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Background: The EF-hand Ca 2+ sensor protein S100A1 has been identified as a molecular regulator and enhancer of cardiac performance. The ability of S100A1 to recognize and modulate the activity of targets such as SERCA2a (sarcoplasmic reticulum Ca 2+ ATPase) and RyR2 (ryanodine receptor 2) in cardiomyocytes has mostly been ascribed to its hydrophobic C-terminal α-helix (residues 75-94). We hypothesized that a synthetic peptide consisting of residues 75 through 94 of S100A1 and an N-terminal solubilization tag (S100A1ct) could mimic the performance-enhancing effects of S100A1 and may be suitable as a peptide therapeutic to improve the function of diseased hearts., Methods: We applied an integrative translational research pipeline ranging from in silico computational molecular modeling and in vitro biochemical molecular assays as well as isolated rodent and human cardiomyocyte performance assessments to in vivo safety and efficacy studies in small and large animal cardiac disease models., Results: We characterize S100A1ct as a cell-penetrating peptide with positive inotropic and antiarrhythmic properties in normal and failing myocardium in vitro and in vivo. This activity translates into improved contractile performance and survival in preclinical heart failure models with reduced ejection fraction after S100A1ct systemic administration. S100A1ct exerts a fast and sustained dose-dependent enhancement of cardiomyocyte Ca 2+ cycling and prevents β-adrenergic receptor-triggered Ca 2+ imbalances by targeting SERCA2a and RyR2 activity. In line with the S100A1ct-mediated enhancement of SERCA2a activity, modeling suggests an interaction of the peptide with the transmembrane segments of the sarcoplasmic Ca 2+ pump. Incorporation of a cardiomyocyte-targeting peptide tag into S100A1ct (cor-S100A1ct) further enhanced its biological and therapeutic potency in vitro and in vivo., Conclusions: S100A1ct is a promising lead for the development of novel peptide-based therapeutics against heart failure with reduced ejection fraction.

Aims: The multi-systemic effects of heart failure (HF) resemble the spread observed during cancer. We propose a new score, named HLM, analogous to the TNM classification used in oncology, to assess the prognosis of HF. HLM refers to H: heart damage, L: lung involvement, and M: systemic multiorgan involvement. The aim was to compare the HLM score to the conventional New York Heart Association (NYHA) classification, American College of Cardiology/American Heart Association (ACC/AHA) stages, and left ventricular ejection fraction (LVEF), to assess the most accurate prognostic tool for HF patients., Methods and Results: We performed a multicentre, observational, prospective study of consecutive patients admitted for HF. Heart, lung, and other organ function parameters were collected. Each patient was classified according to the HLM score, NYHA classification, ACC/AHA stages, and LVEF assessed by transthoracic echocardiography. The follow-up period was 12 months. The primary endpoint was a composite of all-cause death and rehospitalization due to HF. A total of 1720 patients who completed the 12 month follow-up period have been enrolled in the study. 520 (30.2%) patients experienced the composite endpoint of all-cause death and rehospitalization due to HF. 540 (31.4%) patients were female. The mean age of the study population was 70.5 ± 12.9. The mean LVEF at admission was 42.5 ± 13%. Regarding the population distribution across the spectrum of HLM score stages, 373 (21.7%) patients were included in the HLM-1, 507 (29.5%) in the HLM-2, 587 (34.1%) in the HLM-3, and 253 (14.7%) in the HLM-4. HLM was the most accurate score to predict the primary endpoint at 12 months. The area under the receiver operating characteristic curve (AUC) was greater for the HLM score compared with the NYHA classification, ACC/AHA stages, or LVEF, regarding the composite endpoint (HLM = 0.645; NYHA = 0.580; ACC/AHA = 0.589; LVEF = 0.572). The AUC of the HLM score was significantly better compared with the LVEF (P = 0.002), ACC/AHA (P = 0.029), and NYHA (P = 0.009) AUC., Conclusions: The HLM score has a greater prognostic power compared with the NYHA classification, ACC/AHA stages, and LVEF assessed by transthoracic echocardiography in terms of the composite endpoint of all-cause death and rehospitalization due to HF at 12 months of follow-up., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Glucocorticoid treatment remains the cornerstone of therapy for immune checkpoint inhibitor (ICI) myocarditis, but data supporting the use of additional immunotherapy for steroid refractory cases remains limited. We investigate the safety and efficacy of infliximab in patients with ICI myocarditis who are refractory to corticosteroids. Additionally, we highlight the importance of a multi-disciplinary approach in the care for these complex patients., Methods: We retrospectively identified consecutive patients who developed ICI myocarditis at our institution between January 2017 and January 2020. Baseline characteristics, laboratory data and clinical outcomes were compared between patients who received infliximab and those who did not., Results: Of a total of 11 patients who developed ICI myocarditis, 4 were treated with infliximab. Aside from age, there were no significant differences in baseline patient characteristics between the two groups including total number of ICI doses received and duration from initial ICI dose to onset of symptoms. The time to troponin normalization was 58 vs. 151.5 days (p = 0.25). The duration of prednisone taper was longer in the infliximab group (90 vs. 150 days p = 0.32). All patients survived initial hospital admission. Over a median follow-up period of 287 days, two of the 4 patients died from sepsis 2 and 3 months after initial treatment of their myocarditis; one of these patients was on a steroid taper and the other patient had just completed a steroid taper., Conclusions: Infliximab, despite its black box warning in patients with heart failure, may be a safe and effective treatment for ICI myocarditis.

The lifespan assessment and maintenance planning of high-voltage power systems requires condition monitoring of all the operational equipment in a specific area. Electrical insulation of electrical apparatuses is prone to failure due to high electrical stresses, and thus it is a critical aspect that needs to be monitored. The ageing process of the electrical insulation in high voltage equipment may accelerate due to the occurrence of partial discharge (PD) that may in turn lead to catastrophic failures if the related defects are left untreated at an initial stage. Therefore, there is a requirement to monitor the PD levels so that an unexpected breakdown of high-voltage equipment is avoided. There are several ways of detecting PD, such as acoustic detection, optical detection, chemical detection, and radiometric detection. This paper focuses on reviewing techniques based on radiometric detection of PD, and more specifically, using received signal strength (RSS) for the localization of faults. This paper explores the advantages and disadvantages of radiometric techniques and presents an overview of a radiometric PD detection technique that uses a transistor reset integrator (TRI)-based wireless sensor network (WSN).

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are a relatively new class of antihyperglycemic drug with salutary effects on glucose control, body weight, and blood pressure. Emerging evidence now indicates that these drugs may have a beneficial effect on outcomes in heart failure with reduced ejection fraction (HFrEF). Post-approval cardiovascular outcomes data for three of these agents (canagliflozin, empagliflozin, and dapagliflozin) showed an unexpected improvement in cardiovascular endpoints, including heart failure hospitalization and mortality, among patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease or risk factors. These studies were followed by a placebo controlled trial of dapagliflozin in patients with HFrEF both with and without T2DM, showing a reduction in all-cause mortality comparable to current guideline-directed HFrEF medical therapies such as angiotensin-converting enzyme inhibitors and beta-blockers. In this review, we discuss the current landscape of evidence, safety and adverse effects, and proposed mechanisms of action for use of these agents for patients with HFrEF. The United States (US) and European guidelines are reviewed, as are the current US federally approved indications for each SGLT2 inhibitor. Use of these agents in clinical practice may be limited by an uncertain insurance environment, especially in patients without T2DM. Finally, we discuss practical considerations for the cardiovascular clinician, including within-class differences of the SGLT2 inhibitors currently available on the US market (217/300).

Aims: The recent coronavirus disease 19 (COVID-19) pandemic outbreak forced the adoption of restraint measures, which modified the hospital admission patterns for several diseases. The aim of the study is to investigate the rate of hospital admissions for heart failure (HF) during the early days of the COVID-19 outbreak in Italy, compared with a corresponding period during the previous year and an earlier period during the same year., Methods and Results: We performed a retrospective analysis on HF admissions number at eight hospitals in Italy throughout the study period (21 February to 31 March 2020), compared with an inter-year period (21 February to 31 March 2019) and an intra-year period (1 January to 20 February 2020). The primary outcome was the overall rate of hospital admissions for HF. A total of 505 HF patients were included in this survey: 112 during the case period, 201 during intra-year period, and 192 during inter-year period. The mean admission rate during the case period was 2.80 admissions per day, significantly lower compared with intra-year period (3.94 admissions per day; incidence rate ratio, 0.71; 95% confidence interval [CI], 0.56-0.89; P = 0.0037), or with inter-year (4.92 admissions per day; incidence rate ratio, 0.57; 95% confidence interval, 0.45-0.72; P < 0.001). Patients admitted during study period were less frequently admitted in New York Heart Association (NYHA) Class II compared with inter-year period (P = 0.019). At covariance analysis NYHA class was significantly lower in patients admitted during inter-year control period, compared with patients admitted during case period (P = 0.014)., Conclusions: Admissions for HF were significantly reduced during the lockdown due to the COVID-19 pandemic in Italy., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Purpose of Review: Although the utilization of mechanical circulatory support (MCS) devices is increasing, ethical dilemmas regarding device deactivation and dying process persist, potentially complicating delivery of optimal and compassionate care at end-of-life (EOL). This review aims to study EOL challenges, left ventricular assist devices (LVADs) as a nuanced life support treatment, legal history in the US impacting EOL care, and suggestions to improve EOL care for patients on MCS support., Recent Findings: Recent studies have demonstrated challenging aspects of EOL care for patients on LVAD support: low use of advanced directives, high rates of surrogate decision-making due to lack of patient capacity, difficult decision-making involving LVAD deactivation even with cooperating patients, and high rates of death in the hospital and ICU settings. Recent studies also suggest lack of consensus even among clinicians in approaching LVAD deactivation as beliefs equating LVAD deactivation with physician-assisted suicide and/or euthanasia remain. Optimal care at EOL will likely require collaborative efforts among multiple specialties, caregivers, and patients. In light of the complex medical, logistical, and ethical challenges in EOL care for LVAD patients, there is room for improvement by multidisciplinary efforts to reach consensus about LVAD deactivation and best practices for EOL care, development and implementation of LVAD-specific advance planning, and protocols for LVAD deactivation. Programmatic involvement of hospice and palliative care in the continuum of care of LVAD patients has the potential to increase and improve advance care planning, support surrogate decision-making, improve EOL compassionate care, and to support caregivers.

Advanced heart failure (AdHF) represents a challenging aspect of heart failure patients. Because of worsening clinical symptoms, high rates of re-hospitalization and mortality, AdHF represents an unstable condition where standard treatments are inadequate and additional interventions must be applied. A heart transplant is considered the optimal therapy for AdHF, but the great problem linked to the scarcity of organs and long waiting lists have led to the use of mechanical circulatory support with ventricular-assist device (VAD) as a destination therapy. VAD placement improves the prognosis, functional status, and quality of life of AdHF patients, with high rates of survival at 1 year, similar to transplant. However, the key element is to select the right patient at the right moment. The complete assessment must include a careful clinical evaluation, but also take into account psychosocial factors that are of crucial importance in the out-of-hospital management. It is important to distinguish between AdHF and end-stage HF, for which advanced therapy interventions would be unreasonable due to severe and irreversible organ damage and, instead, palliative care should be preferred to improve quality of life and relief of suffering. The correct selection of patients represents a great issue to solve, both ethically and economically., Competing Interests: The authors declare no conflict of interests.

Heart Failure with Preserved Ejection Fraction (HFpEF) is increasing in prevalence due to the aging of the United States population as well as the current obesity epidemic. While obesity is very common in patients with HFpEF, obesity may represent a specific phenotype of HFpEF characterized by unique hemodynamics and structural abnormalities. Obesity induces a systemic inflammatory response that may contribute to myocardial fibrosis and endothelial dysfunction. The most obese patients continue to be excluded from HFpEF clinical trials, and thus ongoing research is needed to determine the role of pharmacologic and interventional approaches in this growing population., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Despite ventricular assist devices (VADs) becoming more common in heart failure (HF) treatment, it is still uncertain which patients are more prone to complications. One potential risk factor is increased body mass index (BMI), which is known to increase both all-cause mortality and mortality from ischemic heart disease; however, the role of the BMI in predicting morbidity and mortality following device implantation is unclear., Methods: The study population for this single-institution retrospective chart review consisted of 136 patients with HF, who underwent VAD implantation between 2004 and 2015. Patients were divided into 2 groups based on their BMI: a nonobese group (18.5 < BMI < 30.0; n = 82) or an obese group (BMI >30.0; n = 54). These groups were compared at baseline and after implantation for survival, hospital readmission, and adverse events., Results: No significant difference was found in initial hospital length of stay, number or length of readmissions, or readmission diagnosis. At 1 year, rates of ongoing device support, orthotopic heart transplant (OHT), and death were not significantly different between groups ( P = .89, P = .90, and P = .70, respectively). Multivariate analysis did not identify obesity as an independent predictor of mortality ( P = .90); only biventricular assist device implantation was associated with decreased survival (hazard ratio [HR] = 5.90, P = .002)., Conclusion: Obesity in itself should not preclude the use of VAD support in patients with HF, as carefully selected obese patients were shown to have similar rates of hospital readmission, 1-year outcomes, and survival following device implantation compared to nonobese patients.

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/m 2 . 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 American Academy of Sleep Medicine)

Aims: Patients with recent onset non-ischaemic cardiomyopathy have a variable clinical course with respect to recovery of left ventricular ejection fraction (LVEF). The aim of this study was to understand whether temporal changes in diastolic function (DF) are associated with clinical outcomes independent of LVEF recovery., Methods and Results: The Intervention in Myocarditis and Acute Cardiomyopathy (IMAC)-2 study was a prospective, multicentre trial investigating myocardial recovery in subjects with symptoms onset of <6 months and LVEF ≤40% of non-ischaemic dilated cardiomyopathy related to idiopathic cardiomyopathy or myocarditis. LVEF and DF were measured at presentation and at 6-month follow-up. Of 147 patients (mean age 46 ± 14 years, 40% female), baseline LVEF was 23 ± 8%. At 6 months, LVEF improved to 41 ± 12%, with 71% increasing by at least 10% ejection fraction units. DF improved in 58%, was unchanged in 28%, and worsened in 14%. Over a mean follow-up of 1.8 ± 1.2 years, there were 18 events: 11 heart failure (HF) hospitalizations, 3 deaths, and 4 heart transplants. LVEF (HR = 0.94, 95% CI 0.91-0.98, P = 0.002) and DF improvements at 6 months (HR = 0.32, 95% CI 0.11-0.92, P = 0.03) were independently associated with lower likelihood for the combined end point of death, transplantation, and HF hospitalization. Diastolic functional improvement at 6-month follow-up was as prognostically important as LVEF recovery for these patients, and provided incremental prognostic value to the risk stratification (X(2) increased from 12.6 to 18, P = 0.02)., Conclusion: In patients with recent onset non-ischaemic cardiomyopathy, DF recovery was associated with favourable outcomes independent of LVEF improvement, adding incremental prognostic value to these patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: Younger age as an independent predictor of death or all-cause rehospitalization at 30 days post-randomization for hospitalized heart failure (HF) patients has not been well described., Methods and Results: ASCEND-HF enrolled 7141 hospitalized acute HF patients (categorized by age: <45, 45 to <55, 55 to <65, 65 to <75, and ≥75 years) and followed them for 30 days to assess clinical outcomes, which included death or rehospitalization. Patients 45 to <55 years had the lowest percentages of death (1.4%) and total rehospitalizations (10.7%); percentages increased for younger (3.0% and 12.2%, respectively, for age <45 y) and older (5.8% and 12.5%, respectively, for age ≥75 y) patients. For those rehospitalized, the total HF-induced readmissions were highest in the youngest (68%) and declined with increasing age (P = .03). Although patients ≥55 years of age were more likely to die or be rehospitalized within 30 days of randomization for each additional 10 years of life, those <55 years of age had a significant reduction in death or HF rehospitalization for each 10-year increase in age (similar findings for death and HF rehospitalization)., Conclusions: There is a dichotomous relationship between age and risk of death or rehospitalization, and death or HF rehospitalization-risk decreases as age increases up to age 55 years, then increases after age 55 years., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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., (© 2016 American Heart Association, Inc.)

We experienced a case with the left atrium almost completely filled with a thrombus after orthotopic heart transplantation while the patient was supported on extracorporeal membrane oxygenation for primary graft failure. The patient had recurrent thrombosis even after successful surgical thrombectomy and appropriate anticoagulation. The cardiac thrombosis resolved only after starting plasmapheresis., (© 2015 Wiley Periodicals, Inc.)

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., (© 2015 American Academy of Sleep Medicine.)

Heart failure is a common syndrome caused by different abnormalities of the cardiovascular system that result in impairment of the ventricles in filling or ejecting blood. It is one of the most common causes of hospitalization in the United States, with a very high cost to the health care system. This article focuses on the causes of left ventricle dysfunction and the presentation and management of heart failure, both acute and chronic., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Despite the advances in medical management of congenital and acquired cardiac disease, heart transplant remains the only curative option for certain patients. Transplant physicians aim to maintain a fine balance between too much and too little immunosuppression, so as to prevent complications such as infections, malignant growths, and toxic effects of drugs on one hand and acute or chronic rejection of the graft on the other hand. The ImmuKnow assay (by Cylex, recently acquired by Viracor-IBT Laboratories, Inc) was first introduced in 2002 by the Food and Drug Administration for detecting cell-mediated global immunity, thus providing an additional tool to help identify patients at risk for infection and rejection. All studies done to date are reviewed to examine the use of ImmuKnow in heart transplant recipients, both adults and children. Advantages and disadvantages are described, as well as areas in need of further investigation and improvement.

Left ventricular assist devices (LVADs) have become an established treatment for patients with advanced heart failure as a bridge to transplantation or for permanent support as an alternative to heart transplantation. Continuous-flow LVADs have been shown to improve outcomes, including survival, and reduce device failure compared with pulsatile devices. Although LVADs have been shown to be a good option for patients with end-stage heart failure, unanticipated complications may occur. We describe dynamic left atrial and left ventricular chamber collapse related to postural changes in a patient with a recent continuous-flow LVAD implantation., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Given the potential for recovery in recent onset nonischemic cardiomyopathy (ROCM), the timing and need for implantable cardioverter-defibrillator (ICDs) remains controversial. We examined the utilization of ICDs and the impact on survival for subjects with ROCM., Methods and Results: An National Heart, Lung, and Blood Institute sponsored registry enrolled 373 subjects with ROCM, all with a left ventricular ejection fraction (LVEF) ≤0.40 and ≤6 months of symptoms. The mean age was 45 ± 14 years, 38% were female, 21% black, 75% New York Heart Association II/III, and the mean LVEF was 0.24 ± 0.08. Survival was comparable for subjects with an ICD within 1 month of entry (n = 43, 1/2/3 year % survival = 97/97/92) and those with no ICD at 1 month (n = 330, % survival = 98/97/95, P = .30) and between those with and without an ICD at 6 months (ICD, n = 73, 1/2/3 year % survival = 98/98/95; no ICD, n = 300, % survival = 98/96/95, P = .95). There were only 6 sudden cardiac deaths (SCD) noted (% survival free from SCD = 99/98/97) and these occurred in 1.9% of subjects without ICD and 0.9% of those with a device (P = .50)., Conclusions: In a multicenter cohort of ROCM the risk of SCD was low at 1% per year. Early ICD placement did not impact survival and can be deferred while assessing potential for myocardial recovery., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Whether myocardial recovery occurs more frequently in peripartum cardiomyopathy (PPCM) than in recent onset cardiomyopathies in men and nonperipartum women has not been prospectively evaluated. This was examined through an analysis of outcomes in the Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC2) registry., Methods and Results: IMAC2 enrolled 373 subjects with recent onset nonischemic dilated cardiomyopathy. Left ventricular ejection fraction (LVEF) was assessed at entry and 6 months, and subjects followed for up to 4 years. Myocardial recovery was compared between men (group 1), nonperipartum women (group 2) and subjects with PPCM (group 3). The cohort included 230 subjects in group 1, 104 in group 2, and 39 in group 3. The mean LVEF at baseline in groups 1, 2, and 3 was 0.23 ± 0.08, 0.24 ± 0.08, and 0.27 ± 0.07 (P = .04), and at 6 months was 0.39 ± 0.12, 0.42 ± 0.11, and 0.45 ± 0.14 (P = .007). Subjects in group 3 had a much greater likelihood of achieving an LVEF >0.50 at 6 months than groups 1 or 2 (19 %, 34%, and 48% respectively, P = .002)., Conclusions: Prospective evaluation confirms myocardial recovery is greatest in women with PPCM, poorest in men, and intermediate in nonperipartum women. On contemporary therapy, nearly half of women with PPCM normalize cardiac function by 6 months., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: We sought to determine clinical and demographic predictors of recovery of left ventricular function for subjects with recent onset cardiomyopathy (ROCM)., Background: Although ROCM is a frequent reason for consultation and transplantation referral, its prognosis and natural history on contemporary therapy are unknown., Methods: In the multicenter IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 study, subjects with a left ventricular ejection fraction (LVEF) of ≤0.40, fewer than 6 months of symptom duration, and an evaluation consistent with idiopathic dilated cardiomyopathy or myocarditis were enrolled. LVEF was reassessed at 6 months, and subjects were followed up for 4 years. LVEF and event-free survival were compared by race, sex, and clinical phenotype., Results: The cohort of 373 persons was 38% female and 21% black, with a mean age of 45 ± 14 years. At entry, 91% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and 82% were receiving beta-blockers, which increased to 92% and 94% at 6 months. LVEF was 0.24 ± 0.08 at entry and 0.40 ± 0.12 at 6 months (mean increase: 17 ± 13 ejection fraction units). Transplant-free survival at 1, 2, and 4 years was 94%, 92%, and 88%, respectively; survival free of heart failure hospitalization was 88%, 82%, and 78%, respectively. In analyses adjusted for sex, baseline LVEF, and blood pressure, LVEF at 6 months was significantly lower in blacks than in nonblacks (p = 0.02). Left ventricular end-diastolic diameter at presentation was the strongest predictor of LVEF at 6 months (p < 0.0001)., Conclusions: Outcomes in ROCM are favorable but differ by race. Left ventricular end-diastolic diameter by transthoracic echo at presentation was most predictive of subsequent myocardial recovery. (Genetic Modulation of Left Ventricular Recovery in Recent Onset Cardiomyopathy; NCT00575211)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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 S100A1's effects in human cardiomyocytes and strengthen the rationale for future molecular-guided therapy of human HF., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Mycotic pseudoaneurysm of the ascending aorta is a rare but potentially life-threatening complication after orthotopic heart transplantation. We present a case of a 53-year-old man who developed a mycotic pseudoaneurysm of the ascending aorta after orthotopic heart transplantation. The pseudoaneurysm was surgically resected and the ascending aorta was replaced with allograft. The Gram stain and multiple cultures of the pseudoaneurysm wall revealed that the causative microorganism was coagulase-negative Staphylococcus. To the best of our knowledge, this is the first case report that describes mycotic pseudoaneurysm owing to coagulase-negative Staphylococcus infection after heart transplantation. Although S aureus and Pseudomonas aeruginosa are common pathogens in previously published literatures describing mycotic pseudoaneurysms in heart transplant recipients, coagulase-negative Staphylococcus is aslo an important and virulent pathogen that can cause mycotic aortic pseudoaneurysm in immunosuppressed patients. Once diagnosed, aggressive surgical treatment with prudent operative strategy, appropriate postoperative antibiotic therapy and close follow-up by radiographic study are mandatory in managing patients with this potentially fatal condition., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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.

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 significantly 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.

In the Adhere (Acute Decompensated Heart Failure Registry) National Registry, hyponatremia (serum sodium <130 mEq/l) at clinical presentation was noted in 5% of patients with HF. The enhanced release of arginine vasopressin (AVP) can lead to hyponatremia by binding to the V2 receptor results in free-water retention and hyponatremia. Given the central role of AVP in causing hyponatremia in patients with congestive heart failure, decreasing vasopressin activity has been a therapeutic focus. With no current therapy to decrease production of AVP, attention was turned to decreasing the effect of AVP by blocking the receptor.

In a national heart failure registry, hyponatremia (serum sodium < 130 mEq/L) was initially reported in 5% of patients and considered a risk factor for increased morbidity and mortality. In a chronic heart failure study, serum sodium level on admission predicted an increased length of stay for cardiovascular causes and increased mortality within 60 days of discharge. Hyponatremia in patients with congestive heart failure (CHF) is associated with a higher mortality rate. Also, by monitoring and increasing serum sodium levels during hospitalization for CHF, patient outcomes may improve. This review describes the pathophysiology of hyponatremia in relation to CHF, including the mechanism of action of vasopressin receptors in the kidney, and assesses the preclinical and clinical trials of vasopressin receptor antagonists--agents recently developed to treat hyponatremia. In hospitalized patients with CHF, hyponatremia plays a major role in poor outcomes. Vasopressin receptor antagonists have been shown to be safe and effective in clinical trials in patients with hyponatremia.

Cardiomyopathy represents a diverse and heterogenous group of disorders affecting the myocardium and ultimately resulting in cardiac dysfunction. The prevalence of heart failure is high (5 million symptomatic patients in the United States) and increasing. Cardiomyopathy is the leading cause of hospitalization in patients older than 65 years of age, resulting in enormous healthcare expenditure and lost productivity. Ischemic cardiomyopathy accounts for about half of these patients, but in several large clinical trials the prevalence of potentially reversible nonischemic cardiomyopathy is also significant, ranging from 20% to 50%. There is epidemiological evidence that the prognosis of these reversible nonischemic cardiomyopathies is better than ischemic or other nonreversible cardiomyopathies. Early and precise diagnosis of the etiology of heart failure is important for determining prognosis and effective treatments.

Heart Failure is the only cardiovascular disease diagnosis increasing in prevalence in the United States. Currently there are more than 5 million people diagnosed with heart failure in the United States and that population is increasing exponentially. Clinical trials in advanced pharmacological therapies have shown a significant value in reducing the morbidity and mortality of the disease process. Nevertheless, many patients who are optimally treated with drug therapy continue to progress from asymptomatic left ventricular dysfunction to symptomatic and then end-stage heart failure. Beyond drug therapy, devices have begun to make a significant impact on symptoms and clinical outcomes in patients, particularly those with more advanced forms of heart failure. New technologies being investigated include destination and bridge LV assist devices. Due to the invasive nature of these devices a new generation of "less invasive" percutaneous devices are now being studied. These new generation devices offer the promise of improved LV function and an enhanced neurohormonal profile for the failing ventricle, thus improving the quality of life in the ever-burgeoning heart failure population.

Heart failure is a growing epidemic with an estimated 5 million Americans suffering from this condition. Several clinical trials have demonstrated a high correlation between congestive heart failure (CHF) and cognitive impairment. The severity of cognitive impairment correlates positively with the degree of CHF. The underlying mechanism for cognitive impairment remains unclear but appears to be related to cerebral hypoperfusion and impaired cerebral reactivity with selective impairment of verbal memory and attention domains. Furthermore, cognitive dysfunction represents one aspect of frailty, a novel concept that encompasses a range of clinical conditions that results in functional impairment in patients with heart failure. In addition, frailty independently predicts mortality in CHF patients. Cognitive impairment is a common and predictable effect of CHF that contributes with social and behavioral problems to decreased compliance to prescribed therapy and increased hospital readmissions. A multidisciplinary approach is necessary to deal with the complexity of this clinical syndrome.

Heart failure is the only cardiovascular disease diagnosis increasing in prevalence in the United States. A number of drugs have been shown to reduce morbidity and mortality in patients with chronic heart failure. Despite these advances, the frequency of hospitalization for heart failure has continued to increase, and clinical trial data are lacking in demonstrable benefit of drug therapy for patients hospitalized with acute, decompensated heart failure. A number of percutaneous devices have been developed and are in various stages of investigation and use to improve symptoms and clinical outcomes in patients hospitalized with heart failure. These include "add-on" devices, such as continuous aortic flow augmentation and ultrafiltration devices, and "rescue" devices to be used in patients who are rapidly deteriorating despite medical therapy. In addition to the intra-aortic balloon pump, newer approaches include percutaneous ventricular assist devices that are available for short-term use to stabilize patients until recovery can occur or as "bridges" to longer-term assist or cardiac transplantation. In the coming years, expanded clinical investigation is likely to explore the potential for devices to normalize underlying cardiac function and thereby improve long-term clinical outcomes.

Congestive heart failure (CHF) is an increasingly common medical condition and the fastest growing cardiovascular diagnosis in North America. Over one-third of patients with heart failure also have renal insufficiency. It has been shown that renal insufficiency confers worsened outcomes to patients with heart failure. However, a majority of the larger and therapy-defining heart failure medication and device trials exclude patients with advanced renal dysfunction. These studies also infrequently perform subgroup analyses based on the degree of renal dysfunction. The lack of information on heart failure patients who have renal insufficiency likely contributes to their being prescribed mortality and morbidity reducing medications and receiving diagnostic and therapeutic procedures at lower rates than heart failure patients with normal renal function. Inclusion of patients with renal insufficiency in heart failure studies and published guidelines for medication, device, and interventional therapies would likely improve patient outcomes.

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.

Background: Although there is an increasing body of evidence for a deleterious effect of mismatched donor HLA antigens on the outcome of human cardiac transplantation, the role of anti-HLA lymphocytotoxic antibodies remains controversial. Thus, their appearance after cardiac transplantation has been associated with poor outcome by some groups; whereas others have reported them to be of no clinical significance. Furthermore, their presence prior to cardiac transplantation has also been the subject of similarly conflicting reports. The deleterious effect of such pre-existing antibodies has been predicted by a positive lymphocyte cross-match (LCM), which, for most patients awaiting renal transplantation and in many requiring a cardiac allograft, leads to cancellation of the operation. The reason for undertaking the current study was to test the hypothesis that the constraints which a positive LCM result impose in preventing renal transplantation may not apply to orthotopic heart transplantation (OHT)., Patients and Methods: Four sensitized patients underwent OHT across a positive prospective LCM. Three were females, and one of those females also underwent cadaveric renal transplantation at the time of OHT. All four patients received aggressive early post-transplant immunosuppressive therapy, which included plasmapheresis, intravenous immunoglobulin (IVIg), antiproliferative agents (cyclophosphamide, basiliximab) and cytokine down-regulators (calcineurin inhibitors, muromonab-CD3) and anticell antibodies (OKT3, ATG). They also received standard immunosuppressive therapy which included corticosteroids. Complement-dependent cytotoxicity (CDC) was used for the identification of anti-HLA lymphocytotoxic antibodies. Reactivity of the latter against more than 10% of a panel of well-characterized T cells was considered sensitization, and required LCM to be performed prospectively, which test was also performed using the CDC technique., Results: Three of the patients exhibited evidence suggestive of acute or hyperacute rejection in endomyocardial biopsy specimens by postoperative day (POD) 7. Two of the three patients with rejection also exhibited haemodynamic instability (elevated filling pressures and reduced cardiac index) on POD 1, which improved with inotropic support. One patient sustained a cardiac arrest on POD 7, and was successfully resuscitated without sequelae. All patients are now doing well, postoperatively (follow-up: 17-57 months) post-transplant. Two patients have normal left ventricular function and one patient has mild left ventricular dysfunction. Two have no further evidence of sensitization (PRA < 10%)., Conclusions: Although the number of patients in this study is small, the long-term successful outcome of OHT following positive prospective cross-matches suggests that such a test result, in contrast to the restraints it imposes on renal transplantation, may not be a contra-indication to transplantation of the human heart. If OHT proceeds after the LCM is reported positive, aggressive immunotherapy should not only be initiated early, but should also be targeted at humoral-vascular rejection in particular.

There are between 3 and 5 million visits to EDs each year for complaints of chest pain. Of these, about one half of the patients have a noncardiac cause for their chest pain. Of the remainder, about 30% to 50% have significant coronary disease. It is quite clear that patients who are at high risk for a coronary event should be admitted to the hospital. For the low-to-moderate risk patients, the decision to admit or discharge the patient from the ED is not quite so easy. The emergency physician has to decide which tests can be helpful in the decision-making process, this can be undertaken in conjunction with a consultative cardiologist. It can be argued that if a patient does not have a normal test result whichever that evaluatory test is), then the patient should be admitted for further work-up and evaluation. The easiest test to perform in the ED setting is an echocardiogram. The images can be sent by telecommunication to a qualified echocardiogram reader for interpretation. This also has a reasonable NPV, although not necessarily as good as some of the other modalities available, unless interpreted in light of cardiac enzyme test results. If the index of suspicion is still high, then a stress echocardiogram can be considered. This has an excellent NPV and can be easily performed in [table: see text] most patients. This should not be undertaken in the face of an evolving MI, and patients should be observed for at least 8 hours after their initial presentation to the ED prior to undergoing a provocative test. Nuclear scintigraphy, another modality available for cardiac risk stratification, can be a logistical nightmare. The nuclear isotopes are strictly regulated by the Nuclear Regulatory Commission. The emergency physician may inject the isotopes, provided that he or she has undergone the necessary radiation training. Also, the patient must be removed from the ED to a radioisotope-approved area for the duration of the scan. One of the most difficult questions left open after review of all these analytical modalities is the duration of time these test results remain valid; when does an individual patient need to be reevaluated as to their specific pretest probability? The answer to this question lies in the presenting clinical scenario. If the patient presents with a similar inciting trigger for his or her symptoms, and the cardiac risk profile has not changed appreciably, then the previous study (whether a provocative stress test or even a cardiac catheterization) probably can be reliably counted. If the patient's risk profile has changed or the symptoms are new or more intense, the physician is compelled to pursue this encounter as a new, acute event. This can be true even in the setting of a previous cardiac catheterization that showed nonobstructive coronary disease, because plaque rupture can be acute and unpredictable. Ultimately, optimal care calls for each institution to develop a specific approach, in conjunction with their consultative cardiologist or critical care specialist, to enhance patient care, safety, and diagnostic outcome, while maintaining cost efficiency.

Retrospective analysis of 200 homograft valve recipients at our institution revealed two cases of fungal endocarditis. Pathogenesis appears to be related to either recipient seeding in one elderly immunocompromised patient or a previously contaminated donor valve implanted in an otherwise healthy recipient. Therefore, our experience underscores the need for both meticulous prevention of fungal infection preoperatively in the recipient and elimination of previously contaminated homograft valves from the donor pool.

Although there is increasing evidence that mismatched donor HLA antigens are associated with a lowering of survival of human cardiac allografts, the effect of antibodies that bind those antigens is less clear. The existence of lymphocytotoxic antibodies prior to cardiac transplantation has been associated with a poor outcome in the majority of reports of relevant studies, as has their appearance post-transplantation. But how such antibodies, especially those with HLA specificity, cause poor outcomes has been poorly understood. The purpose of this study was to investigate the effect of anti-HLA antibodies appearing in the circulation after human orthotopic heart transplantation. Such antibodies were identified by a standard microlymphocytotoxicity technique using panels of frozen lymphocytes from normal donors who had been tissue typed. Of 74 patients transplanted over a 12-month period, 4 (5.4%) developed alloantibodies specific for mismatched donor HLA antigens. The first patient developed antibodies to HLA-A23 and B44 together with poor ventricular function and vascular rejection requiring retransplantation within 4 months. The other patients (3) developed antibodies specific for HLA-DQ antigens and experienced variable numbers of episodes of cellular rejection with no evidence of vascular rejection on endomyocardial biopsy. Two of these three patients died (8 and 11 months post-transplant) after three and six rejection episodes, respectively. The one surviving patient had seven rejection episodes and continues to have poor ventricular function 18 months post-transplant. We conclude that alloantibodies specific for mismatched donor HLA antigens may have a deleterious effect on the outcome of the human cardiac allograft and should be monitored closely post-transplant. Furthermore, such antibodies may mediate effects on the transplanted heart which are not detectable in specimens obtained by endomyocardial biopsy.

Objectives: This study analyzes our experience with transplantation of small donor hearts in a subgroup of moribund patients who could not be bridged to transplantation with mechanical assist devices., Background: The major problem facing transplant programs in the United States is the lack of donor heart availability. One method of expanding the donor pool may be to liberalize the criteria for an acceptable donor heart., Methods: We analyzed the growth and adaptation of 14 undersized and 14 conventionally sized donor hearts over a period of 10 weeks after heart transplantation. The left ventricular systolic and diastolic diameters, septal and posterior wall thicknesses, left ventricular mass calculated by the Penn convention and left ventricular ejection fraction were obtained by M-mode and two-dimensional echocardiography and documented by a single reader in blinded manner. Echocardiographic measurements were obtained before implantation and at 5 and 10 weeks after orthotopic heart transplantation., Results: The mean (+/- SD) donor/recipient weight ratios were 0.53 +/- 0.06 for undersized hearts and 0.98 +/- 0.05 for normal-sized hearts. All 28 patients received similar immunosuppressive regimens, including intravenous steroids, cyclosporine and azathioprine. The length of hospital stay after transplantation did not vary significantly between the two groups. All the patients had at least one rejection episode during the 10-week study period. There was a tendency toward higher pulmonary pressures in undersized hearts, which was not statistically significant. Heart rate was significantly higher for undersized hearts, due in part to the use of theophylline or terbutaline to maintain tachycardia. There was a significant increase in left ventricular systolic and diastolic dimensions in undersized hearts compared with conventionally sized hearts. Undersized hearts increased in left ventricular mass over the 10-week period, whereas the conventionally sized donor hearts did not change between 5 and 10 weeks., Conclusions: In undersized hearts the increase in left ventricular mass and internal dimensions, with preservation of the posterior/septal wall thickness ratio, suggests that the left ventricle adapts to the larger recipient circulation early after transplantation. Despite denervation and a mismatched load, undersized transplanted hearts adapt appropriately to their new hemodynamic milieu.

A 29-year-old woman had an acute myocardial infarction 5 days after giving birth. Serial coronary angiography showed multiple progressive coronary artery dissections, which eventually involved both the right and left coronary trees. Persistent cardiogenic shock necessitated emergent orthotopic heart transplantation. Examination of the cardiectomy specimen confirmed the presence of multiple myocardial infarctions, coronary artery dissection, and fibromuscular dysplasia of the coronary arteries. Fibromuscular dysplasia combined with changes in the arterial ground substance and hormonal milieu attributable to pregnancy or parturition are proposed as possible causes of coronary artery dissection in this case.

We reviewed our experience with 54 cluster headache patients (23 episodic, 31 chronic) admitted to our headache center 64 tines over the past five years and treated with repetitive intravenous dihydroergotamine (IV DHE). DHE therapy was initiated on admission and prophylactic medication regimens were started or adjusted. All 54 patients had complete relief of their cluster headache, usually within two days. Most (82.8%) had no side effects. The average length of hospitalization was 6.7 days. At the three month followup, 92.9% of the episodic cluster patients were headache-free and 7.1% had a 50-74% improvement; at six months, all were headache-free. Of the chronic cluster patients, 44.4% were headache-free at three months and 52.8% had at least 50% improvement. At six months, 75% were headache-free and 22.2% were at least 75% improved, probably as a result of continued prophylactic medication. Repetitive IV DHE safely, rapidly, and effectively controls cluster headache.