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Objectives The purpose of this study was to evaluate the effects of intravenous levosimendan on hemodynamics and 6-min walk distance (6MWD) in patients with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF). Background There are no proven effective treatments for patients with PH-HFpEF. Methods Patients with mean pulmonary artery pressure (mPAP) ≥35 mm Hg, pulmonary capillary wedge pressure (PCWP) ≥20 mm Hg, and LVEF ≥40% underwent 6MWD and hemodynamic measurements at rest, during passive leg raise, and supine cycle exercise at baseline and after an open-label 24-h levosimendan infusion (0.1 μg/kg/min). Hemodynamic responders (those with ≥4 mm Hg reduction of exercise-PCWP) were randomized (double blind) to weekly levosimendan infusion (0.075 to 0.1ug/kg/min for 24 h) or placebo for 5 additional weeks. The primary end point was exercise-PCWP, and key secondary end points included 6MWD and PCWP measured across all exercise stages. Results Thirty-seven of 44 patients (84%) met responder criteria and were randomized to levosimendan (n = 18) or placebo (n = 19). Participants were 69 ± 9 years of age, 61% female, and with resting mPAP 41.0 ± 9.3 mm Hg and exercise-PCWP 36.8 ± 11.3 mm Hg. Compared with placebo, levosimendan did not significantly reduce the primary end point of exercise-PCWP at 6 weeks (−1.4 mm Hg; 95% confidence interval [CI]: −7.8 to 4.8; p = 0.65). However, levosimendan reduced PCWP measured across all exercise stages (−3.9 ± 2.0 mm Hg; p = 0.047). Levosimendan treatment resulted in a 29.3 m (95% CI: 2.5 to 56.1; p = 0.033) improvement in 6MWD compared with placebo. Conclusions Six weeks of once-weekly levosimendan infusion did not affect exercise-PCWP but did reduce PCWP incorporating data from rest and exercise, in tandem with increased 6MWD. Further study of levosimendan is warranted as a therapeutic option for PH-HFpEF. (Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF [HELP]; NCT03541603 )

Gastrointestinal bleeding (GIB) is a common cause of morbidity among patients supported by left ventricular assist devices (LVADs). The aim of this study was to identify if pre-LVAD right ventricular (RV) dysfunction is associated with risk of GIB after LVAD implantation. Of 398 patients implanted with LVADs between July 2008 and July 2016, 130 (33%) developed GIB at a median of 2.6 months following LVAD implantation. Arteriovenous malformations (AVMs) were found in 42 (34%) GIB patients. Patients with GIB were older and more likely to have hypertension, diabetes, and ischemic cardiomyopathy. On pre-LVAD echocardiography, GIB patients had increased RV diastolic dimension (4.7 ± 0.8 vs. 4.4 ± 0.9 cm, p = 0.02), a higher rate of greater than mild tricuspid valve (TV) regurgitation (73 [60%] vs. 120 [47%], p = 0.006), and underwent TV repair more often (38 [30%] vs. 43 [16%], p = 0.0006) during LVAD implantation. After multivariable adjustment, preoperative greater than mild RV enlargement (hazard ratio [HR] 2.32, 95% CI 1.12-5.03; p = 0.03), TV regurgitation (HR 1.83, CI 1.02-3.44; p = 0.01), and TV repair (HR 3.76, confidence interval [CI] 1.02-4.44; p = 0.01) remained associated with risk of GIB. This finding was driven by the AVM-GIB subgroup. Preoperative RV enlargement and TV regurgitation are associated with post-LVAD AVM-related GIB.

Cardiomyopathy and more specifically the dilated cardiomyopathy, regardless of severity, is associated with activation of neuro-hormonal, cytokine and oxidative stress signaling pathways that alter the structure and function of cardiac myocytes and non-myocyte cells. These cellular alterations culminate in the morphological changes in cardiac structure termed as cardiac remodeling, a maladaptive process that contributes to further left ventricular dysfunction and heart failure development. This pathological progression is mainly driven by circulating mediators, in particular angiotensin II and norepinephrine. Natriuretic peptides, endothelin-1, vasopressin play also an important role in the progression of the cardiomyopathy. Cardiac inflammation, mediated by cytokines such as tumor necrosis factor-α (TNF-α), interleukins 1 (IL-1) and 6 (IL-6), as well as the oxidative stress were also shown to worsen the cardiac function. Although these pathways have been described separately, they are critically inter-dependent in the response to the development and progression of the dilated cardiomyopathy. This chapter reviews the cellular basis for cardiac remodeling and the mechanisms that contribute to these cellular abnormalities and, more broadly, to the pathophysiology of dilated cardiomyopathy, its progression and its potential treatments.

Pulmonary hypertension (PH) in patients with chronic obstructive pulmonary disease (COPD) is associated with an increase in the risk of COPD exacerbation, increased hospitalization, and worse survival in this patient population. No specific treatment is available for PH in COPD. However, reported out-of-proportion PH may benefit from a certain type of treatment. This study shows that the use of selexipag in the treatment of out-of-proportion PH in COPD patients was associated with an improvement in functional status evaluated by a six-minute walk test (6MWT) and a mean pulmonary artery pressure at 6 +/- 2 months of treatment.

Pulmonary arterial hypertension (PAH) is a progressive and devastating disease characterized by pulmonary artery vasoconstriction and vascular remodeling leading to vascular rarefaction with elevation of pulmonary arterial pressures and pulmonary vascular resistance. Often PAH will cause death from right heart failure. Current PAH-targeted therapies improve functional capacity, pulmonary hemodynamics and reduce hospitalization. Nevertheless, today PAH still remains incurable and is often refractory to medical therapy, underscoring the need for further research. Over the last three decades, PAH has evolved from a disease of unknown pathogenesis devoid of effective therapy to a condition whose cellular, genetic and molecular underpinnings are unfolding. This article provides an update on current knowledge and summarizes the progression in recent advances in pharmacological therapy in PAH.

The purpose of this study was to evaluate the effects of intravenous levosimendan on hemodynamics and 6-min walk distance (6MWD) in patients with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF).There are no proven effective treatments for patients with PH-HFpEF.Patients with mean pulmonary artery pressure (mPAP) ≥35 mm Hg, pulmonary capillary wedge pressure (PCWP) ≥20 mm Hg, and LVEF ≥40% underwent 6MWD and hemodynamic measurements at rest, during passive leg raise, and supine cycle exercise at baseline and after an open-label 24-h levosimendan infusion (0.1 μg/kg/min). Hemodynamic responders (those with ≥4 mm Hg reduction of exercise-PCWP) were randomized (double blind) to weekly levosimendan infusion (0.075 to 0.1 ug/kg/min for 24 h) or placebo for 5 additional weeks. The primary end point was exercise-PCWP, and key secondary end points included 6MWD and PCWP measured across all exercise stages.Thirty-seven of 44 patients (84%) met responder criteria and were randomized to levosimendan (n = 18) or placebo (n = 19). Participants were 69 ± 9 years of age, 61% female, and with resting mPAP 41.0 ± 9.3 mm Hg and exercise-PCWP 36.8 ± 11.3 mm Hg. Compared with placebo, levosimendan did not significantly reduce the primary end point of exercise-PCWP at 6 weeks (-1.4 mm Hg; 95% confidence interval [CI]: -7.8 to 4.8; p = 0.65). However, levosimendan reduced PCWP measured across all exercise stages (-3.9 ± 2.0 mm Hg; p = 0.047). Levosimendan treatment resulted in a 29.3 m (95% CI: 2.5 to 56.1; p = 0.033) improvement in 6MWD compared with placebo.Six weeks of once-weekly levosimendan infusion did not affect exercise-PCWP but did reduce PCWP incorporating data from rest and exercise, in tandem with increased 6MWD. Further study of levosimendan is warranted as a therapeutic option for PH-HFpEF. (Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF [HELP]; NCT03541603).

Background Patients with continuous flow left ventricular assist device (LVAD) may develop right ventricular failure in perioperative period of LVAD implantation. Some of these patients require temporary support with right ventricular assist device (RVAD). There is paucity of data regarding the impact of RVAD support on incidence of ventricular arrhythmias (VA) in LVAD patients. Purpose To assess the impact of perioperative RVAD support on the incidence of VA in the first 6 months after LVAD implant. Methods This is a retrospective study including 316 patients undergoing LVAD implantation at the University of Nebraska Medical Center, USA since 2012. Patients were divided into 2 groups- those who required perioperative RVAD support (BiVAD group) and those who did not require it (LVAD only group). VA was defined as any sustained ventricular tachyarrhythmia lasting more than 30 seconds or requiring therapy from implantable cardioverter-defibrillator. Incidence of VA in the first 6 months post-LVAD implantation was analyzed and compared between the groups using Cox proportional hazards regression analysis. Results Out of 316 total patients, 52 (16%) patients required RVAD support. The difference in age, gender, race and medications between the two groups was not statistically significant. The patients in BiVAD group had a higher incidence of post-LVAD VA (35%) as compared to LVAD only group (21%). On Cox proportional hazards regression analysis, the difference was found to be statistically significant even after adjusting for history of pre-LVAD VAs (HR: 2.27; p=0.02) (Figure 1). Conclusion In this large single center cohort of LVAD patients, we noticed a statistically higher incidence of VA in subgroup of patients requiring perioperative RVAD support. Figure 1 Funding Acknowledgement Type of funding source: None

Purpose To assess the efficacy and safety of macitentan in pts with PH post-LVAD. Methods SOPRANO (NCT02554903) was a double-blind, randomized, study of macitentan 10 mg once-daily vs placebo. Pts were ≥18 years with LVAD implanted within 90 days prior to randomization, had mean pulmonary arterial pressure (mPAP) ≥25 mmHg, pulmonary artery wedge pressure (PAWP) ≤18 mmHg and pulmonary vascular resistance (PVR) >3 Wood units (WU). The primary endpoint was change in PVR at week 12 of therapy from baseline. Results Fifty-seven pts were randomized: macitentan (n=28) or placebo (n=29). Baseline pt demographics and characteristics were well balanced. Baseline PVR (mean [SD]) was 4.3 [0.9] WU (macitentan) and 4.3 [1.3] WU (placebo). At week 12, mean PVR decreased to 58.5% (macitentan) and to 75.5% (placebo) of baseline. Mean placebo-corrected reduction in PVR of macitentan was 26.1% (95% CI: 58.0, 94.3; p=0.0158). Predefined secondary endpoints, notably including changes in PAWP, were not significantly different with macitentan vs placebo (Table). Another relevant hemodynamic parameter, transpulmonary gradient, significantly decreased with macitentan vs placebo (p=0.0499). The incidence of treatment adverse events (TAEs) was 21.4% (macitentan) and 24.1% (placebo); no TAEs occurred in >1 patient in the macitentan arm. AEs of interest included edema, anemia and hypotension: reported in 7 (25.0%), 3 (10.7%), and 4 (14.3%) pts on macitentan (mostly mild-moderate) and in 5 (17.2%), 2 (6.9%) and 1 (3.6%) pts on placebo, respectively. Two pts on macitentan and 1 pt on placebo discontinued for treatment-related AEs. Conclusion In the first prospective, multicenter, randomized controlled trial of pulmonary vasodilators in the early post-LVAD population, macitentan significantly reduced PVR and was well tolerated. The impact of macitentan on post-LVAD exercise capacity and RV failure warrants further study.

The incidence of pulmonary hypertension (PH) has been rising enormously over the past few years, with more systemic diseases being found to be associated with it. A better understanding of the pathophysiology of PH has led to the development of more effective therapies that have impacted the survival and morbidity of these patients. However, the adverse effects associated with these medical therapies are often serious and not trivial. Here we present a case of an inadvertent overdose of oral treprostinil diolamine that led to refractory vasoplegic shock.

Neuregulins are important growth factors involved in cardiac development and response to stress. Certain isoforms and fragments of neuregulin have been found to be cardioprotective. The effects of a full-length neuregulin-1β isoform, glial growth factor 2 (GGF2; USAN/INN; also called cimaglermin) were investigated in vitro. Various dosing regimens were then evaluated for their effects on left ventricular (LV) function in rats with surgically-induced myocardial infarction. In vitro, GGF2 bound with high affinity to erythroblastic leukemia viral oncogene (ErbB) 4 receptors, potently promoted Akt phosphorylation, as well as reduced cell death following doxorubicin exposure in HL1 cells. Daily GGF2 treatment beginning 7-14 days after left anterior descending coronary artery ligation produced improvements in LV ejection fraction and other measures of LV function and morphology. The improvements in LV function (e.g. 10% point increase in absolute LV ejection fraction) with GGF2 were dose-dependent. LV performance was substantially improved when GGF2 treatment was delivered infrequently, despite a serum half-life of less than 2h and could be maintained for more than 10 months with treatment once weekly or once every 2 weeks. These studies confirm previous findings that GGF2 may improve contractile performance in the failing rat heart and that infrequent exposure to GGF2 may improve LV function and impact remodeling in the failing myocardium. GGF2 is now being developed for the treatment of heart failure in humans.

Visual Abstract, Highlights • Cimaglermin is a recombinant neuregulin that appears to be important for essential cardiac repair processes. • Forty patients with significant left ventricular dysfunction and heart failure were randomized in a phase 1 double blind, placebo controlled, single ascending dose study to examine safety and tolerability. • An infusion of cimaglermin was generally tolerated except for transient nausea and headache. • A dose-limiting toxicity of transient elevated liver transaminases and bilirubin was observed at the highest planned dose. • There was a sustained improvement in left ventricular ejection fraction over 3 months at higher doses tested compared to lower doses or placebo., Summary A first-in-human, phase 1, double blind, placebo-controlled, single ascending dose study examined the safety, tolerability, and exploratory efficacy of intravenous infusion of a recombinant growth factor, cimaglermin alfa, in patients with heart failure and left ventricular systolic dysfunction (LVSD). In these patients on optimal guideline-directed medical therapy, cimaglermin treatment was generally tolerated except for transient nausea and headache and a dose-limiting toxicity was noted at the highest planned dose. There was a dose-dependent improvement in left ventricular ejection fraction lasting 90 days following infusion. Thus, cimaglermin is a potential therapy to enhance cardiac function in LVSD and warrants further investigation.

Introduction Digoxin use within the heart failure population remains controversial, as studies have suggested increased arrhythmia risk and lower survival. Despite decades of use in heart failure, little is known regarding digoxin utilization post-left ventricular assist device (LVAD). We aimed to evaluate if digoxin use impacts overall survival or incidence of right ventricular (RV) failure after LVAD implantation. Methods Analysis was performed on 320 patients who underwent LVAD implantation from 2004-2017 and survived to hospital discharge. Patients were divided into groups based on digoxin utilization at discharge following LVAD placement. RV failure was defined as a composite of central venous pressure > 16mmHg or need for inotropic medication post-discharge or admission for intravenous diuretic therapy. Survival was assessed via Kaplan-Meier method and compared via log-rank test. Between group differences were assessed using independent sample t-tests and Fisher's exact tests. Results The cohort (n=320) had an average age of 56.2 (±13) years and contained 70 (21.9%) female patients. A majority ((n=129 (60%)) were implanted as destination therapy with 112 (35%) patients prescribed digoxin at the time of discharge (See Figure 1). Patients on digoxin were more likely to have a non-ischemic cardiomyopathy (p=0.002), had higher pulmonary vascular resistance (PVR) (p=0.03), and had larger left ventricular (p Conclusions Despite concerns about its continued use in different heart failure populations, overall survival was similar in LVAD patients with and without digoxin use at the time of initial discharge. A trend of reduced RV failure was present with digoxin use. Further studies are needed to fully elucidate the optimal patient population that may benefit from digoxin use following LVAD implantation.

Background— Adverse events (AEs), such as intracranial hemorrhage, thromboembolic event, and progressive aortic insufficiency, create substantial morbidity and mortality during continuous flow left ventricular assist device support yet their relation to blood pressure control is underexplored. Methods and Results— A multicenter retrospective review of patients supported for at least 30 days and ≤18 months by a continuous flow left ventricular assist device from June 2006 to December 2013 was conducted. All outpatient Doppler blood pressure (DOPBP) recordings were averaged up to the time of intracranial hemorrhage, thromboembolic event, or progressive aortic insufficiency. DOPBP was analyzed as a categorical variable grouped as high (>90 mm Hg; n=40), intermediate (80–90 mm Hg; n=52), and controlled (P =0.012 versus controlled and 2.6 [0.93–7.4]; P =0.068 versus intermediate). Overall, a similar association was noted for the risk of intracranial hemorrhage ( P =0.015) and progressive aortic insufficiency ( P =0.078) but not for thromboembolic event ( P =0.638). Patients with an AE had a higher DOPBP (90±10 mm Hg) in comparison with those without an AE (85±10 mm Hg; P =0.05). Conclusions— In a population at risk, higher DOPBP during continuous flow left ventricular assist device support was significantly associated with a composite of AEs.

Background: Left ventricular assist devices (LVAD) are an increasingly used therapy for patients with advanced heart failure. Arrhythmias are common complications following LVAD implantation requiring admission, initiation, and escalation of medical therapy. Despite their frequent use in the treatment of arrhythmias, little has been reported regarding electrocardiographic changes, antiarrhythmic utilization, and outcomes post-LVAD. Methods: A total of 309 patients who received a LVAD underwent retrospective chart review pre- and post-LVAD. Kaplan-Meier curves were calculated and compared using the log-rank test. Cox regression model was used for univariate analysis and those with a p Results: There was a significant reduction in both the QRS interval (p=0.0001) and QTc interval (p=0.0074) following LVAD implantation. Ventricular tachycardia is common following LVAD implant at 31.1%. Amiodarone use was frequent prior to LVAD (52.1%) and on discharge (68.6%). Amiodarone use (p=0.019, HR 1.7, 95% CI 1.1-2.6), age at implant (p Conclusion: Amiodarone is a commonly used antiarrhythmic in advanced heart failure and its use prior to LVAD implantation may increase the risk of long-term mortality. Amiodarone's efficacy needs to be weighed against its long-term side effects and implant on clinical outcomes. Copyright: © 2018 The Author(s). This is an open access article published under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/lice nses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided that the original author(s) and the publication source are credited.

Background With recent legislation imposing penalties on hospitals for above-average 30-day all-cause readmissions for patients with acute decompensated heart failure (ADHF), there is concern these penalties will more heavily impact hospitals serving socioeconomically vulnerable and underserved populations. Hypothesis Patients with ADHF and low socioeconomic status have better postdischarge mortality and readmission outcomes when cardiologists are involved in their in-hospital care. Methods We retrospectively searched the electronic medical record for patients hospitalized for ADHF from 2001 to 2010 in 3 urban hospitals within a large university-based health system. These patients were divided into 2 groups based on whether a cardiologist was involved in their care or not. Measured outcomes were 30- and 60-day postdischarge mortality and readmission rates. Results Out of the 7516 ADHF patients, 1434 patients were seen by a cardiologist (19%). These patients had lower 60-day mortality (5.4% vs 7.0%; hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.52-0.96, P = 0.034) and lower 30- and 60-day readmission rates (16.7% vs 20.6%; HR: 0.76, 95% CI: 0.66-0.89, P = 0.002, and 26.1% vs 30.2%; HR: 0.81, 95% CI: 0.72-0.92, P = 0.003, respectively). There was no significant difference in the in-hospital mortality between the 2 groups. Compared with other races, whites with systolic HF have marginally lower HF-related readmission rates when treated by cardiologists. Conclusions In this cohort of ADHF patients from the Bronx, New York, involvement of a cardiologist resulted in improved short-term mortality and readmission outcomes compared with treatment by general internal medicine.

Cyclic guanosine monophosphate (cGMP) plays an important role as pulmonary vasodilator and currently there are targeted therapy to stimulate cGMP in the management of patients with pulmonary hypertension. It is known that patients with pulmonary hypertension and heart failure have impairment of cGMP

Introduction Patients who have undergone a previous cardiovascular surgery prior to implantation of a left ventricular assist device (LVAD) is extremely common. Limited data are available as to the outcomes of these patients following LVAD implantation. We hypothesized that patients with a history of prior median sternotomy are at an increased risk of mortality following LVAD implantation. Methods All patients who underwent LVAD implantation at the University of Nebraska Medical Center between July 2005 and November 2017 underwent retrospective chart review evaluating for pre-operative risk factors and post-operative outcomes. Patients were censored at the time of heart transplantation and LVAD explantation/defunctionalization. Cox regression models were used to perform univariate and multivariate analyses. Overall survival curve was calculated using the Kaplan-Meier method and compared using the log-rank test. Results A total of 309 patients underwent LVAD implantation. The average age was 56.7 years old (12.9), 240 patients (77.7%) were male sex, 163 patients (52.8%) had a history of ischemic cardiomyopathy, and a total of 100 patients (32%) had a history of prior median sternotomy at the time of LVAD implantation. Prior median sternotomy was associated with increased mortality compared to those without prior sternotomy (Figure 1). On multivariate analysis, history of prior median sternotomy remained an independent predictor of mortality with a HR of 2.3 (95%CI 1.41-3.62, p Discussion Patients who have undergone prior median sternotomy have an increased risk of mortality following LVAD implantation. Pre-operative risk factor modification is essential in these patients to try and optimize post-operative outcomes as much as possible.

Surgical left ventricular assist device (LVAD) explantation remains the main method for device deactivation. However, such reoperation in patients with advanced cardiac disease carries significant potential risks. The role of a percutaneous LVAD deactivation program, including patient selection and

Introduction While cytomegalovirus (CMV) reactivation occurs frequently in immunocompetent patients who are critically ill and has been associated with worse outcomes, very few cases of CMV reactivation have been reported following left ventricular assist device (LVAD) implantation. We aimed to evaluate the incidence and risk factors for CMV reactivation following LVAD implantation as well as treatment strategies for these CMV infections. Methods Retrospective chart review of patients of patients who had undergone LVAD implantation between July 2004 and January 2019 was performed. Cases with CMV reactivation post-LVAD were randomly matched by sex, LVAD type, and implant year in a 1:2 fashion with controls utilizing SAS macros. Days-to-reactivation post-implantation were calculated in cases and corresponding times post-implantation were determined in control patients for variable comparisons. Fisher's exact and paired sample t-tests were performed to evaluate for differences between categorical and continuous variables, respectively. Results Of the 349 patients reviewed, 213 (61%) patients were positive for CMV IgG prior to LVAD implantation. Of these 213 patients, 8 (3.8%) patients had CMV reactivation following LVAD implantation. Six (75%) of the 8 patients had CMV viremia, while the other 2 had colitis and pneumonia without evidence of viremia. Full between group comparisons are listed in Figure 1. In comparison to matched controls, patients who had CMV reactivation had a higher creatinine (p=0.039), higher RDW (p=0.05), were more likely to have received steroids within the previous week (p=0.028), and were more likely to have a concurrent bacterial infection (p=0.001). Seven (87.5%) of the 8 patients underwent treatment for their CMV reactivation, with all of them receiving intravenous ganciclovir as initial therapy. The one patient who did not receive treatment had low level viremia and was asymptomatic. Full description of the management of the CMV reactivation cohort is listed in Figure 2. Conclusions CMV reactivation following LVAD implantation is more frequent than previously expected. Awareness of this clinical entity for early testing, diagnosis, and treatment in at risk patients (i.e. renal failure, steroid use, elevated RDW) is important to ensuring good clinical outcomes.

Background Exercise-induced pulmonary hypertension (EiPH) can cause a significant deterioration in quality of life as well as a decrease in life expectancy. Additionally, EiPH may precede the development of manifest PH in a proportion of patients. In this study, we evaluated the effect of riociguat on the functional capacity of patients with EiPH. Hypothesis Riociguat improves 6-minute walk test in patients with exercise-induced pulmonary hypertension. Methods We reviewed the medical records of patients who were started on riociguat for exercise induced pulmonary hypertension. All patients had a right heart catheterization done at baseline that showed normal pulmonary hemodynamics (mPAP 30 mmHg, PVR> 3 Wood units at maximum arm exercise). All patients had a baseline 6-minute walk test, and a repeat test at 6 months (+/− 2 months) after starting riociguat. Results Out of the nine patients included in this study, seven patients showed improvement of 6-minute walk distance (from 891 feet to 1197 feet, mean change 306 feet). One patient showed worsening of 6MWT (from 991 feet to 905 feet) and one patient did not show any significant change from baseline. Conclusions In this case series of patients with exercise induced pulmonary hypertension, the use of riociguate was associated with an improvement in the functional status of patients with EiPH at 6 months. Larger size prospective studies are needed to confirm the findings.

Background Pulmonary hypertension (PH) in patients with COPD is associated with an increase in the risk of COPD exacerbation, increased hospitalization and worse survival in this patient population. The majority of patients with COPD have a mild degree of pulmonary hypertension (with mean pulmonary artery pressure, mPAP Hypothesis Selexipag improves functional capacity in COPD patients with out of proportion pulmonary hypertension. Methods We reviewed the medical records of COPD patients who were started on selexipag for out of proportion pulmonary hypertension. The patients were diagnosed with COPD according to their history, pulmonary function tests and chest imaging. All patients had a right heart catheterization done at baseline that showed pulmonary hypertension with mPAP ≥ 35 mmHg at rest. Six-minute walk test was done at baseline and repeated at 6 months (+/- 2 months) after starting selexipag. Results Out of the six patients included in this study, five patients showed improvement of 6-minute walk distance (from 512 feet to 681 feet, mean change 169 feet) while 1 patient worsened (from 1177 feet to 913 feet). Conclusions In this case series of COPD patients with out of proportion pulmonary hypertension, the use of selexipag was associated with an improvement in functional status at 6 months. Larger size prospective studies are needed to confirm the findings.

Aim Acute decompensated heart failure (ADHF) is associated with significant morbidity and mortality but the relationship between LVEF and outcomes is unclear. We explored the association between LVEF and 30 and 180 day mortality in 7007 ADHF patients enrolled in the Acute Studies of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. Methods and results We explored the association between LVEF and 30 and 180 day mortality in 7007 ADHF patients enrolled in the Acute Studies of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. LVEF was analysed both as a continuous variable and according to three categories: 50% [preserved ejection fraction (PresEF)]. Of the patients in the trial, 4474 (78.7%) had LowEF, 674 (11.9%) had IntEF, and 539 (9.5%) had PresEF. The unadjusted 30 and 180 day mortality was similar for LowEF (3.7%, 12.3%), IntEF (3.4%, 13.1%), and PresEF (4.3%, 14.1%), respectively (P > 0.05). After multivariable adjustment, the hazard ratio (HR) for 180 day mortality remained similar for the LowEF [HR 0.96, 95% confidence interval (CI) 0.75–1.24; P = 0.77] and IntEF (0.91, 95% CI 0.66–1.3; P = 0.58) compared to PresEF patients. By contrast, when LVEF was evaluated as a continuous measure, it exhibited a U-shaped pattern with mortality. After matching for age and sex, the mortality risk attributed to LVEF was attenuated, as the LVEF increased as a continuous variable over 35%. However, in patients with EF

Treatment of right ventricular failure (RVF) can be challenging due to the correlation between RVF and worsening renal function with diuretic therapy. Nesiritide has been studied in patients with left ventricular failure but has not been evaluated in isolated RVF. The authors retrospectively analyzed 140 patients admitted with RVF, pulmonary hypertension (PH), and preserved left ventricular systolic function. Seventy patients were treated with nesiritide while the remaining patients received only furosemide (no nesiritide group). Serum creatinine and GFR at baseline, 72 hours, discharge, and 1 month post-treatment, as well as hemodynamic data were compared between the groups. In the nesiritide group, there was a significant decrease in mean GFR (42.7725.33, P 25% decrease in GFR anytime through day 30 (47.14% vs 25.71%, P=.036) between the two groups. On multivariate analysis, nesiritide remained an important predictor of renal function at discharge and at 1 month (P 25% decrease in GFR anytime through day 30 (P=.007). Thus, nesiritide is associated with worsening kidney function in patients with RVF in the setting of PH. Congest Heart Fail. 2012;18:18‐24. � 2011 Wiley Periodicals, Inc.

Endothelin-1 (ET-1), a potent vasoconstrictor, is elevated in heart failure as well as in pulmonary arterial hypertension (PAH). Heart failure with preserved EF (HFpEF) is the most common cause of pulmonary hypertension (D-PH). To date, there is no known level of ET-1 in rest and exercise conditions

Background Despite the limited donor pool, current guidelines recommend against the use of hearts from donors that abuse alcohol. Study aim To explore the effect of donor alcohol abuse (AA) on cardiac allograft arrhythmias, function, and outcomes in heart transplant (HTx) recipients. Methods Overall, 370 HTx recipients transplanted between 2005 and 2016 were divided into two groups: (1) the AA donor group (AD, n=58), and (2) the non-AA donor group (NAD, n=312). The median follow-up was 4.0 (25%-75% IQR 1.8-5.8) years. Results Recipients in the AD group had a slower heart rate (HR, 86±13 vs. 93±13, p=0.004) and an increased incidence of early atrial fibrillation [17 (30%) vs. 34 (11%), p=0.003]. Echocardiographic left ventricular mass was higher in AA donors (171.7±66.7 vs. 151.6±54.7, p=0.02). This difference became even more prominent 1 year following HTx (185±43 vs. 166±42, p=0.007). E/E’ was higher in the AD group (9.5±3.9 vs. 8.4±2.9, p=0.04) and a larger number of AD recipients had a ventilatory equivalent for VCO 2 >34 (50% vs. 31%, p=0.04) on cardiopulmonary stress test. There was no significant difference in rejection, cardiac allograft vasculopathy (CAV), or survival between the groups. Conclusions Our data suggest that donor AA is associated with an increased incidence of post-HTx atrial fibrillation and impaired cardiac allograft diastolic function. Therefore, although the incidence of rejection, CAV, and intermediate-term survival were not affected, hearts from donors that abuse alcohol should be used with caution.

Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1-receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure.We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient's clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes.Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists.Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.).

Background: The current recommendation for cardiac resynchronization therapy (CRT) in congestive heart failure (CHF) patients is based on QRS duration, not on QRS morphology. It is not known whether patients with right bundle branch block (RBBB) respond to CRT. Hypothesis: This study was performed to compare the effects of CRT in CHF patients with pure RBBB vs those with a coexisting left hemiblock (LHB). Methods and Patient Population: A total of 271 consecutive patients who underwent CRT at Montefiore Medical Center were analyzed. Baseline ECGs were analyzed by 2 reviewers for RBBB and further classified into those with a coexisting LHB. Response to CRT was defined to be, at ≥6 months after CRT, either an improvement in ejection fraction (EF) of at least 5 %, or an improvement in New York Heart Association (NYHA) CHF class. A total of 44 patients were identified: 1 8 had pure RBBB and 2 6 had a coexisting LHB. The 2 groups were similar in respect to baseline characteristics (P > 0.05). Results: Only 4 out of 1 8 patients with pure RBBB compared to 1 8 out of 2 6 with LHB (P = 0.005) had an improvement in EF ≥5%. The mean EF was ―1% in the pure RBBB group, but +5.4% in those with LHB (P = 0 . 0031 ). Improvement in NYHA class was seen in o out of 1 8 with pure RBBB vs 7 out of 26 patients with LHB (P = 0.03). Conclusion: If patients with RBBB also had LHB, their response to CRT was significantly better than if they had RBBB alone.

Chronic heart failure (CHF) and chronic kidney disease (CKD) are serious medical conditions with significant morbidity and mortality. Emerging evidence indicates that the function of these two organ systems are affected by each other in a complex interplay. Most patients with CKD suffer frequently from cardiac abnormalities including left ventricular hypertrophy (LVH), left ventricular dilatation (LVD), left ventricular (LV) diastolic and/or systolic dysfunction. Although previously thought that LV systolic dysfunction was an absolute contraindication to renal transplantation, several observational studies have shown this not to be true and that transplantation can lead to significant improvement in LV systolic function. Furthermore, correction of the uremic state by renal transplantation leads to improvement of LVD and possibly regression of LVH. In fact, the reduction of LVH postkidney transplantation was shown to be dependent on adequate renal function and hypertension control. Diabetes mellitus does not seem to be a confounding factor in the improvement of uremic cardiomyopathy with renal transplantation.

Background Heart failure is associated with reversal to a fetal gene expression pattern of contractile and metabolic genes. Substantial recovery of ventricular function with assist devices is rare. Our goal was to evaluate the effects of assist devices on fetal gene expression and hypoxia inducible factor-1α (HIF-1α), a transcriptional factor in hypoxic signaling. Methods Human heart tissue was obtained from the left ventricular apex at the time of assist device implantation and again from the left ventricular free wall during cardiac transplantation. Non-failing tissue was obtained from unused hearts from human donors. Gene expression was measured with the Affymetrix 133 plus 2 Array. HIF-1α was measured by Western blotting with commercially available antibodies. Results Heart failure was associated with a decrease in α-myosin heavy chain and sarcoplasmic reticulum-Ca 2+ adenosine triphosphatase messenger RNA expression along with an increase in skeletal tropomyosin. This pattern persisted after assist device therapy. Heart failure was also associated with abnormalities in regulatory metabolic genes including glucose transporter 1 (GLUT1). These patterns also persisted after assist device therapy despite a reduction in atrial natriuretic peptide expression and normalization of HIF-1α. Conclusions Failure of assist devices to produce sustained recovery of myocardial contractile function may be due in part to persistent fetal transcriptional patterns of contractile and metabolic genes.

Background: Pulmonary hypertension (PH) is a multifactorial disease characterized by endothelial dysfunction and inflammation. In line with this, pleiotropic effects of statins have been found beneficial in PH resulting in hemodynamic improvement. However, the role of statins in subgroups of PH, especially inflammation triggered chronic obstructive pulmonary disease (COPD) is unknown and their effect on mortality has not yet been studied. Methods: Consecutive patients ≥18 years with severe PH (pulmonary artery systolic pressure ≥60 mmHg) and preserved left ventricular function (ejection fraction ≥50%) defined by transthoracic echocardiograms were included from January 2002 to August 2012. Patients were divided into two groups based on being on statin therapy for 12 consecutive months after diagnosis of PH. Propensity score matching was performed for all baseline demographics, comorbidities, labs, lipid profile, and medications with ratio matching of 1 (treated) to 5 (untreated controls). Subgroup analysis was done based on COPD status. Study endpoint was 1-year all-cause mortality. Results: 2,363 patients (age 71±16; 31% male) were included, 140 (6%) patients were on statin therapy. 1-year mortality for the entire population was 34%. Following propensity score matching, 137 patients on statin (statin group) and 625 patients not on statin (controls), all-cause mortality was significantly lower in statin group compared to controls (15.3% vs. 36.2%, HR 0.38 [95% CI 0.25, 0.60], p Conclusions: In this study, we identify statin therapy as an independent predictor of lower 1-year mortality in patients with severe PH but interestingly not in the subgroup of patients with COPD. This observation might be linked to the high severity of PH in our study population and less likely to the lack of anti-inflammatory effects. However the overall survival benefit in patients with severe PH is a novel and promising finding that needs to be confirmed in large randomized trials.

Background In chronic heart failure due to a dilated cardiomyopathy phenotype, the molecular bases for contractile dysfunction and chamber remodeling remain largely unidentified. Methods To investigate the feasibility of measuring global gene expression serially in the intact failing human heart, we performed repeated messenger RNA (mRNA) expression profiling using RNA extracted from endomyocardial biopsy specimens and gene chip methodology in 8 subjects with idiopathic dilated cardiomyopathy. In patients treated with β-blocking agents or placebo, myocardial gene expression was measured in endomyocardial biopsy material and radionuclide ejection fraction was measured at baseline and after 4 to 12 months of treatment. Gene expression was measured for 12,625 gene sequences by using Affymetrix U95 gene chips and commercially available software. For 6 mRNAs, gene chip results were compared with measurements made by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Results In an unfiltered composite analysis of changes in expression detected in the patients with high-signal intensity chips, 241 genes showed an increase and 331 genes a decrease in mRNA abundance. There was good agreement between changes measured by quantitative RT-PCR and those determined by gene chips. There was less variance between differences in phenotype in patients sampled serially as compared between subjects with similar phenotypes sampled at baseline. Conclusions Serial gene expression profiling with association to phenotypic change is feasible in the intact human heart and may offer advantages to cross-sectional expression profiling. This study suggests that the intact failing remodeled human heart is in an activated state of gene expression, with a large net reduction in gene expression occurring as phenotypic improvement occurs.

While bronchiolitis obliterans organizing pneumonia (BOOP) has been associated with the use of sirolimus (SIR), the incidence in a consecutive group of patients given SIR to replace a calcineurin-inhibitor (CI) is unknown. Twenty-nine consecutive cardiac transplant recipients were switched from a CI to SIR to ameliorate CI-associated nephropathy or coronary graft atherosclerosis. Seven patients (24%) developed BOOP. The clinical characteristics and biopsy results of these patients are presented. The clinical course and response to withdrawal of SIR in all and steroids in four of seven patients suggested the diagnosis of BOOP. Chest X-rays and CT scans showed typical findings of BOOP in all seven patients. Infection was excluded in all patients. Biopsy results were characteristic of BOOP in six of seven patients. Six patients recovered and one died. BOOP is a common and potentially serious adverse event in cardiac transplant patients switched from a CI to SIR, especially when SIR is started late post-transplantation.