH/C18 enhanced in the DCM-HF group, suggesting a diminution of the long-chain hydroxyl acyl-CoA dehydrogenase activity. Our results suggest down-regulation of fatty acid oxidation in children with heart failure. Such lipidomic alteration could worsen heart function and may suggest considering a metabolic treatment of heart failure in children.

#6530 WHAT IS IMPORTANT IN PRIMARY CARDIORENAL INTERACTION SYNDROME

Abstract Background and Aims Renal function is important in congestive heart failure syndrome because existing or secondary-induced renal weakness contributes to the worsening and progression of heart failure. Decreased ejection fraction in acute heart failure leads to more acute kidney damage compared to patients with preserved ejection fraction. Also, heart failure with a drop in the ejection fraction of the left ventricle is not a dominant characteristic of patients with cardiorenal syndrome type 2. A significant risk factor in the first type of cardiorenal syndrome is, among others, age and diabetes. The prevalence of heart failure with preserved ejection fraction and increased left ventricular mass is higher in the elderly. The aim of the work is how to differentiate and which factors predispose the occurrence of the first and second types of primary cardiorenal syndrome. Method 42 subjects, 24 men and 18 women, with an average age of 70.72±9.26 years, with a diagnosis of worsening heart function that led to kidney dysfunction, were analyzed. The first type of cardiorenal syndrome accounted for 57.14% and the second type of cardiorenal syndrome accounted for 42.86%. The study was designed as a cross-sectional comparative study, and the main criterion for the inclusion of subjects was the existence of a new or previously diagnosed clinically manifest cardiovascular disease. Continuous variables are presented with mean values, standard deviations and medians, and categorical variables with frequencies and percentages. The normality of the distribution of continuous variables was determined by the Shapiro-Wilk test. Depending on the normality of the distribution of continuous variables, the comparison of continuous variables between two groups was performed by the student's t-test of unknown samples in the case of normality, or by the Mann-Whitney test in the case that the distribution deviates from normality. Determining the difference in the representation of categorical variable modalities between groups was determined by the chi-squared test. Values of p<0.05 were considered statistically significant. Results Based on everything is done, the following was determined as statistically significant:Patients with CRS2 are statistically significantly older than patients with CRS1 (p<0.05, Student's t-test of independent samples), and they also have a statistically significantly higher value of HDL-C (p<0.05).Patients with diabetes (p = 0.0488) and with sinus rhythm (p = 0.0442) were statistically significantly more represented in patients with CRS1.Patients with CRS1 had statistically significantly higher values of serum urea and serum creatinine compared to patients with CRS2 (p<0.05, Mann-Whitney test).In patients with CRS2, the value of AOPP was statistically significantly higher than in patients with CRS1 (p<0.01, Student's t-test of independent samples). Conclusion The results obtained in our study are related to the assessment of the functional state of the heart and kidneys in primary cardiorenal syndrome type one and two in which the main predisposing factors are age, diabetes and reduction of renal function. By correlation analysis in the second type of cardiorenal syndrome, HDL-C particles were significantly elevated. Although the values of nitrogen products were lower in the second type of cardiorenal syndrome, AOPP stood out as statistically significant in the lower functional class.

Heart failure is associated with accumulation of long chain acylcarnitines in children suffering from cardiomyopathy

Heart failure in adults is characterized by a reduction in beta oxidation of long-chain fatty acids in favor of carbohydrate metabolism. Thus, the reduction of beta oxidation leads to a decrease in energy production and an accumulation of toxic derivatives such as LC acylcarnitines. This lipidomic disturbance has been shown to impair cardiac function, and is called cardiolipotoxicity. No data are available concerning lipid homeostasis modification in heart failure in children. We compared acylcarnitines profiles performed in our centre from 2015 to 2021 in children explored for a non-metabolic dilated cardiomyopathy (DCM) and in control children. Sixteen children aged from 3 months to 15 years old referred to our centre for DCM were included. Eight of them had clinical symptoms of heart failure and elevated NT pro BNP (DCM-HF), while the 8 others had no symptoms of HF and normal NT pro BNP (DCM-N). Sums of total acylcarnitines, as well as sum of long chain, medium chain or short chain acylcarnitines were enhanced in DCM-HF children compared to the control population, and also compared to DCM-N children ( Figure 1 ). C16OH-Car/C16-Car, and C14:1-Car/C12:1-Car ratio were significantly higher in DCM-HF group than in DCM-N group or control group, suggesting a downregulation of specific enzymes of long chain fatty acids beta oxidation. Our results support a reduction of fatty acid oxidation in children with DCM-HF. This metabolic modification needs to be further investigated in a larger scale study. Such lipidomic alteration could worsen heart function and may suggest considering a metabolic treatment of heart failure in children.

Heart failure is associated with accumulation of long chain acylcarnitines in children suffering from cardiomyopathy

Cardiac failure in adults is associated with down regulation of fatty acid beta oxidation and accumulation of long chain (LC) fatty acid derivatives such as LC acylcarnitines [1] , [2] . These lipidomic disturbances have been shown to impair cardiac function [3] . No data are available concerning metabolic modification in heart failure in children. We retrospectively collected acylcarnitines profiles, NT pro BNP, clinical and echographical data and MRI performed in children explored for a non-metabolic cardiomyopathy in our centre from 2015 to 2021. Eighteen children aged from 1 month to 16 years old (median 2.7 years old) met the inclusion criteria. Thirteen were diagnosed for a dilated cardiomyopathy (DCM) [with normal left ventricular ejection fraction (LVEF) for 5 of them], 4 had a hypertrophic cardiomyopathy and 1 suffered from a restrictive cardiomyopathy. Seven children had clinical symptoms of cardiac insufficiency, and nine showed elevation of NT pro BNP. Considering first only children with DCM, sum of total acylcarnitines and sum of LC acylcarnitines were significantly enhanced in patients with impaired LVEF compared to those with normal LVEF (40.0 ± 16.8 vs. 16.2 ± 5.7 μM, P < 0.01, and 4.8 ± 1.6 vs. 3.1 ± 0.7 μM, P < 0.05, respectively). Similarly, considering the whole patients with cardiomyopathy, children with an elevation of NT pro BNP level displayed accumulation of total acylcarnitines and LC acylcarnitines compared to those with a normal NT pro BNP level (38.9 ± 16.9 vs. 15.5 ± 8.2 μM, P < 0.01, and 5.2 ± 2.4 vs. 2.8 ± 1.1 μM, P < 0.01, respectively). Our results suggest alteration of fatty acid oxidation in children with cardiomyopathy and impaired LVEF or elevated NT pro BNP. This metabolic modification needs to be confirmed with a larger scale study. Such lipidomic alteration could worsen heart function, and may suggest considering a metabolic treatment of heart failure in children.

Preliminary Study on the Safety and Efficacy of One-Stop Treatment of Percutaneous LAAO Combined with Coronary Intervention for Higher Risk of Bleeding in Patients with AF Complicated with CHD.

To explore the feasibility, safety, and efficacy of 1-stop treatment of percutaneous left atrial appendage occlusion (LAAO) combined with coronary intervention for patients with nonvalvular atrial fibrillation (AF) complicated with coronary heart disease (CHD). We retrospectively analyzed the clinical data of 6 patients with AF combined with CHD admitted from Zhuhai People's Hospital from April 2017 to June 2018. After the operation, all patients were treated with aspirin (100 mg qd) and clopidogrel (75 mg qd) for 1 year, which is considered long-term use of aspirin/clopidogrel. The effects of LAAO and coronary intervention were evaluated immediately. The location of the left atrial appendage occluder, thrombosis, residual leak, and clinical manifestations were observed during the 90-day follow-up. The patients were implanted with Watchman™ devices and coronary stents. After the operation, the immediate sealing effect was satisfactory. The Watchman occluder was used in accordance with the PASS principle (position, anchor, size, seal), and the coronary intervention was satisfactory. During the operation, there were no device-related thrombosis, tamponade, or vascular complications. Follow-up results showed that in the 6 patients, there were no hemorrhagic strokes, worsening heart function, residual leakage, device-related thrombosis, angina pectoris, myocardial infarction, skin ecchymosis, gastrointestinal bleeding, or cerebral hemorrhage. For patients with nonvalvular AF combined with CHD, the safety and feasibility of 1-stop treatment with left atrial appendage and coronary intervention are reliable, and the curative effects were also satisfactory at short- and medium-term follow-up.

1004 Male mouse offspring of diabetic mothers have worsening heart function with age

The objective of this study is to characterize the post-natal heart function in offspring of diabetic mothers stratified by sex and age. We hypothesize that maternal diabetes will lead to abnormal heart function in her progeny postnatally and will differ in respect to sex and aging. 8-week old CD1 female mice were given with a one-time dose of 150 mg/kg of Streptozotocin or normal saline, respectively. Hyperglycemic and control females were mated with normal CD1 males. A Kaplan-Meier survival curve was used to track survival of offspring in both cohorts. Transthoracic left ventricular (LV) echocardiograms were performed on the (n=7) offspring of diabetic mothers (ODM) and (n=15) offspring of control mothers (OCM) mothers at 4, 8, and 24-28 weeks. High frequency oscillation echocardiograms were performed by a single blinded examiner. Non-parametric data was analyzed through Mann-Whitney tests, Kruskal-Wallis tests, and two-way ANOVA with post-Hoc Tukey test where appropriate. P-values < 0.05 were considered significant. All graphs and analysis performed via GraphPad Prism 8 software. All experiments were approved and performed in accordance with the Institute of Animal Care and Use Committee at Vanderbilt University Medical Center (Protocol #: M1700155-00). ODM have a lower post-natal survival rate than relative controls (77% vs 95% , p < 0.0001). Compared with OCM at 24-28 weeks, male ODM have a lower cardiac output (31.26 +/- 4.45 ml/min vs 21.65 +/- 4.74 ml/min, p<0.001), smaller internal ventricle diameter (1.8 +/- 0.33 mm vs. 1.3 +/- 0.14, p<0.001) and thicker posterior wall (1.77+/-0.19 mm vs. 1.98 +/- 0.11, p<0.001). Male offspring of diabetic mothers demonstrated significant changes in cardiac function and heart size from the male offspring of control mothers at 24-28 weeks old. Female offspring of diabetic mother did not have a significant difference in similar cardiac indices from female offspring of control mothers at 24-28 weeks. Male ODM have an increased vulnerability to abnormal cardiac function parameters that persist overtime than female ODM.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

The effect of 5-day course of hydroxychloroquine and azithromycin combination on QT interval in non-ICU COVID19(+) patients

BackgroundThe combination of Hydroxychloroquine (HCQ) and azithromycin showed effectiveness as a treatment for COVID-19 and is being used widely all around the world. Despite that those drugs are known to cause prolonged QT interval individually there is no study assessing the impact of this combination on electrocardiography (ECG). This study aimed to assess the impact of a 5-day course of HCQ and azithromycin combination on ECG in non-ICU COVID19(+) patients. MethodsIn this retrospective observational study, we enrolled 109 COVID19(+) patients who required non-ICU hospitalization. All patients received 5-day protocol of HCQ and azithromycin combination. On-treatment ECGs were repeated 3-6 h after the second HCQ loading dose and 48-72 h after the first dose of the combination. ECGs were assessed in terms of rhythm, PR interval, QRS duration, QT and QTc intervals. Baseline and on-treatment ECG findings were compared. Demographic characteristics, laboratory results were recorded. Daily phone call-visit or bed-side visit were performed by attending physician. ResultsOf the 109 patients included in the study, the mean age was 57.3 ± 14.4 years and 48 (44%) were male. Mean baseline PR interval was 158.47 ± 25.10 ms, QRS duration was 94.00 ± 20.55 ms, QTc interval was 435.28 ± 32.78 ms, 415.67 ± 28.51, 412.07 ± 25.65 according to Bazett's, Fridericia's and Framingham Heart Study formulas respectively. ∆PR was −2.94 ± 19.93 ms (p = .55), ∆QRS duration was 5.18 ± 8.94 ms (p = .03). ∆QTc interval was 6.64 ± 9.60 ms (p = .5), 10.67 ± 9.9 ms (p = .19), 14.14 ± 9.68 ms (p = .16) according to Bazett's, Fridericia's and Framingham Heart Study formulas respectively. There were no statistically significant differences between QTc intervals. No ventricular tachycardia, ventricular fibrillation or significant conduction delay was seen during follow-up. There was no death or worsening heart function. ConclusionThe 5-day course of HCQ- AZM combination did not lead to clinically significant QT prolongation and other conduction delays compared to baseline ECG in non-ICU COVID19(+) patients.

The tumor suppressor RASSF1A modulates inflammation and injury in the reperfused murine myocardium

Inflammation is a central feature of cardiovascular disease, including myocardial infarction and heart failure. Reperfusion of the ischemic myocardium triggers a complex inflammatory response that can exacerbate injury and worsen heart function, as well as prevent myocardial rupture and mediate wound healing. Therefore, a more complete understanding of this process could contribute to interventions that properly balance inflammatory responses for improved outcomes. In this study, we leveraged several approaches, including global and regional ischemia/reperfusion (I/R), genetically modified mice, and primary cell culture, to investigate the cell type-specific function of the tumor suppressor Ras association domain family member 1 isoform A (RASSF1A) in cardiac inflammation. Our results revealed that genetic inhibition of RASSF1A in cardiomyocytes affords cardioprotection, whereas myeloid-specific deletion of RASSF1A exacerbates inflammation and injury caused by I/R in mice. Cell-based studies revealed that RASSF1A negatively regulates NF-κB and thereby attenuates inflammatory cytokine expression. These findings indicate that myeloid RASSF1A antagonizes I/R-induced myocardial inflammation and suggest that RASSF1A may be a promising target in immunomodulatory therapy for the management of acute heart injury.

Guideline-based Management of Patients With Atrial Fibrillation

Abstract Atrial fibrillation (AF) has become a significant public health concern. An epidemiologic study conducted in 2010 estimated there are over 33.5 million people worldwide diagnosed with AF with that number predicted to rise by 5% annually. In the United States, AF is the primary diagnosis in over 500,000 hospital admissions annually. Guideline-based knowledge of treatment options is imperative in decreasing stroke risk, prevention of worsening heart function, and maintaining quality of life. It is also important for nurse practitioners to have this knowledge to make educated treatment recommendations to keep our patients safe and to help them to set realistic expectations.

2-Arachidonoylglycerol mobilizes myeloid cells and worsens heart function after acute myocardial infarction.

Myocardial infarction (MI) leads to an enhanced release of endocannabinoids and a massive accumulation of neutrophils and monocytes within the ischaemic myocardium. These myeloid cells originate from haematopoietic precursors in the bone marrow and are rapidly mobilized in response to MI. We aimed to determine whether endocannabinoid signalling is involved in myeloid cell mobilization and cardiac recruitment after ischaemia onset. Intravenous administration of endocannabinoid 2-arachidonoylglycerol (2-AG) into wild type (WT) C57BL6 mice induced a rapid increase of blood neutrophil and monocyte counts as measured by flow cytometry. This effect was blunted when using cannabinoid receptor 2 knockout mice. In response to MI induced in WT mice, the lipidomic analysis revealed significantly elevated plasma and cardiac levels of the endocannabinoid 2-AG 24 h after infarction, but no changes in anandamide, palmitoylethanolamide, and oleoylethanolamide. This was a consequence of an increased expression of 2-AG synthesizing enzyme diacylglycerol lipase and a decrease of metabolizing enzyme monoacylglycerol lipase (MAGL) in infarcted hearts, as determined by quantitative RT-PCR analysis. The opposite mRNA expression pattern was observed in bone marrow. Pharmacological blockade of MAGL with JZL184 and thus increased systemic 2-AG levels in WT mice subjected to MI resulted in elevated cardiac CXCL1, CXCL2, and MMP9 protein levels as well as higher cardiac neutrophil and monocyte counts 24 h after infarction compared with vehicle-treated mice. Increased post-MI inflammation in these mice led to an increased infarct size, an impaired ventricular scar formation assessed by histology and a worsened cardiac function in echocardiography evaluations up to 21 days. Likewise, JZL184-administration in a myocardial ischaemia-reperfusion model increased cardiac myeloid cell recruitment and resulted in a larger fibrotic scar size. These findings suggest that changes in endocannabinoid gradients due to altered tissue levels contribute to myeloid cell recruitment from the bone marrow to the infarcted heart, with crucial consequences on cardiac healing and function.

Stress and Inflammation in Coronary Artery Disease: A Review Psychoneuroendocrineimmunology-Based.

Recent findings have deeply changed the current view of coronary heart disease, going beyond the simplistic model of atherosclerosis as a passive process involving cholesterol build-up in the subintimal space of the arteries until their final occlusion and/or thrombosis and instead focusing on the key roles of inflammation and the immune system in plaque formation and destabilization. Chronic inflammation is a typical hallmark of cardiac disease, worsening outcomes irrespective of serum cholesterol levels. Low-grade chronic inflammation correlates with higher incidence of several non-cardiac diseases, including depression, and chronic depression is now listed among the most important cardiovascular risk factors for poor prognosis among patients with myocardial infarction. In this review, we include recent evidence describing the immune and endocrine properties of the heart and their critical roles in acute ischaemic damage and in post-infarct myocardial remodeling. The importance of the central and autonomic regulation of cardiac functions, namely, the neuro-cardiac axis, is extensively explained, highlighting the roles of acute and chronic stress, circadian rhythms, emotions and the social environment in triggering acute cardiac events and worsening heart function and metabolism in chronic cardiovascular diseases. We have also included specific sections related to stress-induced myocardial ischaemia measurements and stress cardiomyopathy. The complex network of reciprocal interconnections between the heart and the main biological systems we have presented in this paper provides a new vision of cardiovascular science based on psychoneuroendocrineimmunology.

The Dipeptidyl Peptidase 4 Substrate CXCL12 Has Opposing Cardiac Effects in Young Mice and Aged Diabetic Mice Mediated by Ca2+ Flux and Phosphoinositide 3-Kinase γ.

Blood glucose-lowering therapies can positively or negatively affect heart function in type 2 diabetes, or they can have neutral effects. Dipeptidyl peptidase 4 (DPP-4) inhibitors lower blood glucose by preventing the proteolytic inactivation of glucagon-like peptide 1 (GLP-1). However, GLP-1 is not the only peptide substrate of DPP-4. Here, we investigated the GLP-1-independent cardiac effects of DPP-4 substrates. Pointing to GLP-1 receptor (GLP-1R)-independent actions, DPP-4 inhibition prevented systolic dysfunction equally in pressure-overloaded wild-type and GLP-1R knockout mice. Likewise, DPP-4 inhibition or the DPP-4 substrates substance P or C-X-C motif chemokine ligand 12 (CXCL12) improved contractile recovery after no-flow ischemia in the hearts of otherwise healthy young adult mice. Either DPP-4 inhibition or CXCL12 increased phosphorylation of the Ca2+ regulatory protein phospholamban (PLN), and CXCL12 directly enhanced cardiomyocyte Ca2+ flux. In contrast, hearts of aged obese diabetic mice (which may better mimic the comorbid patient population) had diminished levels of PLN phosphorylation. In this setting, CXCL12 paradoxically impaired cardiac contractility in a phosphoinositide 3-kinase γ-dependent manner. These findings indicate that the cardiac effects of DPP-4 inhibition primarily occur through GLP-1R-independent processes and that ostensibly beneficial DPP-4 substrates can paradoxically worsen heart function in the presence of comorbid diabetes.

Ataxia telangiectasia mutated kinase deficiency impairs the autophagic response early during myocardial infarction.

Ataxia telangiectasia mutated kinase (ATM) is activated in response to DNA damage. We have previously shown that ATM plays a critical role in myocyte apoptosis and cardiac remodeling after myocardial infarction (MI). Here, we tested the hypothesis that ATM deficiency results in autophagic impairment in the heart early during MI. MI was induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. Structural and biochemical parameters of the heart were measured 4 h after left anterior descending artery ligation. M-mode echocardiography revealed that MI worsens heart function, as evidenced by reduced percent ejection fraction and fractional shortening in both groups. However, MI-induced increase in left ventricular end-diastolic and end-systolic diameters and volumes were significantly lower in hKO hearts. ATM deficiency resulted in autophagic impairment during MI, as evidenced by decreased microtubule-associated protein light chain 3-II increased p62, decreased cathepsin D protein levels, and increased aggresome accumulation. ERK1/2 activation was only observed in WT-MI hearts. Activation of Akt and AMP-activated protein kinase (AMPK) was lower, whereas activation of glycogen synthase kinase (GSK)-3β and mammalian target of rapamycin (mTOR) was higher in hKO-MI hearts. Inhibition of ATM using KU-55933 resulted in autophagic impairment in cardiac fibroblasts, as evidenced by decreased light chain 3-II protein levels and formation of acidic vesicular organelles. This impairment was associated with decreased activation of Akt and AMPK but enhanced activation of GSK-3β and mTOR in KU-55933-treated fibroblasts. Thus, ATM deficiency results in autophagic impairment in the heart during MI and cardiac fibroblasts. This autophagic impairment may occur via the activation of GSK-3β and mTOR and inactivation of Akt and AMPK. NEW & NOTEWORTHY Ataxia telangiectasia mutated kinase (ATM) plays a critical role in myocyte apoptosis and cardiac remodeling after myocardial infarction (MI). Here, we provide evidence that ATM deficiency results in autophagic impairment during MI. Further investigation of the role of ATM in autophagy post-MI may provide novel therapeutic targets for patients with ataxia telangiectasia suffering from heart disease.

Preliminary Investigation of Cardiovascular-Renal Disorders in Dogs with Chronic Mitral Valve Disease.

BackgroundVeterinary literature lacks data about cardiovascular–renal disorders (CvRD) and cardiorenal‐anemia syndrome (CRAS) in dogs.HypothesisA direct correlation exists between ACVIM class and IRIS stage; chronic kidney disease (CKD) complicates chronic mitral valve disease (CMVD) more often than does anemia in dogs.AnimalsOne hundred and fifty‐eight client‐owned dogs with CMVD.MethodsSignalment, physical examination findings, electrocardiography, thoracic radiographs, echocardiography, and blood analysis were retrospectively evaluated to assess the prevalence of CKD and anemia in dogs with CMVD and to investigate the relationships among ACVIM class, IRIS stage, and survival.ResultsThe prevalence of CKD and anemia in dogs with CMVD was significantly higher than in the general population of dogs. Dogs being treated for heart failure had a significantly higher prevalence of CKD than did dogs that had not received treatment. A statistically significant direct correlation was found between ACVIM class and IRIS stage. Severe heart disease, severe renal disease or both, furosemide administration, and advanced age at diagnosis of heart disease were associated with shorter survival time. Survival time of dogs affected by CvRD was statistically shorter than survival time of dogs affected by CMVD alone.Conclusion and Clinical RelevanceChronic mitral valve disease is associated with increased prevalence of CKD and anemia in dogs. Treatment for medical management of heart failure may play a role in inducing CKD. Class of heart disease and IRIS stage were directly correlated. Cardiovascular–renal disorders decrease survival time compared to the only presence of CMVD alone, whereas anemia does not play a central role in worsening heart function.

Reverse Epidemiology of Blood Pressure in Peritoneal Dialysis Associated with Dynamic Deterioration of Left Ventricular Function.

♦ Reverse epidemiology of blood pressure (BP) in end-stage kidney disease (ESKD) is manifested as higher mortality at lower blood pressure. We hypothesize that this phenomenon is partially mediated by deterioration of cardiac structure and function. ♦ Seventy-seven prevalent ESKD patients starting renal replacement therapy on peritoneal dialysis (PD) from 2007 to 2012 were evaluated for the primary outcome of all-cause mortality. Longitudinal data were obtained from 1,930 patient-encounters including monthly clinic BP and serial echocardiograms. Generalized linear mixed models using data from the last observation moving backward, and time-to-event analysis using time-varying Cox-survival models to estimate mortality risk at different blood pressure categories were applied. ♦ There were 39 males (50.6%). Mean age was 51 years (standard deviation [SD] = 15). During follow-up, 20 patients (25%) died. As compared to systolic blood pressure (SBP) of 140-159 mmHg, unadjusted risk of mortality was 7.3 (95% confidence interval [CI]: 1.5-35.7, p = 0.008) at level < 120 mmHg. Systolic BP trended down to an average of 117 mmHg prior to death in non-survivors as compared to 141 mmHg in survivors (p < 0.05). In non-survivors, percentage with concentric left ventricular hypertrophy (LVH) decreased by 20% at the expense of a 20% reciprocal increase in eccentric hypertrophy associated with a 30% increase in percentage with low ejection fraction (EF) (< 50%). After adjusting for EF, risk of mortality at SBP < 120 mmHg attenuated to 3.4 (95% CI: 0.7-17.7, p = 0.14). ♦ We conclude that higher mortality associated with lower BP may be mediated in part by worsening heart function in ESKD patients receiving PD.

Abstract 243: Echocardiographic Changes of Left Ventricular Geometry and Function Associated with Reverse Epidemiology of Blood Pressure in End Stage Kidney Disease.

Background: We hypothesize that reverse epidemiology of blood pressure (BP) defined as higher mortality associated with lower BP in ESKD is partially mediated by deteriorating left ventricular (LV) function and configuration. Methods: In a prospective observation 2136 patient-visits from 88 consecutive eligible prevalent ESKD patients on peritoneal dialysis from a single center between 2007 and 2012 were assessed. Monthly clinic BP was recorded. Routinely performed 285 interpretable serial echocardiograms were obtained. Patients were followed to primary end-point of all-cause mortality. Generalized linear mixed models using BP from last observation moving backward to assess trends, and time to event analysis using time varying Cox-survival models to estimate mortality hazard ratio of different BP categories were applied. Results: There were 47 males (53.4%). Mean age was 50 years (SD=15). Median follow up was 35 months. During follow up 22 patients (25%) died. As compared to BP of 140-159 mmHg, BP&lt;120 mmHg was associated with 8.6-fold (95% CI: 1.8-40, P=0.006) higher mortality. As compared to survivors who did not show any change, in deceased patients systolic BP (SBP) declined to a statistically lower level 9 months prior to death (117 vs 141 mmHg, P&lt;0.05), left ventricular mass index (LVMI) increased by 40% from 83 to 128 g/m 2 , EF&lt;50% increased by 30%, and concentric left ventricular hypertrophy (LVH) decreased by 20% at the expense of a 20% reciprocal increase in eccentric LVH. After adjusting for LVMI, risk of mortality at SBP&lt;120 mmHg decreased to 4.4 (95% CI: 0.8 to 24, P=0.09). Conclusion: Higher mortality with lower BP was likely mediated by worsening heart function.

Targeting Autophagy for the Therapeutic Application of Histone Deacetylase Inhibitors in Ischemia/Reperfusion Heart Injury

Ischemic heart disease is a leading cause of morbidity and mortality in the United States and other parts of the world. Despite therapeutic breakthroughs over the past decades such as percutaneous coronary intervention, antiplatelet and antithrombotic therapies, and angioplasty, the prevalence of ischemic heart diseases remains extremely high and constitutes a devastating factor for heart failure.1,2 Among various therapeutic strategies for ischemic heart disease, enormous efforts have been made to limit ischemia/reperfusion (I/R) injury, which occurs when the ischemic myocardium is reperfused with oxygen and substrate-rich blood, which paradoxically worsens heart function.2 Ischemic myocardium, with nutrient and oxygen deprivation and buildup of reactive oxygen species (ROS), uses glycolysis as the primary source of metabolic energy. As a consequence, metabolic acidosis, hyperkalemia, and Ca2+ overload develop in cardiomyocytes after coronary artery occlusion, leading not only to cardiomyocyte apoptosis during the acute phase but also to delayed adverse myocardial remodeling, which further compromises cardiac function.2 Therefore, limiting I/R-induced myocardial ROS accumulation and apoptosis benefits both short- and long-term survival and quality of life. Although the mechanism responsible for I/R-induced cardiac abnormalities has been focused largely on necrosis and type I (apoptotic) programmed cell death,2 an intriguing and provocative paradigm has emerged recently that highlights a unique role for dysregulated macroautophagy (hereafter referred to as autophagy) in the heart that may render cardiomyocytes more prone to I/R injury and long-term postinfarction cardiac remodeling.1,3 It has been perceived that autophagy induced by ischemic preconditioning is essential for cardioprotection. To this end, new and innovative strategies to maintain or restore myocardial autophagy homeostasis and its attendant, cardiomyocyte survival, have been the subject of intensive investigation. Article see p 1139 Autophagy is a tightly regulated, lysosome-dependent catabolic process responsible for turnover of long-lived proteins and intracellular …

Voluntary Physical Activity Protects from Susceptibility to Skeletal Muscle Contraction–Induced Injury But Worsens Heart Function in mdx Mice

It is well known that inactivity/activity influences skeletal muscle physiological characteristics. However, the effects of inactivity/activity on muscle weakness and increased susceptibility to muscle contraction-induced injury have not been extensively studied in mdx mice, a murine model of Duchenne muscular dystrophy with dystrophin deficiency. In the present study, we demonstrate that inactivity (ie, leg immobilization) worsened the muscle weakness and the susceptibility to contraction-induced injury in mdx mice. Inactivity also mimicked these two dystrophic features in wild-type mice. In contrast, we demonstrate that these parameters can be improved by activity (ie, voluntary wheel running) in mdx mice. Biochemical analyses indicate that the changes induced by inactivity/activity were not related to fiber-type transition but were associated with altered expression of different genes involved in fiber growth (GDF8), structure (Actg1), and calcium homeostasis (Stim1 and Jph1). However, activity reduced left ventricular function (ie, ejection and shortening fractions) in mdx, but not C57, mice. Altogether, our study suggests that muscle weakness and susceptibility to contraction-induced injury in dystrophic muscle could be attributable, at least in part, to inactivity. It also suggests that activity exerts a beneficial effect on dystrophic skeletal muscle but not on the heart.