Dominik Berliner

Bromocriptine for the treatment of peripartum cardiomyopathy: a multicentre randomized study

Abstract Aims An anti-angiogenic cleaved prolactin fragment is considered causal for peripartum cardiomyopathy (PPCM). Experimental and first clinical observations suggested beneficial effects of the prolactin release inhibitor bromocriptine in PPCM. Methods and results In this multicentre trial, 63 PPCM patients with left ventricular ejection fraction (LVEF) ≤35% were randomly assigned to short-term (1W: bromocriptine, 2.5 mg, 7 days) or long-term bromocriptine treatment (8W: 5 mg for 2 weeks followed by 2.5 mg for 6 weeks) in addition to standard heart failure therapy. Primary end point was LVEF change (delta) from baseline to 6 months assessed by magnetic resonance imaging. Bromocriptine was well tolerated. Left ventricular ejection fraction increased from 28 ± 10% to 49 ± 12% with a delta-LVEF of + 21 ± 11% in the 1W-group, and from 27 ± 10% to 51 ± 10% with a delta-LVEF of + 24 ± 11% in the 8W-group (delta-LVEF: P = 0.381). Full-recovery (LVEF ≥ 50%) was present in 52% of the 1W- and in 68% of the 8W-group with no differences in secondary end points between both groups (hospitalizations for heart failure: 1W: 9.7% vs. 8W: 6.5%, P = 0.651). The risk within the 8W-group to fail full-recovery after 6 months tended to be lower. No patient in the study needed heart transplantation, LV assist device or died. Conclusion Bromocriptine treatment was associated with high rate of full LV-recovery and low morbidity and mortality in PPCM patients compared with other PPCM cohorts not treated with bromocriptine. No significant differences were observed between 1W and 8W treatment suggesting that 1-week addition of bromocriptine to standard heart failure treatment is already beneficial with a trend for better full-recovery in the 8W group. Clinical trial registration ClinicalTrials.gov, study number: NCT00998556.

Prognostic impact of subclinical thyroid dysfunction in heart failure

BACKGROUND Therapeutic and prognostic implications of subclinical thyroid dysfunction in patients with heart failure (HF) are unclear. We compared the prognostic impact of euthyroidism, subclinical thyroid dysfunction, and euthyroid sick syndrome (ESS) in systolic HF. METHODS We included 1032 patients hospitalized for systolic HF (left ventricular ejection fraction [LVEF] ≤40%) who participated in a randomized trial assessing the effects of a HF disease management program. Patients with incomplete thyroid function tests or thyrotropic medication were excluded. In the remaining 758 subjects, the risk of all-cause death was estimated based on TSH only, or full thyroid function profile. Changes of thyroid function after six months were assessed in 451 subjects. RESULTS Subclinical thyroid dysfunction was present in 103 patients at baseline (14%). No differences were found between groups regarding NYHA class (P=0.29), and LVEF (P=0.60). After a median follow-up of three years patients with ESS (n=13) had a 3-fold age-adjusted increased risk of death compared to euthyroid patients (P=0.001). However, neither subclinical hyperthyroidism (HR 1.18, 95%CI:0.82-1.70) nor hypothyroidism (HR 1.07, 95%CI:0.58-1.98) were associated with increased age-adjusted mortality risk. Subclinical thyroid dysfunction had normalized spontaneously at follow-up in 77% of patients. However, persistent subclinical thyroid dysfunction was also not associated with worse outcome. CONCLUSIONS In this large well-characterized HF cohort, subclinical thyroid dysfunction did not predict an increased mortality risk. Thus, in patients with moderate to severe HF, further diagnostic and therapeutic procedures for subclinical thyroid dysfunction appear dispensable. ESS was an infrequent but important indicator of a poor prognosis in HF. CLINICAL TRIAL REGISTRATION URL http://www.controlled-trials.com. Unique identifier: ISRCTN23325295.

Outcome of subsequent pregnancies in patients with a history of peripartum cardiomyopathy

Subsequent pregnancies (SSPs) in patients with peripartum cardiomyopathy (PPCM) have a high risk of heart failure relapse. We report on outcome of SSPs in PPCM patients in Germany, Scotland, and South Africa.

Clinical hemodynamic evaluation of patients implanted with a fully magnetically levitated left ventricular assist device (HeartMate 3)

BACKGROUND The HeartMate 3 (HM3) is a Conformiteé Européenne (CE) mark-approved left ventricular assist device (LVAD) with a fully magnetically levitated rotor with features consisting of a wide range of operational speeds, wide flow paths and an artificial pulse. We performed a hemodynamic and echocardiographic evaluation of patients implanted with the HM3 LVAD to assess the speed range for optimal hemodynamic support. METHODS Sixteen HM3 patients underwent pump speed ramp tests with right heart catheterization (including central venous pressure [CVP], pulmonary artery pressure, pulmonary capillary wedge pressure [PCWP] and blood pressure [BP]) and 3-dimensional echocardiography (3DE). Data were recorded at up to 13 speed settings. Speed changes were in steps of 100 revolutions per minute (rpm), starting at 4,600 rpm and ramping up to 6,200 rpm. RESULTS Mean original speed was 5,306 ± 148 rpm, with a majority of patients (10 of 16, 62.5%) having normal CVPs and PCWPs at their original rpm settings. Going from lowest to highest speeds, cardiac output improved at the rate of 0.08 ± 0.08 liter/min per 100 rpm (total change 1.25 ± 1.20 liters/min) and PCWP decreased at the rate of -0.48 ± 0.27 mm Hg per 100 rpm (total change -6.13 ± 3.72 mm Hg). CVP and systolic BP did not change significantly with changes in rpm. Left ventricular end-diastolic dimension (LVEDD) decreased at a rate of -0.15 ± 0.09 cm per 100 rpm. Number of rpm was adjusted based on test results to achieve CVPs and PCWPs as close to normal limits as possible, which was feasible in 13 (81.3%) patients. For the remaining 3 patients, medical management was pursued to optimize hemodynamic support. CONCLUSION Hemodynamic normalization of pressures was achieved in the majority of patients implanted with the HM3 pump within a narrow speed range.

Effect of lung deflation with indacaterol plus glycopyrronium on ventricular filling in patients with hyperinflation and COPD (CLAIM): a double-blind, randomised, crossover, placebo-controlled, single-centre trial

BACKGROUND Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) is associated with reduced biventricular end-diastolic volumes and increased morbidity and mortality. The combination of a long-acting β agonist (LABA) and a muscarinic antagonist (LAMA) is more effective in reducing hyperinflation than LABA-inhaled corticosteroid combination therapy but whether dual bronchodilation improves cardiac function is unknown. METHODS We did a double-blind, randomised, two-period crossover, placebo-controlled, single-centre study (CLAIM) at the Fraunhofer Institute of Toxicology and Experimental Medicine (Hannover, Germany), a specialty clinic. Eligible participants were patients aged at least 40 years with COPD, pulmonary hyperinflation (defined by a baseline residual volume >135% of predicted), a smoking history of at least ten pack-years, and airflow limitation (FEV1 <80% predicted and post-bronchodilator FEV1: forced vital capacity <0·7). Patients with stable cardiovascular disease were eligible, but those with arrhythmias, heart failure, unstable ischaemic heart disease, or uncontrolled hypertension were not. We randomly assigned participants (1:1) to either receive a combined inhaled dual bronchodilator containing the LABA indacaterol (110 μg as maleate salt) plus the LAMA glycopyrronium (50 μg as bromide salt) once per day for 14 days, followed by a 14-day washout, then a matched placebo for 14 days, or to receive the same treatments in reverse order. The randomisation was done using lists and was concealed from patients and investigators. The primary endpoint was the effect of indacaterol-glycopyrronium versus placebo on left-ventricular end-diastolic volume measured by MRI done on day 1 (visit 4) and day 15 (visit 5) in treatment period 1 and on day 29 (visit 6) and day 43 (visit 7) in treatment period 2 in the per-protocol population. Left-ventricular end-diastolic volume was indexed to body surface area. Safety was assessed in all participants who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02442206. FINDINGS Between May 18, 2015, and April 20, 2017, we randomly assigned 62 eligible participants to treatment; 30 to indacaterol-glycopyrronium followed by placebo and 32 to placebo followed by indacaterol-glycopyrronium. The 62 randomly assigned patients were included in the intent-to-treat analysis. There were two protocol violations and therefore 60 were included in the per-protocol analysis. 57 patients completed both treatment periods. After indacaterol-glycopyrronium treatment, left-ventricular end-diastolic volume increased from a mean 55·46 mL/m2 (SD 15·89) at baseline to a least-squares (LS) mean of 61·76 mL/m2 (95% CI 57·68-65·84), compared with a change from 56·42 mL/m2 at baseline (13·54) to 56·53 mL/m2 (52·43-60·62) after placebo (LS means treatment difference 5·23 mL/m2 [95% CI 3·22 to 7·25; p<0·0001]). The most common adverse events reported with indacaterol-glycopyrronium were cough (in nine patients [15%] of 59) and throat irritation (in seven [12%]). With placebo, the most common adverse events reported were headache (in five patients [8%] of 61) and upper respiratory tract infection (in four [7%]). Two patients had serious adverse events: one (2%) after indacaterol-glycopyrronium (endometrial cancer) and one (2%) after placebo (myocardial infarction); these were not thought to be treatment related. No patients died during the study. INTERPRETATION This is the first study to analyse the effect of LABA-LAMA combination therapy on cardiac function in patients with COPD and lung hyperinflation. Dual bronchodilation with indacaterol-glycopyrronium significantly improved cardiac function as measured by left-ventricular end-diastolic volume. The results are important because of the known association of cardiovascular impairment with COPD, and support the early use of dual bronchodilation in patients with COPD who show signs of pulmonary hyperinflation. FUNDING Novartis Pharma GmbH.

First series of mechanical circulatory support in non-compaction cardiomyopathy: Is LVAD implantation a safe alternative?

BACKGROUND Left ventricular non-compaction (LVNC) is a rare cardiac disorder characterized by prominent trabeculae and deep recesses of the ventricular myocardium. Patients with LVNC may develop severe congestive heart failure refractory to medical therapy. However, heart transplantation is strongly limited due to donor organ shortage. Thus mechanical circulatory support by left ventricular assist devices (LVADs) is a promising alternative. Nevertheless, hypertrabeculation and proarrhythmogenic potential in LVNC might represent important hurdles for success of LVAD therapy in these patients. METHODS AND RESULTS We retrospectively analyzed the data of a total of 5 patients (3 HVAD, Heartware®; 2 HeartMate II, Thoratec®) with LVNC who underwent LVAD implantation in our institution between 2010 and 2014. Mean follow-up time was 86.5weeks. 30-day survival was 100% without major intrahospital complications. During follow-up, 3 patients developed pump thrombosis requiring pump replacement. Arrhythmias were not detected during follow-up as assessed by ICD interrogation. CONCLUSIONS LVAD implantation in LVNC can be performed with low intrahospital complication rates. However, we observed a high incidence of pump thrombosis during follow-up, possibly related to thromboembolic predisposition by the underlying LVNC. Therefore, careful management of anticoagulation appears to be critical in these patients.

Prognostic implication of right ventricular involvement in peripartum cardiomyopathy: a cardiovascular magnetic resonance study

Peripartum cardiomyopathy (PPCM) is a major cause of acute heart failure in the peripartum period and considered potentially life threatening. While many aspects of its clinical profiles have been frequently reported, functional analysis, in particular of the right ventricle, and tissue characterization by cardiovascular magnetic resonance (CMR) imaging have been only sporadically described. The aim of the present study was to analyse pathological alterations and their prognostic relevance found in CMR imaging of patients newly diagnosed with PPCM.

Early ivabradine treatment in patients with acute peripartum cardiomyopathy: Subanalysis of the German PPCM registry.

Peripartum Cardiomyopathy (PPCM) is a pregnancy associated form of heart failure and with a considerable rate of morbidity and mortality [1,2]. Although the pathophysiology of PPCM is not fully understood, emerging evidence point to vascular endothelial damage with subsequent impairment of the microcirculation as an essential pathomechanism of PPCM [3,4]. Current treatment recommendations for PPCM are based on standard heart failure therapy [1,5], although evidence-based data on any treatment option for PPCMare still missing. Among determinants of poor outcome very low baseline LVEF (b25%), LV dilatation and right ventricular function were identified in studies from different regions [6–9]. Importantly, elevated resting heart rate (HR) is common among PPCM patients and considered a negative predictor of outcome, in particular when coupled with low blood pressure (BP) [10]. In some patients with acute PPCM and severely reduced ejection fraction associated with particular poor outcome, the application of beta-blockers at higher doses is often limited due to low BP and, thus, with insufficient HR slowing effects in these patients [10]. Thus, additional HR reduction may be achieved by the “funny” (f)-channel blocker ivabradine, an established medication for patients with chronic heart failure [11]. While recommended in stable chronic heart failure at HR N70 bpm [12] data on application of ivabradine in

The Differential Diagnosis of Dyspnea.

BACKGROUND Dyspnea is a common symptom affecting as many as 25% of patients seen in the ambulatory setting. It can arise from many different underlying conditions and is sometimes a manifestation of a life-threatening disease. METHODS This review is based on pertinent articles retrieved by a selective search in PubMed, and on pertinent guidelines. RESULTS The term dyspnea refers to a wide variety of subjective perceptions, some of which can be influenced by the patients emotional state. A distinction is drawn between dyspnea of acute onset and chronic dyspnea: the latter, by definition, has been present for more than four weeks. The history, physical examination, and observation of the patients breathing pattern often lead to the correct diagnosis, yet, in 30-50% of cases, more diagnostic studies are needed, including biomarker measurements and other ancillary tests. The diagnosis can be more difficult to establish when more than one underlying disease is present simultaneously. The causes of dyspnea include cardiac and pulmonary disease (congestive heart failure, acute coronary syndrome; pneumonia, chronic obstructive pulmonary disease) and many other conditions (anemia, mental disorders). CONCLUSION The many causes of dyspnea make it a diagnostic challenge. Its rapid evaluation and diagnosis are crucial for reducing mortality and the burden of disease.

Left Ventricular Assist Device Implantation With Outflow Graft Tunneling Through the Transverse Sinus

Impairment of coronary artery flow, in either acute or chronic conditions, is a severe complication of transcatheter aortic valve (TAV) implantation, which can arise due to improper TAV positioning. However, little work has been done to quantify the effects of the TAV positioning on the coronary flow. In this study, a realistic in vitro model of coronary artery flow was developed and used to investigate the impact of TAV deployed orientations on coronary flow. The coronary hemodynamics was first replicated mathematically using a lumped parameter model with time-varying myocardial resistance. Based on the analytical model, two stepper motor controlled stopcock valves were integrated in a left heart simulator to represent the variable myocardial resistance in the experimental setup. The coronary flow and pressure waveforms obtained from the in vitro system were consistent with published data. With a TAV deployed in different orientations, the measured results demonstrated that TAV orientation does not have a significant impact on the coronary flow. The developed in vitro model can be further utilized to simulate coronary flow under various pathological conditions.