Vojtech Melenovsky - Academia.edu (original) (raw)

Papers by Vojtech Melenovsky

Journal of the American College of Cardiology, 2019

Background: Pulmonary hypertension (PH) is associated with adverse outcomes in HFpEF but its mech... more Background: Pulmonary hypertension (PH) is associated with adverse outcomes in HFpEF but its mechanisms are unclear. Neurohormonal activation may contribute to PH severity and be amenable to treatment. Methods: Invasive hemodynamics, right ventricular (RV) function (tissue Doppler echocardiography), and levels of C-terminal proendothelin-1 [ET-1] and mid-regional pro adrenomedullin [ADM]) were measured at rest and during exercise in subjects with HFpEF (n=38) and controls without HF (n=20). Results: Compared to controls, HFpEF subjects displayed elevated ET-1 and ADM (69 [56, 74] vs. 105 [83, 130] pmol/L; 0.6 [0.5, 0.7] vs. 1.0 [0.8, 1.4] nmol/L; both p<0.0001). ET-1 and ADM levels were directly correlated with mean pulmonary artery (PA) pressure and inversely correlated with PA compliance (Figure). Compared to controls, HFpEF subjects displayed reduced peak oxygen consumption (14.2±4.1 vs. 7.8±2.4 ml/min•kg; p<0.0001) and impaired RV reserve (increase in RV s' 3.2±2.9 vs. 1.0±2.3 cm/sec; p=0.01). ET-1 and ADM levels were inversely correlated with RV reserve (r=-0.59 and r=-0.67), cardiac output responses (r=-0.59 and r=-0.61), and exercise capacity (r=-0.60 and r=-0.67; all p<0.05). Conclusion: Activation of the endothelin and adrenomedullin axes are associated with pulmonary vascular disease and RV reserve limitations in HFpEF. Further study is required to determine if therapies targeting these pathways can improve outcomes in patients with the HFpEF-PH phenotype.

Scientific Reports

Mechanisms of right ventricular (RV) dysfunction in heart failure (HF) are poorly understood. RV ... more Mechanisms of right ventricular (RV) dysfunction in heart failure (HF) are poorly understood. RV response to volume overload (VO), a common contributing factor to HF, is rarely studied. The goal was to identify interventricular differences in response to chronic VO. Rats underwent aorto-caval fistula (ACF)/sham operation to induce VO. After 24 weeks, RV and left ventricular (LV) functions, gene expression and proteomics were studied. ACF led to biventricular dilatation, systolic dysfunction and hypertrophy affecting relatively more RV. Increased RV afterload contributed to larger RV stroke work increment compared to LV. Both ACF ventricles displayed upregulation of genes of myocardial stress and metabolism. Most proteins reacted to VO in a similar direction in both ventricles, yet the expression changes were more pronounced in RV (pslope: < 0.001). The most upregulated were extracellular matrix (POSTN, NRAP, TGM2, CKAP4), cell adhesion (NCAM, NRAP, XIRP2) and cytoskeletal protein...

Frontiers in Pharmacology, 2021

Chronic volume overload induces multiple cardiac remodeling processes that finally result in ecce... more Chronic volume overload induces multiple cardiac remodeling processes that finally result in eccentric cardiac hypertrophy and heart failure. We have hypothesized that chronic angiotensin-converting enzyme (ACE) inhibition by trandolapril might affect various remodeling processes differentially, thus allowing their dissociation. Cardiac remodeling due to chronic volume overload and the effects of trandolapril were investigated in rats with an aortocaval fistula (ACF rats). The aortocaval shunt was created using a needle technique and progression of cardiac remodeling to heart failure was followed for 24 weeks. In ACF rats, pronounced eccentric cardiac hypertrophy and contractile and proarrhythmic electrical remodeling were associated with increased mortality. Trandolapril substantially reduced the electrical proarrhythmic remodeling and mortality, whereas the effect on cardiac hypertrophy was less pronounced and significant eccentric hypertrophy was preserved. Effective suppression ...

Kidney and Blood Pressure Research, 2019

Background: Some patients with heart failure (HF) are more prone to systemic congestion than othe... more Background: Some patients with heart failure (HF) are more prone to systemic congestion than others. The goal of this study was to identify clinical and humoral factors linked to congestion and its prognostic impact in HF patients. Methods: A total of 371 advanced HF patients underwent physical examination, echocardiography, right heart catheterization, blood samplings, and Minnesota Living with HF Questionnaire. Subjects were followed-up for adverse events (death, urgent transplantation, or assist device implantation without heart transplantation). Results: Thirty-one percent of patients were classified as prone to congestion. During a median follow-up of 1,093 days, 159 (43%) patients had an adverse event. In the Cox analysis, the congestion-prone (CP) status was associated with a 43% higher event risk. The CP status was strongly (p ˂ 0.001) associated with body weight loss, right ventricular dysfunction (RVD), dilated inferior vena cava (IVC), diuretics, and beta-blockers prescri...

$Research paper thumbnail of Right heart dysfunction in heart failure with preserved ejection fraction$

European heart journal, Jan 21, 2014

Right heart function is not well characterized in patients with heart failure and preserved eject... more 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. 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 ...

JACC: Cardiovascular Imaging

Frontiers in Pharmacology

An association between congestive heart failure (CHF) and chronic kidney disease (CKD) results in... more An association between congestive heart failure (CHF) and chronic kidney disease (CKD) results in extremely poor patient survival rates. Previous studies have shown that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, improves the survival rate in CHF induced by aorto-caval fistula (ACF) and attenuates CKD progression. This prompted us to examine if sEH inhibitor treatment would improve the outcome if both experimental conditions are combined. Fawn-hooded hypertensive (FHH) rats, a genetic model showing early CKD development was employed, and CHF was induced by ACF. Treatment with an sEH inhibitor was initiated 4 weeks after ACF creation, in FHH and in fawn-hooded low-pressure (FHL) rats, a control strain without renal damage. The follow-up period was 20 weeks. We found that ACF FHH rats exhibited substantially lower survival rates (all the animals died by week 14) as compared with the 64% survival rate observed in ACF FHL rats. The former group showed pronounced albuminuria (almost 30-fold higher than in FHL) and reduced intrarenal EET concentrations. The sEH inhibitor treatment improved survival rate and distinctly reduced increases in albuminuria in ACF FHH and in ACF FHL rats, however, all the beneficial actions were more pronounced in the hypertensive strain. These data indicate that pharmacological blockade of sEH could be a novel therapeutic approach for the treatment of CHF, particularly under conditions when it is associated with CKD.

International Journal of Molecular Sciences

Doxorubicin’s (DOX) cardiotoxicity contributes to the development of chemotherapy-induced heart f... more Doxorubicin’s (DOX) cardiotoxicity contributes to the development of chemotherapy-induced heart failure (HF) and new treatment strategies are in high demand. The aim of the present study was to characterize a DOX-induced model of HF in Ren-2 transgenic rats (TGR), those characterized by hypertension and hyperactivity of the renin-angiotensin-aldosterone system, and to compare the results with normotensive transgene-negative, Hannover Sprague-Dawley (HanSD) rats. DOX was administered for two weeks in a cumulative dose of 15 mg/kg. In HanSD rats DOX administration resulted in the development of an early phase of HF with the dominant symptom of bilateral cardiac atrophy demonstrable two weeks after the last DOX injection. In TGR, DOX caused substantial impairment of systolic function already at the end of the treatment, with further progression observed throughout the experiment. Additionally, two weeks after the termination of DOX treatment, TGR exhibited signs of HF characteristic fo...

Journal of Cachexia, Sarcopenia and Muscle

Journal of the American College of Cardiology

Cardiac reserve is depressed in patients with heart failure and preserved ejection fraction (HFpE... more Cardiac reserve is depressed in patients with heart failure and preserved ejection fraction (HFpEF). The mechanisms causing this are poorly understood. The authors hypothesized that myocardial injury might contribute to the hemodynamic derangements and cardiac reserve limitations that are present in HFpEF. Markers of cardiomyocyte injury, central hemodynamics, ventricular function, and determinants of cardiac oxygen supply-demand balance were measured. Subjects with HFpEF (n = 38) and control subjects without heart failure (n = 20) underwent cardiac catheterization, echocardiography, and expired gas analysis at rest and during exercise. Central venous blood was sampled to measure plasma high-sensitivity troponin T levels as an index of cardiomyocyte injury. Compared with control subjects, troponins were more than 2-fold higher in subjects with HFpEF at rest and during exercise (p &amp;lt; 0.0001). Troponin levels were directly correlated with left ventricular (LV) filling pressures (r = 0.52; p &amp;lt; 0.0001) and diastolic dysfunction (r = -0.43; p = 0.002). Although myocardial oxygen demand was similar, myocardial oxygen supply was depressed in HFpEF, particularly during exercise (coronary perfusion pressure-time integral; 44 ± 9 mm Hg × s × min × l × dl vs. 30 ± 9 mm Hg × s × min × l × dl; p &amp;lt; 0.0001), and reduced indices of supply were correlated with greater myocyte injury during exercise (r = -0.44; p = 0.0008). Elevation in troponin with exercise was directly correlated with an inability to augment LV diastolic (r = -0.40; p = 0.02) and systolic reserve (r = -0.57; p = 0.0003), greater increases in LV filling pressures (r = 0.55; p &amp;lt; 0.0001), blunted cardiac output response (r = -0.44; p = 0.002), and more severely depressed aerobic capacity in HFpEF. Limitations in LV functional reserve and the hemodynamic derangements that develop secondary to these limitations during exercise in HFpEF are correlated with the severity of cardiac injury, assessed by plasma levels of troponin T. Further study is warranted to determine the mechanisms causing myocyte injury in HFpEF and the potential role of ischemia, and to identify and test novel interventions targeted to these mechanisms. (EXEC [Study of Exercise and Heart Function in Patients With Heart Failure and Pulmonary Vascular Disease]; NCT01418248).

Medical image analysis, 2018

Cardiac allograft vasculopathy (CAV) accounts for about 30% of all heart-transplant (HTx) patient... more Cardiac allograft vasculopathy (CAV) accounts for about 30% of all heart-transplant (HTx) patient deaths. For patients at high risk for CAV complications after HTx, therapy must be initiated early to be effective. Therefore, new phenotyping approaches are needed to identify such HTx patients at the earliest possible time. Coronary optical coherence tomography (OCT) images were acquired from 50 HTx patients 1 and 12 months after HTx. Quantitative analysis of coronary wall morphology used LOGISMOS segmentation strategy to simultaneously identify three wall-layer surfaces for the entire pullback length in 3D: luminal, outer intimal, and outer medial surfaces. To quantify changes of coronary wall morphology between 1 and 12 months after HTx, the two pullbacks were mutually co-registered. Validation of layer thickness measurements showed high accuracy of performed layer analyses with layer thickness measures correlating well with manually-defined independent standard (R = 0.93, y=1.0x-6....

$Research paper thumbnail of Haemodynamics, dyspnoea, and pulmonary reserve in heart failure with preserved ejection fraction$

European Heart Journal

Aims Increases in left ventricular filling pressure are a fundamental haemodynamic abnormality in... more Aims Increases in left ventricular filling pressure are a fundamental haemodynamic abnormality in heart failure with preserved ejection fraction (HFpEF). However, very little is known regarding how elevated filling pressures cause pulmonary abnormalities or symptoms of dyspnoea. We sought to determine the relationships between simultaneously measured central haemodynamics, symptoms, and lung ventilatory and gas exchange abnormalities during exercise in HFpEF. Methods and results Subjects with invasively-proven HFpEF (n = 50) and non-cardiac causes of dyspnoea (controls, n = 24) underwent cardiac catheterization at rest and during exercise with simultaneous expired gas analysis. During submaximal (20 W) exercise, subjects with HFpEF displayed higher pulmonary capillary wedge pressures (PCWP) and pulmonary artery pressures, higher Borg perceived dyspnoea scores, and increased ventilatory drive and respiratory rate. At peak exercise, ventilation reserve was reduced in HFpEF compared wi...

JACC: Heart Failure

This study sought to define the invasive hemodynamic correlates of peak oxygen consumption (Vo) i... more This study sought to define the invasive hemodynamic correlates of peak oxygen consumption (Vo) in both supine and upright exercise in heart failure with preserved ejection fraction (HFpEF) and evaluate its diagnostic role as a method to discriminate HFpEF from noncardiac etiologies of dyspnea (NCD). Peak Vo is depressed in patients with HFpEF. The hemodynamic correlates of reduced peak Vo and its role in the clinical evaluation of HFpEF are unclear. Consecutive patients with dyspnea and normal EF (N = 206) undergoing both noninvasive upright and invasive supine cardiopulmonary exercise testing were examined. Patients with invasively verified HFpEF were compared with those with NCD. Compared with NCD (n = 72), HFpEF patients (n = 134) displayed lower peak Vo during upright and supine exercise. Left heart filling pressures during exercise were inversely correlated with peak Vo in HFpEF, even after accounting for known determinants of O transport according to the Fick principle. Very low upright peak Vo (&amp;lt;14 ml/kg/min) discriminated HFpEF from NCD with excellent specificity (91%) but poor sensitivity (50%). Preserved peak Vo (&amp;gt;20 ml/kg/min) excluded HFpEF with high sensitivity (90%) but had poor specificity (49%). Intermediate peak Vo cutoff points were associated with substantial overlap between cases and NCD. Elevated cardiac filling pressure during exercise is independently correlated with reduced exercise capacity in HFpEF, irrespective of body position, emphasizing its importance as a novel therapeutic target. Noninvasive cardiopulmonary testing discriminates HFpEF and NCD at high and low values, but additional testing is required for patients with intermediate peak Vo.

Kidney and Blood Pressure Research

This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 I... more This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

ESC Heart Failure

Protein-losing enteropathy (PLE) due to leakage of lymph into the gut sometimes occurs in young p... more Protein-losing enteropathy (PLE) due to leakage of lymph into the gut sometimes occurs in young patients after Fontan palliation but is very rarely reported with other aetiologies of chronic heart failure (HF). PLE leads to severe hypoalbuminemia and immunodeficiency and is associated with poor prognosis. The mechanisms and the predispositions to PLE are poorly understood. Here, we report an adult patient with advanced HF due to non-ischaemic non-dilated hypocontractile cardiomyopathy who developed severe PLE, probably owing to increased ventricular stiffness and constraint by atypically placed epicardial electrode encircling both ventricles. Importantly, both PLE and immunodeficiency completely resolved after heart transplantation.

Clinical research in cardiology : official journal of the German Cardiac Society, Jan 26, 2018

We investigated whether the increase of plasma natriuretic peptides (NPs) in atrial fibrillation ... more We investigated whether the increase of plasma natriuretic peptides (NPs) in atrial fibrillation (AF) is independent of the effect of AF on the left atrial (LA) hemodynamics. Hemodynamically stable patients scheduled for AF ablation underwent assessment of B-type natriuretic peptide (BNP) and mid-regional pro-atrial natriuretic peptide (MR-proANP), echocardiography, and direct measurement of left atrial (LA) pressure. Concentrations of the NPs were compared between patients in AF (n = 31) and controls in sinus rhythm (SR; n = 31) who were matched for age, gender, heart rate, left ventricular ejection fraction, LA volume index, and directly measured mean LA pressure. Eighteen patients underwent serial measurement of NPs and LA pressure during native SR and after 20 min of pacing-induced AF. Compared to the patients in SR, the patients in AF had 2.6 times higher unadjusted BNP [median (inter-quartile range), 101 (63, 129) vs. 38 (26, 79) ng/L] and two times higher unadjusted MR-proANP...

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, Jan 6, 2018

Optical coherence tomography (OCT)-based studies of cardiac allograft vasculopathy (CAV) publishe... more Optical coherence tomography (OCT)-based studies of cardiac allograft vasculopathy (CAV) published thus far have focused mainly on frame-based qualitative analysis of the vascular wall. Full capabilities of this inherently 3-dimensional (3D) imaging modality to quantify CAV have not been fully exploited. Coronary OCT imaging was performed at 1 month and 12 months after heart transplant (HTx) during routine surveillance cardiac catheterization. Both baseline and follow-up OCT examinations were analyzed using proprietary, highly automated 3D graph-based optimal segmentation software. Automatically identified borders were efficiently adjudicated using our "just-enough-interaction" graph-based segmentation approach that allows to efficiently correct local and regional segmentation errors without slice-by-slice retracing of borders. A total of 50 patients with paired baseline and follow-up OCT studies were included. After registration of baseline and follow-up pullbacks, a tota...