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Introduction: We aimed to assess the impact of digoxin use following left ventricular assist device (LVAD) implantation on clinical outcomes. Methods: Patients implanted with continuous flow LVADs at a single academic medical center and survived to initial hospital discharge were included in the analysis ( n = 346). Clinical events were captured at a maximum of 2 years of follow up. Digoxin use was defined as 30-day continuous use post-LVAD. Negative binomial regression and Kaplan-Meier method were used to assess the association between digoxin use and clinical outcomes. Results: Mean age of the cohort was 56 years (±13) and 23% (79/346) were female sex. Digoxin was used in 144 patients (41.6%) for a median of 268 days (IQR 154, 616). Digoxin use was associated with a significant reduction in cumulative incidence of gastrointestinal bleeding (GIB) (15% vs 26%, p = 0.004). After adjusting for age, hypertension, post-operative hemoglobin, RDW, potassium, and GFR, and use of angiotensin receptor/neprilysin inhibitor, there remained a significant 47% reduction in GIB incidence in patients treated with digoxin. There was no significant difference in cumulative incidence in right ventricular failure (RVF) between the two groups. There was no difference in overall 2-year survival between groups. Conclusions: Digoxin use was associated with reduction in GIB events, but not in RVF or mortality. Further studies are needed to confirm these findings and to investigate optimal timing and patient population.

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.

Background Exercise performance remains limited in some patients after heart transplantation (HTx). The goal of this study was to assess for association between cardiopulmonary exercise test performance at 1 year after HTx and future development of cardiac allograft vasculopathy (CAV). Methods Overall 243 HTx recipients performed cardiopulmonary exercise testing at 1 year after HTx. During the median follow-up period of 31 (interquartile range 19;61) months, 76 (32%) patients were diagnosed with CAV (CAV group). Results The CAV group patients had lower exercise capacity (5.2 ± 1.9 versus 6.5 ± 2.2 metabolic equivalents; P = 0.001) and duration (9.6 ± 3.5 versus 11.4 ± 4.8 min; P = 0.008), lower peak oxygen consumption (VO2) (18.4 ± 5.4 versus 21.4 ± 6.1 mL/kg/min; P = 0.0005), lower normalized peak VO2 (63% ± 18% versus 71% ± 19%; P = 0.007), and higher minute ventilation (VE)/carbon dioxide production (VCO2) (34 ± 5 versus 32 ± 5, P = 0.04). On Cox proportional hazards regression analysis, normalized peak VO2 ≤60%, and VE/VCO2 ≥34 were associated with a high hazard for CAV (HR = 1.8 [95% CI 1.10-4.53, P = 0.03] and 2.5 [95% CI 1.01-8.81, P = 0.04], respectively). The subgroup of patients with both normalized peak VO2 ≤60% and VE/VCO2 ≥34 was at highest risk for development of CAV (HR = 5.2, 95% CI 2.27-15.17, P = 0.001). Conclusions Normalized peak VO2 ≤60% and VE/VCO2 ≥34 at 1 year after HTx are associated with the development of CAV.

Left ventricular assist device (LVAD) deactivation may be considered in cases of left ventricular recovery, pump thrombosis, infection, and end-of-life palliation. Surgical pump explantation remains the principal method, but percutaneous deactivation presents a safe and effective alternative. We have developed a formal program for percutaneous LVAD deactivation within our advanced heart failure program including patient selection criteria, preprocedure testing, a procedural algorithm, and a postprocedure care plan. Patient selection for percutaneous LVAD deactivation required review by an interdisciplinary heart transplant team including reason for deactivation, cardiac function, surgical risk, and patient preference. All candidates underwent LVAD ramp studies with both transthoracic echocardiography and right heart catheterization assessment. Deactivation was performed under general anesthesia with transesophageal echocardiography guidance. Three Amplatzer Vascular Plug IIs (Abbott, St. Paul, MN) were deployed in the LVAD outflow cannula with the proximal edge of the third plug aligned with the aortic anastomosis of the graft as guided by angiography and 3-dimensional transesophageal echocardiography. In a separate procedure, the LVAD drive line was transected below the skin, which was closed surgically over the driveline stump. Anticoagulation was continued for at least 3 months. Since initiation in January 2017, our program has performed 7 percutaneous LVAD deactivation procedures. All procedures have been successful, 5 of the patients remain medically managed, and 2 have proceeded to heart transplant. Percutaneous LVAD deactivation provides an alternative to surgical explantation. A percutaneous LVAD deactivation program is an important component of an advanced heart failure program.

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.

In selected patients with left ventricular assist device–associated infection or malfunction, pump exchange may become necessary after conservative treatment options fail and heart transplantation is not readily available. We examined the survival and complication rate in patients (⩾19 years of age) who underwent HeartMate II to HeartMate II exchange at our institution from 1 January 2010 to 28 February 2018. Clinical outcomes were analyzed and compared for patients who underwent exchange for pump thrombosis (14 patients), breach of driveline integrity (5 patients), and device-associated infection (2 patients). There were no differences in 30-day mortality (p = 0.58), need for temporary renal replacement therapy (p = 0.58), right ventricular mechanical support (p = 0.11), and postoperative stroke (p = 0.80) among groups. Survival at 1 year was 90% ± 7% for the whole cohort and 85% ± 10% for those who underwent exchange for pump thrombosis. In patients exchanged for device thrombosis, freedom from re-thrombosis and survival free from pump re-thrombosis at 1 year were 49% ± 16% and 42% ± 15%, respectively. No association of demographic and clinical variables with the risk of recurrent pump thrombosis after the first exchange was identified. Survival after left ventricular assist device exchange compares well with published results after primary left ventricular assist device implantation. However, recurrence of thrombosis was common among patients who required a left ventricular assist device exchange due to pump thrombosis. In this sub-group, consideration should be given to alternative strategies to improve the outcomes.

Pulmonary hypertension secondary to left heart disease (WHO Group 2) is a known risk factor in patients with heart failure. The favourable effect of left ventricular assist devices (LVAD) on pulmonary hypertension has been demonstrated before, although this effect has not been well-studied in advanced pulmonary arterial bed disease with a significant elevation in pulmonary vascular resistance.We reviewed the records of 258 LVAD patients in our institution. Patients with elevated mean pulmonary artery pressure (mPAP25mmHg) and elevated pulmonary vascular resistance (PVR ≥3 Wood units) were included in the study. Patients were divided into two groups based on their baseline PVR (PVR=3-5 Wood units (WU) vs. PVR5WU). The groups were studied for the changes in their pulmonary haemodynamics after the placement of LVAD.Fifty-one (51) patients were included in the study. All patients showed a significant improvement in their pulmonary haemodynamic parameters post LVAD placement. In the group with the higher PVR, mPAP dropped from a baseline of 43±7mmHg to 22±6mmHg post LVAD placement (p0.001), while PVR dropped from 6.3±1.2 Wood units to 2.2±1.1 Wood units (p0.001). In a subgroup of patients who underwent cardiac transplantation post LVAD (n=14), all patients maintained a normalised PVR (3WU) one year post cardiac transplantation.Left ventricular assist devices can reverse pulmonary hypertension WHO Group 2 with significantly elevated PVR; this effect is not dependent on the baseline PVR, and is maintained up to one year post cardiac transplantation.

Heart Failure (HF) is a major cause of morbidity and mortality in the US. With aging of the US population, the public health burden of HF is enormous. We aimed to develop an ensemble prediction model for 30-day mortality after discharge using machine learning. Using an electronic medical records (EMR) database, all patients with a non-elective HF admission over 10 years (January 2001 - December 2010) within the Montefiore Medical Center (MMC) health system, in the Bronx, New York, were included. We developed an ensemble model for 30-day mortality after discharge and employed discrimination, range of prediction, Brier index and explained variance as metrics in assessing model performance. A total of 7,516 patients were included. The discrimination achieved by the ensemble model was higher 0.83 (95% CI: 0.80 to 0.87) compared to the benchmark model 0.79 (95% CI: 0.75 to 0.84). The ensemble model also exhibited a better range of prediction as well as a favorable profile with respect to the other metrics employed. In conclusion, an ensemble machine learning approach exhibited an improvement in performance compared to the benchmark logistic model in predicting all-cause mortality among HF patients within 30-days of discharge. Machine learning is a promising alternative approach for risk profiling of HF patients, and it enhances individualized patient management.

Cardiogenic shock remains one of the most challenging clinical syndromes in modern medicine. Mechanical support is being increasingly used in the management of cardiogenic shock. Intra-aortic balloon pump (IABP) is one of the earliest and most widely used types of mechanical circulatory support. The device acts by external counterpulsation and uses systolic unloading and diastolic augmentation of aortic pressure to improve hemodynamics. Although IABP provides less hemodynamic support when compared with newer mechanical circulatory support devices, it can still be the mechanical support device of choice in appropriate situations because of its relative simplicity of insertion and removal, need for smaller size vascular access and better safety profile. In this review, we discuss the equipment, procedural and technical aspects, hemodynamic effects, indications, evidence, current status and recent advances in the use of IABP in cardiogenic shock.

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

While cytomegalovirus (CMV) reactivation occurs 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. Retrospective chart review of patients who had undergone LVAD implantation between July 2004 and December 2018 was performed. Cases with CMV reactivation post-LVAD were randomly matched (1:2) by sex, LVAD type, and implant year with controls utilizing SAS macros. Fisher's exact and paired sample t-tests were performed to evaluate for differences between categorical and continuous variables, respectively. Days to reactivation post-LVAD implantation were calculated in cases, and the corresponding times post-LVAD implantation were determined in control patients for variable comparisons. Survival analysis was performed using the Kaplan-Meier method. Of the 349 patients reviewed, 208 (59.6%) patients were seropositive for CMV before LVAD implantation. Of these 208 patients, eight (3.8%) had CMV reactivation following LVAD implantation. The median time to CMV reactivation following LVAD implantation was 21.5 days (range, 6-177). Six (75%) patients had CMV viremia, and the other two had colitis and pneumonia without viremia. In comparison to controls, patients with CMV had higher creatinine levels (p = 0.039) and higher RDW (p = 0.05) and were more likely to have received steroids within the previous week (p = 0.028) and to have concurrent bacterial infection (p = 0.001). CMV reactivation following LVAD implantation is more frequent than expected. Early testing, diagnosis, and treatment in at-risk patients (i.e., renal failure, steroid use, elevated RDW) might improve clinical outcomes.

Pulmonary arterial hypertension (PAH) is a vascular disorder associated with high morbidity and mortality rate and is characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, ultimately resulting in right ventricular failure and death. Over the past few decades, significant advances in the understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary arterial hypertension have occured. This has led to the development of disease specific treatment including prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, and soluble guanylate cyclase stimulators. These therapies significantly improve exercise capacity, quality of life, pulmonary hemodynamics, but none of the current treatments are actually curative and long-term prognosis remains poor. Thus, there is a clear need to develop new therapies. Several potential pharmacologic agents for the treatment of pulmonary arterial hypertension are under clinical development and some promising results with these treatments have been reported. These agents include tyrosine protein kinase inhibitors, rho-kinase inhibitors, synthetically produced vasoactive intestinal peptide, antagonists of the 5-HT2 receptors, and others. This article will review several of these promising new therapies and will discuss the current evidence regarding their potential benefit in pulmonary arterial hypertension.

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.

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.

Supplemental Digital Content is available in the text., Introduction. Although pulmonary function testing (PFT) is typically performed for heart transplant evaluation, the prognostic utility of PFTs after transplantation is unknown. We evaluated whether PFT parameters were correlated with outcomes following heart transplantation. Methods. International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry data were utilized. Survival was assessed using Kaplan-Meier method and compared via log-rank test. Cox proportional hazard modeling was used to evaluate univariate and multivariate predictors of survival. Results. Eight hundred two patients pretransplant PFT data were available for evaluation. Forced expiratory volume in 1 s (FEV1) 80%. FEV1/FVC

Background The relationship between heart failure (HF) and the serotonergic system has been established in animal studies. However, data on human plasma serotonin level in HF and its significance over the course of the disease is lacking. Methods Serotonin levels were measured in 173 patients (108 males, 65 females), 116 were stable HF and 40 were acute decompensated HF patients. The normal control group included 17 healthy volunteers with no known medical or psychiatric conditions. Patients receiving medications affecting serotonin receptors and those with pulmonary hypertension were excluded. All patients, except for those in the decompensated group, were on stable doses of HF medications. Results Plasma serotonin levels were significantly elevated in decompensated HF patients compared with stable patients (P=0.002). Higher plasma serotonin levels were associated with worse HF symptoms (NYHA class) and the presence of systolic dysfunction, and was borderline associated with low peak oxygen consumption during cardiopulmonary exercise testing (P=0.055). These results were independent of age, gender, race, hypertension, diabetes, renal failure, weight, coronary artery disease (CAD), atrial fibrillation and medication use. Conclusions Serotonin is a marker for decompensation in patients with chronic heart failure. Higher serotonin levels were associated with worse HF symptoms and systolic dysfunction.

Inflammation is an increasingly recognized hallmark of pulmonary hypertension (PH). Statins have been shown to attenuate key pathologic mechanisms via pleiotropic effects in animal models. However, clinical benefit of statins in patients with PH is unknown and their effect on mortality has not been studied. We performed a retrospective analysis of patients between January 2002 to January 2012, with severe PH (pulmonary artery systolic pressure ≥60 mmHg) and preserved left ventricular function (ejection fraction ≥50%), defined by transthoracic echocardiograms. Patients were divided into two groups based on statin therapy for 12 consecutive months after diagnosis of PH. Propensity score matching was performed. Subgroup analysis was done based on COPD status. Study endpoint was 1-year all-cause mortality and hospitalization. 2363 patients (age 71 ± 16; 31% male) were included; 140 (6%) were on statin therapy. Overall 1-year mortality was 34%. Following propensity score matching, 138 patients were included in the statin group and 624 patients in the no-statin group; all-cause mortality was significantly lower in the statin group compared with the no-statin group [15.2 vs. 33.8%, HR 0.42 (95% CI 0.27, 0.66), p

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.

Background While heart failure (HF) is a leading cause of mortality and readmissions, only a small percentage of patients are optimized on guideline-directed medical therapy (GDMT). We developed a multidisciplinary HF clinic to optimize medications, provide education and resources and screen for medical co-morbidities in HF patients. Methods A multidisciplinary clinic composed of Advanced Practice Providers (APPs), pharmacist, nutritionists and nurses was developed and targeted patients with a 30-day HF readmission, ≥ 2 HF-related hospitalizations in last 12 months or new HF diagnosis. The OPTIMIZE clinic consisted of a total of 6 visits approximately two weeks apart seeing an APP at each visit along with pharmacy and nutrition evaluation. Echocardiographic, 6-minute walk, and health related quality of life (EQ5D) outcomes were measured at baseline and at the end of the 12 weeks. Results A total of 62 patients with heart failure with reduced ejection fraction (HFrEF) completed OPTIMIZE clinic over an average of 11.6 weeks. Patients were primarily white (62.3%) males (56.5%) with an average age of 59.1 (±15.3) years. HF etiology was primarily non-ischemic (65%) and patients had typical cardiac comorbidities - hypertension 54%, hyperlipidemia 33%, diabetes 23%, sleep apnea 15%, and chronic kidney disease 24%. Completion of OPTIMIZE clinic resulted in significant improvements in 6-minute walk distance, left ventricular ejection fraction (LVEF), and patient reported quality of life measures as assessed by the EQ5D along with significant reductions in brain natriuretic peptide (BNP) and left ventricular internal diameter in diastole (LVIDd) (Figure 1a). We also saw improved utilization of GDMT with completion of the OPTIMIZE clinic (Figure 1b). During the course of the clinic, only 7 (11%) patients were admitted for CHF exacerbation and 44 referrals were made to various other cardiology or internal medicine subspecialities, the most common being sleep clinic (14 referrals). A total of 13 (21%) patients had enough improvement in LVEF on GDMT as a result of this clinic that they no longer met criteria for implantable cardioverter defibrillator implantation. Conclusion Successful implementation of a multidisciplinary HF optimization clinic can help improve GDMT utilization, HF education, comorbidity recognition, and markers of HF severity. An OPTIMIZE clinic model can be considered in other centers as a way to increase GDMT optimization and improve clinical and functional markers of HF.

Purpose Endothelin-1 (ET-1), a potent vasoconstrictor, is elevated in heart failure as well as in pulmonary arterial hypertension (PAH). To our knowledge little is known about ET-1 level in exercise induced pulmonary hypertension when compared to group 1 and 2 pulmonary hypertension. We aim to assess effect of exercise on ET-1 levels in different types of pulmonary hypertension. Methods A prospective study measuring ET-1 level in patient with PAH, heart failure induced pulmonary hypertension (D-PH), exercise induced PAH and exercise induced D-PH both at rest at peak exercise. Demographic and echo data were collected. Right heart cath was done to confirm diagnosis and type of pulmonary hypertension, which was followed by arm lifting exercise for 4 minutes (30 watts and decrease of MVO2 by >10%) using different weights. Exercise induced PAH defined as mean pulmonary pressure (mPA) 30 mmHg and pulmonary wedge (PW) 30 mmHg and PW >20 mmHg. Blood samples were collected to measure ET-1 level using ET-1 ELISA. Results A total of 77 patients were included in this study. 5 study groups were divided into: 10 control subjects, 18 patients with D-PH, 22 patients with PAH, 15 patients with Exercise D-PH and 12 patients with Exercise PAH. At rest, ET-1 level was the highest in Exercise-PAH compared to other groups 3.6 +/- 2 with p valule 0.04. Whereas, at peak exercise, ET-1 level was the highest in PAH compared to other groups with, 2.91 +/- 1.8 with p value of 0.05 (figure 1). Patients with D-PH had more evidence of diabetes mellitus, Obesity, smoking, dilated right atrium, right ventricular failure and were more elderly male. Conclusion At rest, ET-1 level is the highest in patients with exercise induced PAH, whereas at peak exercise, ET-1 is the highest in patients with PAH. Patients with heart failure induced pulmonary hypertension have more cardiac risk factors with evidence of right sided failure.

Introduction: Pulmonary hypertension (PH) secondary to left-sided heart disease (Group 2 PH) is a frequent complication of heart failure (HF) and is a heterogeneous phenotypic disorder that worsens exercise capacity, increases risk for hospitalization and survival independent of left ventricular ejection fraction (LVEF) or stage of HF. Areas covered: In this review, an update of the current knowledge and some potential challenges about the pathophysiology and treatments of group 2 PH in patients with HF of either preserved or reduced ejection fraction are provided. Also, this review discusses the epidemiology and provides hints for the optimal evaluation and diagnosis of these patients to prevent misclassification of their pulmonary hypertension. Expert opinion: There are many of areas lacking knowledge and understanding in the field of pulmonary hypertension associated to left heart disease (PH-LHD) that should be addressed in the future. Further research should be performed, in terms of pathobiology, and understanding the predisposition (genetic susceptibility and contributing factors) of the different phenotypes of this disorder. More clinical trials targeting new therapeutic options and specific PH therapies are warranted to help this increasing important patient group as the current guidelines recommend to only treat the underlying left-sided heart disease.

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 There is currently no effective treatment for patients with HFpEF and pulmonary hypertension (PH-HFpEF). We hypothesized that levosimendan (LEVO), a calcium sensitizer with inotropic and vascular smooth muscle relaxant properties, would improve hemodynamics and exercise capacity in PH-HFpEF. Methods We conducted a multicenter, double-blind, placebo-controlled trial testing the effects of once-weekly IV LEVO on hemodynamics and 6 minute walk distance (6MWD) in patients with PH-HFpEF. Participants with mean pulmonary artery (mPAP) ≥35 mmHg, PCWP ≥20 mmHg, LVEF ≥40% and NYHA II-III symptoms underwent 6MW and invasive hemodynamic assessments at rest, passive leg raise (PLR) and supine cycle exercise (EX) at baseline and following a 24-hour infusion of LEVO (0.1 μg/kg/min). Hemodynamic responders, defined as those with ≥4 mmHg reduction of EX PCWP, were then randomized, double blind, to a once weekly infusion of LEVO (up to 0.1 μg/kg/min) or placebo for 6 weeks, at which point hemodynamic assessments and 6MW test were repeated. The primary endpoint was between-group difference in the change of EX PCWP. Results Of 44 subjects enrolled, 37 (84%) qualified as responders and were randomized to LEVO (n=18) or placebo (n=19). Patients (69±9 years old, 61% women) displayed severe combined pre- and post-capillary PH at baseline (resting mPAP 41±10, PCWP 25±6 mmHg pulmonary vascular resistance 3.4±2.7). At 6-weeks, LEVO had no significant effect on EX PCWP compared to placebo (-1.4 mmHg, 95% CI, -7.7 to 4.8, p=0.65). However, in a mixed-effect repeated measure regression analysis incorporating rest, PLR, and EX stages, LEVO reduced PCWP by 3.9±2.0 mmHg as compared to placebo (p=0.047, Figure). As compared to placebo, LEVO improved 6MWD by 29 m (95% CI, 3 to 56, p=0.033). LEVO was well-tolerated with no difference in the incidence of adverse events compared to placebo. Conclusions In patients with PH-HFpEF, once-weekly treatment with LEVO for 6 weeks reduced PCWP and increased 6MWD without adverse effects. A phase 3 study to definitively test the safety and efficacy of LEVO as a treatment for PH-HFpEF is warranted.

Background RV remodeling occurs in response to pulmonary hypertension which could be associated with fibrosis and scar formation. However, little is known about the prognostic value of longitudinal change in RV geometry and presence LGE on mortality in patients with group I pulmonary hypertension (PH) vs. group II PH. Methods 60 patients with PH (30 in each group) were prospectively recruited in this study. 40% were women with mean age of 56.8 ± 8.2 years. All patients underwent baseline right heart catheterization at baseline and CMR imaging for the assessment of RV volumes, mass, ejection fraction and presence of non-ischemic and/or RV insertion site LGE. Demographics and baseline RV measurements were performed before initiation of PH specific therapy. Patients were followed for 2 years during which CMR and RHC were repeated at the end of the follow up period. Primary endpoint of the study was the outcome of death. Results 12 patients died during this study with a mean follow up time of 22 ± 3.2 months. The presence of LGE regardless of PH group was an independent predictor of death. Adverse RV remodeling with RV mass reduction overtime, especially in group II PH, was another independent predictor of mortality. It was noted that those patients who died had a further increase in right ventricular end diastolic and end systolic volumes (RVEDV and RVESV respectively), reduction of RVEF and a regression of RV mass after 15 months from initial diagnosis. Persistence LGE or worsening in magnitude at the last follow-up was associated with death (hazard ratio of 0.911, 95% confidence interval 0.892 - 0941, p = 0.002). Conclusion In patients with pulmonary hypertension irrespective of which type, the presence of LGE, RV mass regression with reduced RVEF are associated with increased mortality.

Background Severity of tricuspid regurgitation (TR) is implicated in the prognosis of different cardiac diseases, however little is known about this association in different types of pulmonary hypertension (PH) patients. Methods Single center study where 80 patients were recruited (40 with group I PH and 40 with group II PH). Echocardiogram was performed at 6 months and 12 months intervals after starting pulmonary vasodilators. Right heart cath was done at the beginning and after 12 months follow up. RV free-wall speckle-tracking strain, s’, TAPSE were used to assess RV function. TR severity was measured by echocardiogram and confirmed by cardiac MRI. Non ischemic LGE pattern and RV insertion site LGE were assessed. Patients were followed for a total of 24 months. Results Kaplan-Meier curve showed that patients with more than moderate TR had overall worse outcomes especially in group II PH (log-rank p=0.06). There was noticeable reduction in severity of TR after starting pulmonary vasodilators in the 2 groups, however p value was not significant. RV function improved when TR severity went from severe to mild and this was confirmed both by echo and cardiac MRI especially in group II PH with p value of 0.09. The presence of LGE was associated with worse outcomes regardless of type of PH, p value was 0.001. RV free wall speckle tracking strain improved as severity of TR improves especially from severe to mild and this was mostly noticed in group II PH with overall better outcome. Conclusion Improvement of TR and RV free wall speckle tracking strain was associated with better outcomes especially in group II PH. The presence of LGE regardless of type of PH, was associated with worse outcomes in the long term.