Paul J. Mather

Sepsis-induced cardiomyopathy: a review of pathophysiologic mechanisms

Cardiac dysfunction is a well-recognized complication of severe sepsis and septic shock. Cardiac dysfunction in sepsis is characterized by ventricular dilatation, reduction in ejection fraction and reduced contractility. Initially, cardiac dysfunction was considered to occur only during the “hypodynamic” phase of shock. But we now know that it occurs very early in sepsis even during the “hyperdynamic” phase of septic shock. Circulating blood-borne factors were suspected to be involved in the evolution of sepsis induced cardiomyopathy, but it is not until recently that the cellular and molecular events are being targeted by researchers in a quest to understand this enigmatic process. Septic cardiomyopathy has been the subject of investigation for nearly half a century now and yet controversies exist in understanding it’s pathophysiology. Here, we discuss our understanding of the pathogenesis of septic cardiomyopathy and the complex roles played by nitric oxide, mitochondrial dysfunction, complements and cytokines.

S100A1 Genetically Targeted Therapy Reverses Dysfunction of Human Failing Cardiomyocytes

OBJECTIVES This study investigated the hypothesis whether S100A1 gene therapy can improve pathological key features in human failing ventricular cardiomyocytes (HFCMs). BACKGROUND Depletion of the Ca²⁺-sensor protein S100A1 drives deterioration of cardiac performance toward heart failure (HF) in experimental animal models. Targeted repair of this molecular defect by cardiac-specific S100A1 gene therapy rescued cardiac performance, raising the immanent question of its effects in human failing myocardium. METHODS Enzymatically isolated HFCMs from hearts with severe systolic HF were subjected to S100A1 and control adenoviral gene transfer and contractile performance, calcium handling, signaling, and energy homeostasis were analyzed by video-edge-detection, FURA2-based epifluorescent microscopy, phosphorylation site-specific antibodies, and mitochondrial assays, respectively. RESULTS Genetically targeted therapy employing the human S100A1 cDNA normalized decreased S100A1 protein levels in HFCMs, reversed both contractile dysfunction and negative force-frequency relationship, and improved contractile reserve under beta-adrenergic receptor (β-AR) stimulation independent of cAMP-dependent (PKA) and calmodulin-dependent (CaMKII) kinase activity. S100A1 reversed underlying Ca²⁺ handling abnormalities basally and under β-AR stimulation shown by improved SR Ca²⁺ handling, intracellular Ca²⁺ transients, diastolic Ca²⁺ overload, and diminished susceptibility to arrhythmogenic SR Ca²⁺ leak, respectively. Moreover, S100A1 ameliorated compromised mitochondrial function and restored the phosphocreatine/adenosine-triphosphate ratio. CONCLUSIONS Our results demonstrate for the first time the therapeutic efficacy of genetically reconstituted S100A1 protein levels in HFCMs by reversing pathophysiological features that characterize human failing myocardium. Our findings close a gap in our understanding of S100A1s effects in human cardiomyocytes and strengthen the rationale for future molecular-guided therapy of human HF.

Dynamic Changes in Lymphocyte GRK2 Levels in Cardiac Transplant Patients: A Biomarker for Left Ventricular Function

G protein‐coupled receptor kinase 2 (GRK2), which is upregulated in the failing human myocardium, appears to have a role in heart failure (HF) pathogenesis. In peripheral lymphocytes, GRK2 expression has been shown to reflect myocardial levels. This study represents an attempt to define the role for GRK2 as a potential biomarker of left ventricular function in HF patients. We obtained blood from 24 HF patients before and after heart transplantation and followed them for up to 1 year, also recording hemodynamic data and histological results from endomyocardial biopsies. We determined blood GRK2 protein by Western blotting and enzyme‐linked immunosorbent assay. GRK2 levels were obtained before transplant and at first posttransplant biopsy. GRK2 levels significantly declined after transplant and remained low over the course of the study period. After transplantation, we found that blood GRK2 signifi cantly dropped and remained low consistent with improved cardiac function in the transplanted heart. Blood GRK2 has potential as a biomarker for myocardial function in end‐stage HF. Clin Trans Sci 2010; Volume #: 1–5

Pharmacologic therapy of chronic heart failure.

Over the past 2 decades, investigators have learned more about the pathophysiologic changes that occur in systolic and diastolic dysfunction. Ironically, in some cases, the biologic pathways that have protected the heart during acute dysfunction are the same pathways that cause progressive deleterious effects with chronic activation. In particular, it is the activation of the neurohormonal system that has a significant impact on disease progression. As a result, the neurohormonal system has provided a key target for pharmacologic therapy in patients with heart failure secondary to systolic dysfunction. These targets include the renin-angiotensin-aldosterone system as well as the sympathetic nervous system. Neurohormonal manipulation, however, is often ineffective in the pharmacologic therapy of patients with endstage heart failure, therefore other treatment strategies — including the use of inotropic agents to improve pump function and diuretics to control fluid balance are needed.

Right Ventricular Function in Peripartum Cardiomyopathy at Presentation Is Associated With Subsequent Left Ventricular Recovery and Clinical Outcomes

Background—Peripartum cardiomyopathy has variable disease progression and left ventricular (LV) recovery. We hypothesized that baseline right ventricular (RV) size and function are associated with LV recovery and outcome. Methods and Results—Investigations of Pregnancy-Associated Cardiomyopathy was a prospective 30-center study of 100 peripartum cardiomyopathy women with LV ejection fraction (LVEF) <45% within 13 weeks after delivery. Baseline RV function was assessed by echocardiographic end-diastolic area, end-systolic area, fractional area change, tricuspid annular plane excursion, and RV speckle-tracking longitudinal strain. LV recovery was defined as LVEF of ≥50% at 1 year, persistent severe LV dysfunction as LVEF of ⩽35%, and major events as death, transplant, or LV assist device implantation. RV measurements were feasible for 90 of the 96 patients (94%) with echocardiograms available. Mean baseline LVEF was 36±9%. RV fractional area change was <35% in 38% of patients. Of 84 patients with 1-year follow-up data, 63 (75%) had LV recovery and 11 (13%) had LVEF of ⩽35% or a major event (4 LV assist devices and 2 deaths). Tricuspid annular plane excursion and RV strain did not predict outcome. Baseline RV fractional area change by multivariable analysis was independently associated with subsequent LV recovery and clinical outcome. Conclusions—Peripartum cardiomyopathy patients had a high incidence of LV recovery, but a significant minority had persistent LV dysfunction or a major clinical event by 1 year. RV function per echocardiographic fractional area change at presentation was associated with subsequent LV recovery and clinical outcomes and thus is prognostically important.

Photoplethysmographic Signal to Screen Sleep-Disordered Breathing in Hospitalized Heart Failure Patients: Feasibility of a Prospective Clinical Pathway.

OBJECTIVES The purpose of this study was to evaluate the plethysmographic signal-derived oxygen desaturation index (ODI) as an inpatient screening strategy to identify sleep-disordered breathing (SDB) in patients with congestive heart failure (CHF). BACKGROUND SDB is highly prevalent among patients hospitalized with CHF but is widely underdiagnosed. We evaluated overnight photoplethysmography as a possible screening strategy for hospitalized patients with CHF. METHODS Consecutively admitted heart failure patients with high clinical suspicion of SDB and ODI ≥5 were offered outpatient polysomnography (PSG), which was completed within 4 weeks of discharge. PSG was considered positive if the apnea hypoxia index (AHI) was ≥5. A Bland-Altman plot was used to assess agreement between ODI and AHI. Receiver-operator characteristics were determined for ODI ≥5 and AHI ≥5. RESULTS A screening questionnaire identified 246 of 282 consecutive patients with positive symptoms for SDB. Of these patients, 105 patients were offered further evaluation and 86 had ODI ≥5 (mean ODI 17 ± 17). Among these 86 patients, 68 underwent outpatient PSG within 4 weeks of discharge. PSG showed that 64 (94%) had SDB, with a mean AHI of 28. Inpatient ODI correlated well with PSG-derived AHI. The area under the curve was 0.82 for AHI ≥5. The Bland-Altman plot revealed no major bias. Matthews correlation coefficient revealed that the optimal cut-off for ODI is 5. CONCLUSIONS Screening hospitalized patients with heart failure using targeted inpatient ODI identifies a cohort of patients with a high prevalence of SDB. Our screening strategy provides a potentially cost-effective method for early detection and treatment of SDB.

Obstructive Sleep Apnea in Obese Hospitalized Patients: A Single Center Experience

STUDY OBJECTIVES Obstructive sleep apnea (OSA) is an important health problem associated with significant morbidity and mortality. This condition often is underrecognized in hospitalized patients. The aim of this study was to conduct a clinical pathway evaluation (CPE) among obese patients admitted to a tertiary care hospital. We also assessed oxygen desaturation index (ODI, measured by overnight pulse oximetry) as a potential low-cost screening tool for identifying OSA. METHODS This was a prospective study of 754 patients admitted to an academic medical center between February 2013 and February 2014. Consecutive obese patients (body mass index ≥ 30) admitted to the hospital (medical services) were screened and evaluated for OSA with the snoring, tiredness during daytime, observed apnea, high blood pressure (STOP) questionnaire. The admitting team was advised to perform follow-up evaluation, including polysomnography, if the test was positive. RESULTS A total of 636 patients were classified as high risk and 118 as low risk for OSA. Within 4 w of discharge, 149 patients underwent polysomnography, and of these, 87% (129) were shown to have OSA. An optimal screening cutoff point for OSA (apnea-hypopnea index ≥ 10/h) was determined to be ODI ≥ 10/h [Matthews correlation coefficient = 0.36, 95% confidence interval = 0.24-0.47]. Significantly more hospitalized patients were identified and underwent polysomnography compared with the year prior to introduction of the CPE. CONCLUSIONS Our results indicate that the CPE increased the identification of OSA in this population. Furthermore, ODI derived from overnight pulse oximetry may be a cost-effective strategy to screen for OSA in hospitalized patients.

Sleep Overnight Monitoring for Apnea in Patients Hospitalized with Heart Failure (SOMA-HF Study)

INTRODUCTION Sleep-disordered breathing (SDB) is highly prevalent in hospitalized patients with congestive heart failure (CHF) and the condition is diagnosed and treated in only a minority of these patients. Portable monitoring (PM) is a screening option, but due to costs and the expertise required, many hospitals may find it impractical to implement. We sought to test the utility of an alternative approach for screening hospitalized CHF patients for SDB, high-resolution pulse oximetry (HRPO). METHODS We conducted a prospective controlled trial of 125 consecutive patients admitted to the hospital with CHF. Simultaneous PM and HRPO for a single night was performed. All but one patient were monitored on breathing room air. The HRPO-derived ODI (oxygen desaturation index) was compared with PM-derived respiratory event index (REI) using both receiver operator characteristic (ROC) curve analysis and a Bland-Altman plot. RESULTS Of 105 consecutive CHF patients with analyzable data, 61 (58%) were males with mean age of 64.9 ± 15.1 years and mean body mass index of 30.3 ± 8.3 kg/m2. Of the 105 patients, 10 (9.5%) had predominantly central sleep apnea (central events > 50% of the total events), although central events were noted in 42 (40%) of the patients. The ROC analysis showed an area under the curve of 0.89 for REI > 5 events/h. The Bland-Altman plot showed acceptable agreement with 95% limits of agreement between -28.5 to 33.7 events/h and little bias. CONCLUSIONS We conclude that high-resolution pulse oximetry is a simple and cost-effective screening tool for SDB in CHF patients admitted to the hospital. Such screening approaches may be valuable for large-scale implementation and for the optimal design of interventional trials.

2017 ACC/AHA/HFSA/ISHLT/ACP Advanced Training Statement on Advanced Heart Failure and Transplant Cardiology (Revision of the ACCF/AHA/ACP/HFSA/ISHLT 2010 Clinical Competence Statement on Management of Patients With Advanced Heart Failure and Cardiac Transplant): A Report of the ACC Competency Management Committee

Eric S. Williams, MD, MACC, Chair Jonathan L. Halperin, MD, FACC, Co-Chair Jesse E. Adams III, MD, FACC James A. Arrighi, MD, FACC Eric H. Awtry, MD, FACC Eric R. Bates, MD, FACC John E. Brush Jr, MD, FACC Lori Daniels, MD, MAS, FACC Susan Fernandes, LPD, PA-C Rosario Freeman, MD, MS,

Cardiomyopathy in becker muscular dystrophy: Overview

Becker muscular dystrophy (BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed.