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Reichenbach A.,Institute for Clinical and Experimental Medicine IKEM | Al-Hiti H.,Institute for Clinical and Experimental Medicine IKEM | Malek I.,Institute for Clinical and Experimental Medicine IKEM | Pirk J.,Institute of Clinical and Experimental Medicine IKEM | And 3 more authors.
International Journal of Cardiology | Year: 2013

Background: The goal was to examine the hemodynamic and clinical effects of long-term therapy with PDE5 inhibitor sildenafil (SILD) in patients with advanced, pre-transplant heart failure (HF) and severe pulmonary hypertension (PH), in comparison to a similar control group (CON). Methods: In this non-randomized, retrospective case-control study, 32 middle-aged patients (81% males) with advanced systolic HF (80% ≥ NYHA III, 56% ischemic) and severe pre-capillary PH (transpulmonary pressure gradient > 15 mm Hg) were studied before and after initiation of SILD (dose 73 ± 25 mg/day) and were compared to 15 CON patients, matched for key clinical characteristics (including PH severity, age and co-morbidities), not exposed to SILD. Changes at 3 months and the long-term outcome were compared between groups. Results: SILD significantly reduced pulmonary vascular resistance (- 32% vs. baseline), transpulmonary gradient (- 25%) and increased cardiac output (+ 15%) compared to controls, without affecting systemic or ventricular filling pressures. SILD-treated subjects experienced an improvement in NYHA class and had a steady body weight which contrasted with significant weight loss in the CON group (by - 4.8%, absolutely by 4.3 ± 6 kg). During follow-up (median 349 days from baseline), 60% of patients underwent heart transplantation. Two patients in CON group had severe post-transplant failure of the right ventricle, none in SILD group. Overall pre- and peritransplant survival (censored 30 days after transplantation) was significantly better in SILD than CON group (93.7 vs 60%, p = 0.0048). Conclusions: In patients with advanced HF and severe PH, SILD therapy has beneficial effects on hemodynamics, clinical status, cardiac cachexia, and contributes to improved peri-transplant survival. © 2012 Elsevier Ireland Ltd. All rights reserved.


Hwang S.-J.,Mayo Medical School | Hwang S.-J.,Gyeongsang National University | Melenovsky V.,Mayo Medical School | Melenovsky V.,Institute of Clinical and Experimental Medicine IKEM | Borlaug B.A.,Mayo Medical School
Journal of the American College of Cardiology | Year: 2014

Objectives This study investigated the characteristics, evaluation, prognostic impact, and treatment of coronary artery disease (CAD) in patients with heart failure and preserved ejection fraction (HFpEF). Background CAD is common in patients with HFpEF, but it remains unclear how CAD should be categorized, evaluated for, and treated in HFpEF. Methods Clinical, hemodynamic, echocardiographic, treatment, and outcome characteristics were examined in consecutive patients with previous HFpEF hospitalizations who underwent coronary angiography. Results Of the 376 HFpEF patients examined, 255 (68%) had angiographically-proven CAD. Compared with HFpEF patients without CAD, patients with CAD were more likely to be men, to have CAD risk factors, and to be treated with anti-ischemic medications. However, symptoms of angina and heart failure were similar in patients with and without CAD, as were measures of cardiovascular structure, function, and hemodynamics. Compared with patients without CAD, HFpEF patients with CAD displayed greater deterioration in ejection fraction and increased mortality, independent of other predictors (hazard ratio: 1.71, 95% confidence interval: 1.03 to 2.98; p = 0.04). Complete revascularization was associated with less deterioration in ejection fraction and lower mortality compared with patients who were not completely revascularized, independent of other predictors (hazard ratio: 0.56, 95% confidence interval: 0.33 to 0.93; p = 0.03). Conclusions CAD is common in patients with HFpEF and is associated with increased mortality and greater deterioration in ventricular function. Revascularization may be associated with preservation of cardiac function and improved outcomes in patients with CAD. Given the paucity of effective treatments for HFpEF, prospective trials are urgently needed to determine the optimal evaluation and management of CAD in HFpEF. © 2014 by the American College of Cardiology Foundation. Published by Elsevier Inc.


Reddy V.Y.,Mount Sinai School of Medicine | Knops R.E.,University of Amsterdam | Sperzel J.,Kerckhoff Heart and Thorax Center | Miller M.A.,Mount Sinai School of Medicine | And 12 more authors.
Circulation | Year: 2014

Background-: Conventional cardiac pacemakers are associated with several potential short-and long-term complications related to either the transvenous lead or subcutaneous pulse generator. We tested the safety and clinical performance of a novel, completely self-contained leadless cardiac pacemaker. Methods and Results-: The primary safety end point was freedom from complications at 90 days. Secondary performance end points included implant success rate, implant time, and measures of device performance (pacing/sensing thresholds and rate-responsive performance). The mean age of the patient cohort (n=33) was 77±8 years, and 67% of the patients were male (n=22/33). The most common indication for cardiac pacing was permanent atrial fibrillation with atrioventricular block (n=22, 67%). The implant success rate was 97% (n=32). Five patients (15%) required the use of >1 leadless cardiac pacemaker during the procedure. One patient developed right ventricular perforation and cardiac tamponade during the implant procedure, and eventually died as the result of a stroke. The overall complication-free rate was 94% (31/33). After 3 months of follow-up, the measures of pacing performance (sensing, impedance, and pacing threshold) either improved or were stable within the accepted range. Conclusions-: In a prospective nonrandomized study, a completely self-contained, single-chamber leadless cardiac pacemaker has shown to be safe and feasible. The absence of a transvenous lead and subcutaneous pulse generator could represent a paradigm shift in cardiac pacing. Clinical Trial Registration-: URL: http://clinicaltrials.gov. Unique identifier: NCT01700244. © 2014 American Heart Association, Inc.


Lejskova M.,Institute for Postgraduate Medical Education | Lejskova M.,Thomayer Hospital and Outpatient Clinic | Alusi S.,Institute for Postgraduate Medical Education | Alusi S.,Thomayer Hospital and Outpatient Clinic | And 3 more authors.
Physiological Research | Year: 2012

Cardiovascular disease, while rare in women of reproductive age, is the main cause of mortality in menopause. The purpose of our study was to determine the association of natural menopause with cardiovascular risk factors, including their clustering into metabolic syndrome (MS). A random 5 % representative population sample of women aged 45-54 years was examined. In 575 women, we were able to determine their natural reproductive aging status. Multiple regression analysis was used to calculate the association between age, menopausal status, and risk factors under study. After adjustment for age, there was an increase in the odds ratio of developing MS, as defined by NCEP (OR=2.0; 95 % CI [1.1; 3.7]), and an increase in plasma lipid ratios (total cholesterol/HDL-C, LDL-C/HDL-C, apolipoprotein-B/ apolipoprotein-A1; p<0.05 for all) in postmenopausal women. Age, but not menopausal status, was associated with some single components of MS; only waist circumference significantly increased after menopause, independently of age. Clustering of risk factors in MS and lipid ratios (combined factors) was strongly associated with menopause whereas worsening of single components of MS was strongly associated with age. In conclusion, based on our results, the menopause may pose a risk to women through clustering of cardiovascular risk factors beyond simple aging. © 2012 Institute of Physiology v.v.i.


Knops R.E.,University of Amsterdam | Tjong F.V.Y.,University of Amsterdam | Neuzil P.,Homolka Hospital | Sperzel J.,Kerckhoff Heart and Thorax Center | And 10 more authors.
Journal of the American College of Cardiology | Year: 2015

Background A leadless cardiac pacemaker (LCP) system was recently introduced to overcome lead-related complications of conventional pacing systems. To date, long-term results of an LCP system are unknown. Objectives The aim of this study was to assess the complication incidence, electrical performance, and rate response characteristics within the first year of follow-up of patients implanted with an LCP. Methods We retrospectively assessed intermediate-term follow-up data for 31 of 33 patients from the LEADLESS trial cohort who had an indication for single-chamber pacing and received an LCP between December 2012 and April 2013. Results The mean age of the cohort was 76 ± 8 years, and 65% were male. Between 3 and 12 months of follow-up, there were no pacemaker-related adverse events reported. The pacing performance results at 6- and 12-month follow-up were, respectively, as follows: mean pacing threshold (at a 0.4-ms pulse width), 0.40 ± 0.26 V and 0.43 ± 0.30 V; R-wave amplitude 10.6 ± 2.6 mV and 10.3 ± 2.2 mV; and impedance 625 ± 205 Ω and 627 ± 209 Ω. At the 12-month follow-up in 61% of the patients (n = 19 of 31), the rate response sensor was activated, and an adequate rate response was observed in all patients. Conclusions The LCP demonstrates very stable performance and reassuring safety results during intermediate-term follow-up. These results support the use of the LCP as a promising alternative to conventional pacemaker systems. Continued evaluation is warranted to further characterize this system. (Evaluation of a New Cardiac Pacemaker; NCT01700244) © 2015 American College of Cardiology Foundation.


Kettner J.,Institute of Clinical and Experimental Medicine IKEM | Skalsky I.,Institute of Clinical and Experimental Medicine IKEM | Levcik M.,Institute of Clinical and Experimental Medicine IKEM
Heart Surgery Forum | Year: 2011

Severe aortic stenosis (AS) has a poor prognosis when associated with left ventricular dysfunction and congestive heart failure. Despite a relatively high operative mortality, most patients with severe AS and a depressed left ventricular ejection fraction (LVEF) should be considered candidates for aortic valve replacement. The CentriMag left ventricular assist system (Levitronix) can be used for perioperative or postcardiotomy circulatory support for the failing heart. In this case report, we report the successful use of the Levitronix CentriMag device as perioperative support in a high-risk patient with severe AS, significant mitral insufficiency, and a poor LVEF with advanced organ failure. © 2011 Forum Multimedia Publishing, LLC.


Melenovsky V.,Mayo Medical School | Melenovsky V.,Institute of Clinical and Experimental Medicine IKEM | Hwang S.-J.,Mayo Medical School | Lin G.,Mayo Medical School | And 2 more authors.
European Heart Journal | Year: 2014

Aim Right heart function is not well characterized in patients with heart failure and preserved ejection fraction (HFpEF). The goal of this study was to examine the haemodynamic, clinical, and prognostic correlates of right ventricular dysfunction (RVD) in HFpEF. Methods and results Heart failure and preserved ejection fraction patients (n = 96) and controls (n = 46) underwent right heart catheterization, echocardiographic assessment, and follow-up. Right and left heart filling pressures, pulmonary artery (PA) pressures, and right-sided chamber dimensions were higher in HFpEF compared with controls, while left ventricular size and EF were similar. Right ventricular dysfunction (defined by RV fractional area change, FAC <35%) was present in 33% of HFpEF patients and was associated with more severe symptoms and greater comorbidity burden. Right ventricular function was impaired in HFpEF compared with controls using both load-dependent (FAC: 40 ± 10 vs. 53 ± 7%, P < 0.0001) and load-independent indices (FAC adjusted to PA pressure, P = 0.003), with enhanced afterload-sensitivity compared with controls (steeper FAC vs. PA pressure relationship). In addition to haemodynamic load, RVD in HFpEF was associated with male sex, atrial fibrillation, coronary disease, and greater ventricular interdependence. Over a median follow-up of 529 days (IQR: 143-1066), 31% of HFpEF patients died. In Cox analysis, RVD was the strongest predictor of death (HR: 2.4, 95% CI: 1.6-2.6; P < 0.0001). Conclusion Right heart dysfunction is common in HFpEF and is caused by both RV contractile impairment and afterload mismatch from pulmonary hypertension. Right ventricular dysfunction in HFpEF develops with increasing PA pressures, atrial fibrillation, male sex, and left ventricular dysfunction, and may represent a novel therapeutic target. © 2014 Published on behalf of the European Society of Cardiology.


Abudiab M.M.,Mayo Medical School | Redfield M.M.,Mayo Medical School | Melenovsky V.,Mayo Medical School | Melenovsky V.,Institute of Clinical and Experimental Medicine IKEM | And 4 more authors.
European Journal of Heart Failure | Year: 2013

AimsExercise intolerance is a hallmark of heart failure with preserved ejection fraction (HFpEF), yet its mechanisms remain unclear. The current study sought to determine whether increases in cardiac output (CO) during exercise are appropriately matched to metabolic demands in HFpEF.Methods and resultsPatients with HFpEF (n = 109) and controls (n = 73) exercised to volitional fatigue with simultaneous invasive (n = 96) or non-invasive (n = 86) haemodynamic assessment and expired gas analysis to determine oxygen consumption (VO2) during upright or supine exercise. At rest, HFpEF patients had higher LV filling pressures but similar heart rate, stroke volume, EF, and CO. During supine and upright exercise, HFpEF patients displayed lower peak VO2 coupled with blunted increases in heart rate, stroke volume, EF, and CO compared with controls. LV filling pressures increased dramatically in HFpEF patients, with secondary elevation in pulmonary artery pressures. Reduced peak VO2 in HFpEF patients was predominantly attributable to CO limitation, as the slope of the increase in CO relative to VO2 was 20% lower in HFpEF patients (5.9 ± 2.5 vs. 7.4 ± 2.6 L blood/L O2, P = 0.0005). While absolute increases in arterial-venous O2 difference with exercise were similar in HFpEF patients and controls, augmentation in arterial-venous O2 difference relative to VO2 was greater in HFpEF patients (8.9 ± 3.4 vs. 5.5 ± 2.0 min/dL, P < 0.0001). These differences were observed in the total cohort and when upright and supine exercise modalities were examined individually.ConclusionWhile diastolic dysfunction promotes congestion and pulmonary hypertension with stress in HFpEF, reduction in exercise capacity is predominantly related to inadequate CO relative to metabolic needs. © 2013 The Author.


Melenovsky V.,Institute of Clinical and Experimental Medicine | Melenovsky V.,Mayo Medical School | Kotrc M.,Institute of Clinical and Experimental Medicine | Borlaug B.A.,Mayo Medical School | And 4 more authors.
Journal of the American College of Cardiology | Year: 2013

Objectives This study sought to examine the relationships between right ventricular (RV) function, body composition, and prognosis in patients with advanced heart failure (HF). Background Previous studies investigating HF-related cachexia have not examined the impact of RV function on body composition. We hypothesized that RV dysfunction is linked to weight loss, abnormal body composition, and worsened prognosis in advanced HF. Methods Subjects with advanced HF (n = 408) underwent prospective assessment of body composition (skinfold thickness, dual-energy X-ray absorptiometry), comprehensive echocardiography, and blood testing. Subjects were followed up for adverse events (defined as death, transplantation, or circulatory assist device). Results Subjects with RV dysfunction (51%) had lower body mass index, lower fat mass index, and were more likely to display cachexia (19%). The extent of RV dysfunction correlated with greater antecedent weight loss and a lower fat/lean body mass ratio. Over a median follow-up of 541 days, there were 150 events (37%). Risk of event was greater in subjects with RV dysfunction (hazard ratio: 3.09 [95% confidence interval (CI): 2.18 to 4.45]) and cachexia (hazard ratio: 2.90 [95% CI: 2.00 to 4.12]) in univariate and multivariate analyses. Increased body mass index was associated with a lower event rate (HR per kg/m2: 0.92 [95% CI: 0.88 to 0.96]), and this protection was mediated by a higher fat mass (0.91 [95% CI: 0.87 to 0.96]) but not a fat-free mass index (0.97 [95% CI: 0.92 to 1.03]). Conclusions RV dysfunction and cardiac cachexia often coexist, have additive adverse impact, and might be mechanistically interrelated. Wasting of fat but not of lean mass was predictive of adverse outcome, suggesting that fat loss is either a surrogate of enhanced catabolism or adipose tissue is cardioprotective in the context of HF. © 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.


Simonneau G.,University Paris - Sud | Galie N.,University of Bologna | Jansa P.,Charles University | Meyer G.M.B.,Complexo Hospitalar Sta Casa Of Porto Alegre | And 5 more authors.
International Journal of Cardiology | Year: 2014

Background The double-blind phase of the EARLY study of bosentan remains the only randomized controlled trial of a PAH-targeted therapy in World Health Organization functional class (FC) II patients. We report on the efficacy, safety, disease worsening, survival and prognostic factors in mildly symptomatic pulmonary arterial hypertension (PAH) patients treated with bosentan in the open-label extension phase of the EARLY study. Methods Exploratory efficacy outcomes included 6-minute walk distance (6MWD) and WHO FC. Adverse events were recorded. Kaplan-Meier analysis was used to estimate time to first PAH worsening event (death, initiation of intravenous or subcutaneous prostanoids, atrial septostomy or lung transplantation) and survival. Cox regression analysis determined factors prognostic of survival. Results Median exposure to bosentan (n = 173) was 51 months. At the end of the bosentan-treatment assessment period, 77.8% of patients were in WHO FC I/II. Adverse events led to discontinuation of bosentan in 20.2% of patients. Aminotransferase elevations > 3 × upper limit of normal occurred in 16.8%. Four-year PAH-event-free survival and survival were 79.5% (95% confidence intervals [95% CI] 73.4, 85.6) and 84.8% [95% CI 79.4, 90.2], respectively. Low 6MWD, low mixed venous oxygenation, high N-terminal pro hormone of brain natriuretic peptide levels and PAH associated with connective tissue disease were associated with a higher risk of death. Conclusions The majority of patients exposed to long-term bosentan maintained or improved their functional class. Approximately 20% of the patients discontinued treatment because of adverse events, which were most commonly PAH worsening and elevated liver enzymes. © 2014 unknown.

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