HIV-associated Cardiomyopathy Research Articles

The role of autophagy in the progression of HIV infected cardiomyopathy.

Although highly active antiretroviral therapy (HAART) has changed infection with human immunodeficiency virus (HIV) from a diagnosis with imminent mortality to a chronic illness, HIV positive patients who do not develop acquired immunodeficiency syndrome (AIDs) still suffer from a high rate of cardiac dysfunction and fibrosis. Regardless of viral load and CD count, HIV-associated cardiomyopathy (HIVAC) still causes a high rate of mortality and morbidity amongst HIV patients. While this is a well characterized clinical phenomena, the molecular mechanism of HIVAC is not well understood. In this review, we consolidate, analyze, and discuss current research on the intersection between autophagy and HIVAC. Multiple studies have linked dysregulation in various regulators and functional components of autophagy to HIV infection regardless of mode of viral entry, i.e., coronary, cardiac chamber, or pericardial space. HIV proteins, including negative regulatory factor (Nef), glycoprotein 120 (gp120), and transactivator (Tat), have been shown to interact with type II microtubule-associated protein-1 β light chain (LC3-II), Rubiquitin, SQSTM1/p62, Rab7, autophagy-specific gene 7 (ATG7), and lysosomal-associated membrane protein 1 (LAMP1), all molecules critical to normal autophagy. HIV infection can also induce dysregulation of mitochondrial bioenergetics by altering production and equilibrium of adenosine triphosphate (ATP), mitochondrial reactive oxygen species (ROS), and calcium. These changes alter mitochondrial mass and morphology, which normally trigger autophagy to clear away dysfunctional organelles. However, with HIV infection also triggering autophagy dysfunction, these abnormal mitochondria accumulate and contribute to myocardial dysfunction. Likewise, use of HAART, azidothymidine and Abacavir, have been shown to induce cardiac dysfunction and fibrosis by inducing abnormal autophagy during antiretroviral therapy. Conversely, studies have shown that increasing autophagy can reduce the accumulation of dysfunctional mitochondria and restore cardiomyocyte function. Interestingly, Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has also been shown to reduce HIV-induced cytotoxicity by regulating autophagy-related proteins, making it a non-antiviral agent with the potential to treat HIVAC. In this review, we synthesize these findings to provide a better understanding of the role autophagy plays in HIVAC and discuss the potential pharmacologic targets unveiled by this research.

HIV-Associated Cardiovascular Disease Pathogenesis: An Emerging Understanding Through Imaging and Immunology.

Cardiac abnormalities were identified early in the epidemic of AIDS, predating the isolation and characterization of the etiologic agent, HIV. Several decades later, the causation and pathogenesis of cardiovascular disease (CVD) linked to HIV infection continue to be the focus of intense speculation. Before the widespread use of antiretroviral therapy, HIV-associated CVD was primarily characterized by HIV-associated cardiomyopathy linked to profound immunodeficiency. With increasing antiretroviral therapy use, viral load suppression, and establishment of immune competency, the effects of HIV on the cardiovascular system are more subtle. Yet, people living with HIV still face an increased incidence of cardiovascular pathology. Advances in cardiac imaging modalities and immunology have deepened our understanding of the pathogenesis of HIV-associated CVD. This review provides an overview of the pathogenesis of HIV-associated CVD integrating data from imaging and immunologic studies with particular relevance to the HIV population originating from high-endemic regions, such as sub-Saharan Africa. The review highlights key evidence gaps in the field and suggests future directions for research to better understand the complex HIV-CVD interactions.

Heart Failure and Myocarditis in a 27-Year-Old Male with Human Immunodeficiency Virus

HIV-associated cardiomyopathy is a complication of HIV infection that affects the structure and function of the heart. Early detection and diagnosis is crucial and routine cardiac workup is recommended with people living with HIV. In this report, we have a 27-year-old, Male, who identifies as gay, with a history of AIDS and has been living with HIV since 5 years from admission with a recent undetectable viral load. He presented with undocumented fever, cough and dyspnea over 7 days nonresponsive to Azithromycin. Multimodality imaging stands in the forefront of diagnosis of HIV-associated Cardiomyopathy and cardiomyopathies in general. Transthoracic 2D echocardiography or Cardiac MRI is recommended on initial evaluation among patients suspected to have the disease in order to identify its specific phenotype. Echocardiography is further recommended in monitoring the progression of the disease and response to therapy. Patient’s initial echocardiogram fulfilled the criteria for DCM with an LVEDD of 59mm and a reduced ejection fraction of 40%. Due to scheduling issues, Cardiac MRI was done 77 days after guideline-directed medical therapy for heart failure with reduced ejection fraction ARNI, beta-blockers, SGLT-2 inhibitors, and diuretics as needed. Results showed significant improvement in ejection fraction to 60%, with resolution of previously seen hypokinesia, but persistence of the LV dilatation with an LV volume index of 121 mL/m2. More importantly, post-contrast imaging on the short axis show that there are linear mid-wall enhancement indicative of non-ischemic patterns of enhancement involving the basal to mid anterior septum, basal to mid inferior septum, basal to mid inferolateral, and basal lateral segments characteristic of a post-myocarditis cause of dilated cardiomyopathy.

Altered cardiac structure and function in newly diagnosed people living with HIV: a prospective cardiovascular magnetic resonance study after the initiation of antiretroviral treatment

HIV associated cardiomyopathy (HIVAC) is a poorly understood entity that may progress along a continuum. We evaluated a group of persons newly diagnosed with HIV and studied the evolution of cardiac abnormalities after ART initiation. We recruited a group of newly diagnosed, ART naïve persons with HIV and a healthy, HIV uninfected group. Participants underwent comprehensive cardiovascular evaluation, including cardiovascular magnetic resonance imaging. The HIV group was started on ART and re-evaluated 9 months later. The cardiovascular parameters of the study groups were compared at diagnosis and after 9 months. The ART naïve group’s (n = 66) left- and right end diastolic volume indexed for height were larger compared with controls (n = 22) (p < 0.03). The left ventricular mass indexed for height was larger in the naïve group compared with controls (p = 0.04). The ART naïve group had decreased left- and right ventricular ejection fraction (p < 0.03) and negative, non-linear associations with high HIV viral load (p = 0.02). The left ventricular size increased after 9 months (p = 0.04), while the systolic function remained unchanged. The HIV group had a high rate of non-resolving pericardial effusions. HIV infected persons demonstrate structurally and functionally altered ventricles at diagnosis. High HIV viral load was associated with left- and right ventricular dysfunction. Cardiac parameters and pericardial effusion prevalence did not show improvement with ART. Conversely, a concerning trend of increase was observed with left ventricular size. These subclinical cardiac abnormalities may represent a stage on the continuum of HIVAC that can progress to symptomatic disease if the causes are not identified and addressed.

The Role of Multimodality Imaging in HIV-Associated Cardiomyopathy.

Despite marked advances in therapeutics, HIV infection remains a leading cause of morbidity and mortality worldwide. HIV infection is associated with cardiovascular complications including myocardial dysfunction. The description of HIV-associated cardiomyopathy (HIVAC) has evolved over time from a predominantly dilated cardiomyopathy with systolic dysfunction to one of subclinical diastolic dysfunction. Multimodality cardiovascular imaging plays an integral role in our understanding of the etiology and pathogenesis of HIVAC. Such imaging is also essential in the evaluation of individuals with chronic HIV disease who present with cardiac symptoms, especially of heart failure. In the present review, we will highlight current evidence for the role of multimodality imaging in establishing the diagnosis, etiology and pathophysiology of HIVAC as well as guiding treatment and assessing prognosis.

Evolution of myocardial oedema and fibrosis in HIV infected persons after the initiation of antiretroviral therapy: a prospective cardiovascular magnetic resonance study

BackgroundHuman immunodeficiency virus (HIV) infected persons on antiretroviral therapy (ART) have been shown to have functionally and structurally altered ventricles and may be related to cardiovascular inflammation. Mounting evidence suggests that the myocardium of HIV infected individuals may be abnormal before ART is initiated and may represent subclinical HIV-associated cardiomyopathy (HIVAC). The influence of ART on subclinical HIVAC is not known.MethodsNewly diagnosed, ART naïve persons with HIV infection were enrolled along with HIV uninfected, age- and sex-matched controls. All participants underwent comprehensive cardiovascular assessment, including contrasted cardiovascular magnetic resonance (CMR) with multiparametric mapping on a 1.5T CMR system. The HIV group was started on ART (tenofovir/lamivudine/dolutegravir) and prospectively evaluated 9 months later. Cardiac tissue characterisation was compared in, and between groups using the appropriate statistical tests for the cross sectional data and the paired, prospective data respectively.ResultsSeventy-three ART naïve HIV infected individuals (32 ± 7 years, 45% female) and 22 healthy non-HIV subjects (33 ± 7 years, 50% female) were enrolled. Compared with non-HIV healthy subjects, the global native T1 (1008 ± 31 ms vs 1032 ± 44 ms, p = 0.02), global T2 (46 ± 2 vs 48 ± 3 ms, p = 0.006), and the prevalence of pericardial effusion (18% vs 67%, p < 0.001) were significantly higher in the HIV infected group at diagnosis. Global native T1 (1032 ± 44 to 1014 ± 34 ms, p < 0.001) and extracellular volume (ECV) (26 ± 4% to 25 ± 3%, p = 0.001) decreased significantly after 9 months on ART and were significantly associated with a decrease in the HIV viral load, decreased high sensitivity C-reactive protein, and improvement in the CD4 count (p < 0.001). Replacement fibrosis was significantly higher in the HIV infected group than controls (49% vs 10%, p = 0.02). The prevalence of late gadolinium enhancement did not change significantly over the 9-month study period (49% vs 55%, p = 0.4).ConclusionSubclinical HIVAC may already be present at the time of HIV diagnosis, as suggested by the combination of subclinical myocardial oedema and fibrosis found to be present before administration of ART. Markers of myocardial oedema on tissue characterization improved on ART in the short term, however, it is unclear if the underlying pathological mechanism is halted, or merely slowed by ART. Mid- to long term prospective studies are needed to evaluate subtle myocardial changes over time and to assess the significance of subclinical myocardial fibrosis.

Abstract 14240: Disparities in Implementation of Advanced Heart Failure Therapies Among Patients With HIV: An Analysis of the NIS Database

Background: Highly active anti-retroviral therapy has transformed human immunodeficiency virus (HIV) infection into a chronic disease. HIV+ patients now experience increased mortality from chronic conditions such as heart failure (HF). Nonetheless, limited data has been published on the implementation of advanced HF therapies among this patient population. The aim of our study is to assess current disparities in therapies among HIV+ patients. Methods: We performed a retrospective analysis using the National Inpatient Database (NIS) from 2011 to 2018 to identify patients admitted for HF exacerbation. Patients were stratified according to HIV status. Baseline characteristics and clinical status were recorded. Primary outcome was implementation of advanced HF therapies (left ventricular assist device, LVAD and/or transplantation, HTX). Multivariate analysis models were adjusted for statistically significant differences in baseline characteristics between the groups. Results: A total of 39,527,306 HF patients were identified, of these 207,394 (0.52%) were HIV+. HF/HIV+ patients were less likely to be females (33.6% vs 49.8%, p &lt; 0.001) and obese (11.6% vs 19.1%, p &lt; 0.001). The prevalence of renal disease (50.9% vs 40.1%, p &lt; 0.001) and dialysis dependance (19.7% vs. 5.2%, p &lt; 0.001) was higher among the HF/HIV+ patients. The use of mechanical circulatory support was lower among HF/HIV+ (0.5% vs 0.7%, p &lt; 0.001), despite higher incidences of cardiogenic shock (1.9% vs 1.8%, p = 0.001) among these patients. HF/HIV+ were less likely to go for LVAD (n=65, 0% vs n=2997, 0.1%, OR = 0.245, p &lt; 0.001) or HTX (n=55, 0% vs n=21,089, 0.1%, OR = 0.266, p &lt; 0.001). Conclusions: Access to advanced HF therapies among patients with HIV-associated cardiomyopathy appears to be limited and unequal. These results should encourage further studies to evaluate the short- and long-term clinical outcomes of advanced HF therapies among HF/HIV+ patients.

The hidden continuum of HIVassociated cardiomyopathy: A focussed review with case reports

HIV-associated cardiomyopathy (HIVAC) is a poorly understood group of diseases with a poor prognosis once ventricular dysfunction is present. Cardiovascular magnetic resonance has revealed a previously unappreciated burden of asymptomatic myocardial abnormalities in people living with HIV, including abnormalities already present at the time of HIV diagnosis. These abnormalities include thickened, inflamed ventricles that bear resemblance to cases of symptomatic HIVAC that are reported on in this article. Our understanding and the significance of asymptomatic HIV-associated myocardial pathology will be explored as early disease on a continuum towards more advanced cardiomyopathy. The need for prospective research in persons naïve to anti-retroviral therapy is emphasised as it may provide key findings to better understand this elusive disease process.

Efficacy of ivabradine in HIV-associated dilated cardiomyopathy.

Ivabradine is a pure heart rate-lowering drug that acts directly on the sinus node and does not affect atrioventricular or intraventricular conduction times, myocardial contractility or ventricular repolarization. Ivabradine is used in the treatment of adults with New York Heart Association (NYHA) class II-IV chronic heart failure (CHF) with systolic dysfunction, in sinus rhythm, with a heart rate of ≥75 beats per minute (bpm). This report describes the beneficial effect of ivabradine on clinical parameters in a HIV-infected patient with dilated cardiomyopathy presenting with NYHA class III CHF symptoms. Ivabradine improved functional capacity and left ventricular (LV) systolic function in our patient with HIV-related dilated cardiomyopathy and CHF. This report also lists the summaries of potential clinically significant interaction, likely to require additional monitoring, alteration of drug dosage or timing of administration, between ivabradine and antiretroviral drugs.

Heart* to Heart*: Thrombosed HeartWare LVAD Exchanged to a Heartmate 3 LVAD

<h3>Introduction</h3> Left ventricular assist devices (LVADs) have undergone technological advances over the past several years, however, device thrombosis remains a feared complication. We present a case of a HeartWare HVAD presenting with pump thrombosis which failed medical therapy and was exchanged for an Abbott HeartMate 3 pump. <h3>Case Report</h3> The patient is a 38-year-old male with end stage-systolic heart failure due to a HIV associated cardiomyopathy who underwent HVAD implantation six years prior to presentation. The patient was in his usual state of health when he presented to the hospital due to a "high watt" alarm. He was asymptomatic. The patient, who was maintained on aspirin and warfarin, had a presenting INR which was subtherapeutic (1.2). Interrogation of the device logs showed an abrupt increase in power up to 9W with flows >10 L/min (baseline ∼4.5W and ∼5.5 L/min) (Figure). Computed tomography (CT) angiogram did not reveal an outflow graft thrombosis but did note pulmonary edema. The patient was diagnosed with pump thrombosis and was initially treated with two doses of alteplase 20 mg (Figure arrows). The power and flow normalized. Multiple lactate dehydrogenase (LDH) specimens were hemolyzed, but the LDH 3 days after admission ultimately was 3,550 U/L (baseline 268 U/L). Two days later, power spikes recurred. The patient was given one dose of alteplase 50 mg without success. The patient underwent emergent exchange to a HeartMate 3 LVAD via a re-do sternotomy. Surgery was notable for the epicardial ring of the HVAD being firmly incorporated at the left ventricular apex. To minimize trauma, the epicardial ring of the HeartMate 3 was sutured directly onto the epicardial ring of the HVAD. The Heartmate 3 was then inserted through both epicardial rings while the outflow graft was anastomosed to the remnant outflow graft of the HVAD. The patient did well post-operatively and was discharged on post-operative day number 15. <h3>Summary</h3> A thrombosed HVAD can be successfully managed with exchange to a HeartMate 3 LVAD.

Etiology and pathophysiology of heart failure in people with HIV.

HIV-associated cardiomyopathy is a well-established sequela in people infected with HIV (PHIV). Despite significant advances in HIV management through the use of highly active anti-retroviral therapy (HAART), PHIV on HAART continue to have elevated risk of cardiomyopathy and heart failure, even when accounting for known cardiovascular risk factors. This review article will explore the proposed mechanisms by which chronic HIV infection induces cardiomyopathy and heart failure in the setting of HAART. Evaluation, work-up, and management of cardiomyopathy in PHIV will also be briefly discussed. The advent of HAART has altered the pathophysiology HIV-associated cardiomyopathy from a rapidly progressive cardiomyopathy, often with pericardial involvement, into a chronic process involving inflammation and persistent immune dysregulation. With the significant decrease in AIDS-related deaths, the prevalence of cardiomyopathy and the mortality associated with heart failure in PHIV have increased. Multiple immune-related and inflammatory mechanisms have been proposed, which may provide insight into evaluation and management of cardiomyopathy in PHIV.

Cardiovascular magnetic resonance imaging reveals asymptomatic cardiomyopathy in newly diagnosed, HIV-infected South African adults

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): University of Stellenbosch Cardiology Research Fund and United States National Institutes of Health/Fogarty International Center Background Cardiovascular disease (CVD) is a leading cause of death and disability in people living with HIV (PLWH). The coronary disease burden in high income countries contrast what is experienced in low- and middle-income countries where cardiomyopathy remains prevalent. Cardiovascular magnetic resonance imaging (CMR) has the unique ability to characterise tissues to obtain "virtual histology". Our data support a high burden of myocardial disease, already present at the time of HIV diagnosis in a young South African cohort. Purpose Early, undiagnosed myocardial pathology in some antiretroviral therapy (ART) naïve persons appear to precede the development of poorly prognostic HIV associated cardiomyopathy. The burden and mechanisms underlying the progression to more advanced disease in treatment naïve PLWH remain largely unknown, as does the modifying effect of ART on these abnormalities. Studying early myocardial disease and its progression with serial CMR evaluation will improve our understanding of disease evolution. Methods 24 newly diagnosed, ART naïve adults without known CVD underwent a contrasted, 1.5T CMR study. Assessments included: Left ventricular (LV) volumes, mass, ejection fraction (EF), native and post-contrast T1 mapping, T2 mapping, extracellular volume (ECV) mapping, and late gadolinium enhancement (LGE) imaging. Quantitative measurements were obtained using a semi-automated software. Qualitative LGE findings were reviewed by an EACVI level III accredited cardiologist. Results The median age of the cohort was 33, interquartile range (IQR) 30-43 years. Median CD4 count was 250, IQR 152-520 cells/uL. All patients had non-dilated LV"s according to indexed end diastolic volumes (Mean: 85 ± 15ml/m²). No patient had overt systolic dysfunction (Mean EF: 62 ± 6%). Non-trivial pericardial effusions were present in 71% of cases. Indexed LV mass measured normal (Mean: 65 ± 12g/m²). Mean global native T1 and T2 values were 1043 ± 46 and 49 ± 4ms respectively. Native T1 values were highest in the septum and inferior wall (Mean: 1054 ± 50 and 1047 ± 51ms respectively). Mean global ECV was 28 ± 4%. Non-ischaemic LGE was present in 71% of participants. In those with LGE, midmyocardial enhancement of the inferior septum represented 71% of abnormalities (Figure). Conclusion In this young cohort of newly diagnosed HIV-infected persons, the prevalence of myocardial abnormalities were high. The midmyocardial LGE and abnormal mapping parameters (high for our scanner and high normal for published data) suggest myocardial inflammation and fibrosis already present at HIV-diagnosis. This was most appreciable in the septum and inferior walls, and likely represents a diffuse process that may progress to symptomatic cardiomyopathy over time. Serial evaluation on ART and comparison with a matched HIV-negative control group is planned. This will allow quantitative comparison of tissue characterisation and explore the nature and evolution of these abnormalities. Abstract Figure. Late gadolinium enhancement (Arrows)

Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies.

Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues, yet its impact upon the heart is unknown. Here, we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy, and we show that a potentially novel mouse model of cardiac-specific prelamin A accumulation exhibited a phenotype consistent with inflammatory cardiomyopathy, which we observed to be similar to HIV-associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings (a) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (b) have implications for the management of HIV patients with cardiac disease, suggesting protease inhibitors should be replaced with alternative therapies (i.e., nonnucleoside reverse transcriptase inhibitors); and (c) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy.

Heart health in the age of highly active antiretroviral therapy: a review of HIV cardiomyopathy.

Advancements in highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) has led to increased survival, approaching that of the general population. These patients are at an increased risk for heart disease, specifically HIV-associated cardiomyopathy. Initially, HIV-associated cardiomyopathy was predominantly noted as systolic dysfunction, but diastolic dysfunction has become more common with increased use of HAART. The pathogenesis of HIV-associated cardiomyopathy involves direct viral infection, cytokine activity, focal myocarditis, HAART side effects, immune system dysregulation, and/or ischemia. If cardiomyopathy is diagnosed, an HIV patient should be started, or continued, on HAART and initiated on guideline-directed medical therapy (GDMT) per the ACC/AHA guidelines. The safety and efficacy of mechanical circulatory support and heart transplant in this population has been repeatedly demonstrated, but it remains less available compared with the general advanced heart failure population. The widespread use of HAART has led to prolonged survival in HIV patients to the point that cardiac disease has become the most common cause of death. Patients should be treated with HAART for HIV and GDMT for heart failure. Patients progressing to end-stage heart failure should be referred for advanced therapies to centers with experience treating HIV patients.

HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy

Cardiovascular disease is a leading cause of co-morbidity in HIV-1 positive patients, even those in whom plasma virus levels are well-controlled. The pathogenic mechanism of HIV-1-associated cardiomyopathy is unknown, but has been presumed to be mediated indirectly, owing to the absence of productive HIV-1 replication in cardiomyocytes. We sought to investigate the effect of the HIV-1 auxiliary protein, Nef, which is suspected of extracellular release by infected CD4+ T cells on protein quality control and autophagy in cardiomyocytes. After detection of Nef in the serum of HIV-1 positive patients and the accumulation of this protein in human and primate heart tissue from HIV-1/SIV-infected cells we employed cell and molecular biology approaches to investigate the effect of Nef on cardiomyocyte-homeostasis by concentrating on protein quality control (PQC) pathway and autophagy. We found that HIV-1 Nef-mediated inhibition of autophagy flux leads to cytotoxicity and death of cardiomyocytes. Nef compromises autophagy at the maturation stage of autophagosomes by interacting with Beclin 1/Rab7 and dysregulating TFEB localization and cellular lysosome content. These effects were reversed by rapamycin treatment. Our results indicate that HIV-1 Nef-mediated inhibition of cellular PQC is one possible mechanism involved in the development of HIV-associated cardiomyopathy.

The Causes of HIV-Associated Cardiomyopathy: A Tale of Two Worlds.

Antiretroviral therapy (ART) has transformed the clinical profile of human immunodeficiency virus (HIV) from an acute infection with a high mortality into a treatable, chronic disease. As a result, the clinical sequelae of HIV infection are changing as patients live longer. HIV-associated cardiomyopathy (HIVAC) is a stage IV, HIV-defining illness and remains a significant cause of morbidity and mortality among HIV-infected individuals despite ART. Causes and clinical manifestations of HIVAC depend on the degree of host immunosuppression. Myocarditis from direct HIV toxicity, opportunistic infections, and nutritional deficiencies are implicated in causing HIVAC when HIV viral replication is unchecked, whereas cardiac autoimmunity, chronic inflammation, and ART cardiotoxicity contribute to HIVAC in individuals with suppressed viral loads. The initiation of ART has dramatically changed the clinical manifestation of HIVAC in high income countries from one of severe, left ventricular systolic dysfunction to a pattern of subclinical cardiac dysfunction characterized by abnormal diastolic function and strain. In low and middle income countries, however, HIVAC is the most common HIV-associated cardiovascular disease. Clear diagnostic and treatment guidelines for HIVAC are currently lacking but should be prioritized given the global burden of HIVAC.

Myocardial Diseases: Current Views on Etiopathogenesis, Diagnostic Modalities, and Therapeutic Options

Myocardial Diseases: Current Views on Etiopathogenesis, Diagnostic Modalities, and Therapeutic Options

Abstract 11016: Bag3 Regulates Contractility and Ca Homeostasis in Adult Mouse Ventricular Myocytes

Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart. BAG3 mutations are associated with familial dilated cardiomyopathy and reduced BAG3 expression was observed in murine transverse aortic constriction and porcine myocardial infarction models. BAG3 is expressed in the sarcolemma and t-tubules in adult myocytes. To simulate reduced BAG3 expression in disease states, we downregulated BAG3 in adult myocytes by shRNA (shBAG3). Despite ~50% reduction in BAG3 by shRNA, expression of α-subunit of L-type Ca channel, SR Ca-ATPase, Na/Ca exchanger, α1- and α2-subunits of Na-K-ATPase, and ryanodine receptor was unchanged. At baseline, BAG3 downregulation had no effect on myocyte contraction and [Ca]i dynamics. After isoproterenol, BAG3 downregulation resulted in reduced myocyte contraction amplitudes, shortening and re-lengthening velocities, lower systolic [Ca]i and [Ca]i transient amplitudes, and prolongation in both APD50 and APD90. L-type Ca current (ICa) and sarcoplasmic reticulum (SR) Ca content but not Na/Ca exchange current or SR Ca uptake were reduced in isoproterenol-treated shBAG3 myocytes. Forskolin or dibutyrl cAMP restored ICa amplitude in shBAG3 myocytes to that observed in WT myocytes. On the other hand, BAG3 overexpression resulted in enhanced myocyte contractility after isoproterenol. In addition, BAG3 overexpression rescued the depressed contraction amplitudes in myocytes overexpressing the HIV protein Tat, and improved myocardial contractility in Tg26 (HIV-1 transgenic) mice. We conclude: (1) BAG3 modulates myocyte contraction, Ca dynamics and action potential duration by regulating ion channels and provides a novel paradigm for contractile dysfunction and increased arrhythmia risks in familial dilated cardiomyopathy; (2) BAG3 is a therapeutic target for cardiomyopathy including HIV-associated cardiomyopathy.

A Case of Severe HIV-Associated Cardiomyopathy: Highlighting Susceptibility, Despite a Reassuring CD4

A Case of Severe HIV-Associated Cardiomyopathy: Highlighting Susceptibility, Despite a Reassuring CD4

HIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-Gp120 aptamer.

HIV-associated cardiomyopathy (HIVCM) is of clinical concern in developing countries because of a high HIV-1 prevalence, especially subtype C, and limited access to highly active antiretroviral therapy (HAART). For these reasons, we investigated the direct and indirect effects of HIV-1 subtype C infection of cultured human cardiomyocytes and the mechanisms leading to cardiomyocytes damage; as well as a way to mitigate the damage. We evaluated a novel approach to mitigate HIVCM using a previously reported gp120 binding and HIV-1 neutralizing aptamer called UCLA1. We established a cell-based model of HIVCM by infecting human cardiomyocytes with cell-free HIV-1 or co-culturing human cardiomyocytes with HIV-infected monocyte derived macrophages (MDM). We discovered that HIV-1 subtype C unproductively (i.e. its life cycle is arrested after reverse transcription) infects cardiomyocytes. Furthermore, we found that HIV-1 initiates apoptosis of cardiomyocytes through caspase-9 activation, preferentially via the intrinsic or mitochondrial initiated pathway. CXCR4 receptor-using viruses were stronger inducers of apoptosis than CCR5 utilizing variants. Importantly, we discovered that HIV-1 induced apoptosis of cardiomyocytes was mitigated by UCLA1. However, UCLA1 had no protective effective on cardiomyocytes when apoptosis was triggered by HIV-infected MDM. When HIV-1 was treated with UCLA1 prior to infection of MDM, it failed to induce apoptosis of cardiomyocytes. These data suggest that HIV-1 causes a mitochondrial initiated apoptotic cascade, which signal through caspase-9, whereas HIV-1 infected MDM causes apoptosis predominantly via the death-receptor pathway, mediated by caspase-8. Furthermore the data suggest that UCLA1 protects cardiomyocytes from caspase-mediated apoptosis, directly by binding to HIV-1 and indirectly by preventing infection of MDM.