Novel endotypes in heart failure: effects on guideline-directed medical therapy.

Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.

INTRODUCTION: Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. METHODS AND RESULTS: BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05). CONCLUSION: Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%.

CARDIOCARE: An integrated platform for the management of elderly multimorbid patients with breast cancer therapy induced cardiac toxicity.

Breast cancer (BC) remains the most diagnosed cancer in women, accounting for 12% of new annual cancer cases in Europe and worldwide. Advances in surgery, radiotherapy and systemic treatment have resulted in improved clinical outcomes and increased survival rates in recent years. However, BC therapy-related cardiotoxicity, may severely impact short- and long-term quality of life and survival. This study presents the CARDIOCARE platform and its main components, which by integrating patient-specific data from different categories, data from patient-oriented eHealth applications and wearable devices, and by employing advanced data mining and machine learning approaches, provides the healthcare professionals with a valuable tool for effectively managing BC patients and preventing or alleviating treatment induced cardiotoxicity.Clinical Relevance- Through the adoption of CARDIOCARE platform healthcare professionals are able to stratify patients for their risk for cardiotoxicity and timely apply adequate interventions to prevent its onset.

Disconnect between the effects of serelaxin on renal function and outcome in acute heart failure.

BACKGROUND: We aimed to study whether improvement in renal function by serelaxin in patients who were hospitalized for acute heart failure (HF) might explain any potential effect on clinical outcomes. METHODS: We included 6318 patients from the RELAXin in AHF-2 (RELAX-AHF2) study. Improvement in renal function was defined as a decrease in serum creatinine of ≥ 0.3 mg/dL and ≥ 25%, or increase in estimated glomerular filtration rate of ≥ 25% between baseline and day 2. Worsening renal function (WRF) was defined as the reverse. We performed causal mediation analyses regarding 180-day all-cause mortality (ACM), cardiovascular death (CVD), and hospitalization for HF/renal failure. RESULTS: Improvement in renal function was more frequently observed with serelaxin when compared with placebo [OR 1.88 (95% CI 1.64-2.15, p < 0.0001)], but was not associated with subsequent clinical outcomes. WRF occurred less frequent with serelaxin [OR 0.70 (95% CI 0.60-0.83, p < 0.0001)] and was associated with increased risk of ACM, worsening HF and the composite of CVD and HF or renal failure hospitalization. Improvement in renal function did not mediate the treatment effect of serelaxin [CVD HR 1.01 (0.99-1.04), ACM HR 1.01 (0.99-1.03), HF/renal failure hospitalization HR 0.99 (0.97-1.00)]. CONCLUSIONS: Despite the significant improvement in renal function by serelaxin in patients with acute HF, the potential beneficial treatment effect was not mediated by improvement in renal function. These data suggest that improvement in renal function might not be a suitable surrogate marker for potential treatment efficacy in future studies with novel relaxin agents in acute HF. Central illustration. Conceptual model explaining mediation analysis; treatment efficacy of heart failure therapies mediated by renal function.

The quality of death certification practice in Greece.

BACKGROUND: Death certification represents an excellent source for mortality statistics and appropriate public health surveillance. Errors in reporting the cause of death impede the development of national health policies and, accordingly, allocation of resources. The aim of this study was to determine the frequency of errors in the cause of death and to identify factors that may be associated with inaccuracies in death certificates. METHODS: A cross-sectional study of all natural death certifications in a defined Greek region was conducted over the period 2006-2010. Specific criteria for major and minor errors were adopted for the evaluation of death certificates. RESULTS: A total of 5,828 death certificates due to natural causes were identified. Major errors were found in 64.6 % of them with almost every death certificate having a minor error. Major error rate did not differ per year (p =0.65). Most commonly encountered major errors were a non-acceptable cause of death (31.2 %) and an incorrect sequencing (16.8 %). Factors affecting their frequency were the age of the deceased (older than 80 years, p =0.025), the area of certificate completion (rural and semi-urban, p <0.001) and doctor's grade (consultant, p <0.026). CONCLUSIONS: High rate of recording errors at death certification influences the accuracy of the cause of death in a defined region in Southern Greece. Due to their impact on mortality statistics and health policies, standard practices of death certification should be established. Coordinated educational interventions are expected to play a significant role on this. Hippokratia 2016, 20(1): 19-25.

Noninvasive indexes of left atrial diastolic function in hypertrophic cardiomyopathy.

OBJECTIVES: Our goal was to noninvasively assess left atrial diastolic function and its relation to the impaired left ventricular filling in patients with hypertrophic cardiomyopathy. METHODS AND RESULTS: We studied 34 patients with hypertrophic cardiomyopathy, 26 patients with secondary forms of left ventricular hypertrophy (aortic stenosis, fixed subaortic stenosis, hypertension), and 21 control subjects. Left atrial diastolic function was assessed by measuring acceleration time (SAT), deceleration time (SDT), and the EF (mean deceleration rate) slope of the pulmonary venous flow systolic wave (SW). Left ventricular diastolic function assessed by transmitral Doppler included peak early left ventricular and peak atrial filling velocities, the ratio of early-to-late peak velocities, isovolumic relaxation time, deceleration time, and EF slope. In patients with hypertrophic cardiomyopathy, acceleration time was significantly reduced (P<.05), deceleration time was significantly prolonged (P<.0001), and EF slope was significantly reduced (P<.01). These indexes were similar among the other two groups. No statistically significant difference existed between the subgroups of hypertrophic cardiomyopathy in the above indexes. Patients with hypertrophic cardiomyopathy and secondary forms of left ventricular hypertrophy had evidence of left ventricular diastolic dysfunction. In patients with hypertrophic cardiomyopathy, no correlation existed between left atrial and left ventricular diastolic function indexes (r = -0.26 to 0.33). CONCLUSIONS: Echocardiographic indexes of left atrial relaxation and filling are abnormal in patients with hypertrophic cardiomyopathy but not in secondary forms of left ventricular hypertrophy. These indexes are abnormal in all forms of hypertrophic cardiomyopathy irrespective of left ventricular outflow tract obstruction and distribution of hypertrophy; they are not solely attributable to left ventricular diastolic dysfunction. The above may imply that hypertrophic cardiomyopathy is a cardiac myopathic disease that involves the heart muscle as a whole, irrespective of distribution of hypertrophy and obstruction.

Regulation of apoptosis by angiotensin II in the heart and lungs (Review).

Cell death by apoptosis is now known to be an important mechanism of cell population control in organ development and in normal tissue homeostasis. Inappropriate apoptosis also contributes to the pathogenesis of a number of diseases involving the heart and lungs. Knowledge of the regulation of apoptosis in these organs is therefore of fundamental importance. A growing body of evidence suggests that the renin-angiotensin system (RAS), traditionally viewed as an endocrine system in the regulation of blood pressure, also functions as a regulator of apoptosis in a variety of cell types through both paracrine and autocrine mechanisms that are likely independent of the endocrine RAS. Much of the evidence in support of this premise comes from investigations of cardiac myocytes, endothelial cells and epithelial cells of the lung, both in culture and in situ within human pathological specimens and animal models of heart, vascular and pulmonary disease. Evidence from each of these areas is reviewed and discussed in relation to diseases of the heart, vascular system and lungs.

Combined dynamic cardiomyoplasty and transvenous implantable cardioverter defibrillator system.

A transvenous implantable cardioverter defibrillator (ICD) was implanted in a patient with drug refractory ventricular fibrillation who had undergone latissimus dorsi cardiomyoplasty. The skeletal muscle was stimulated by a pulse train generator (cardiostimulator) implanted at the time of cardiomyoplasty. With proper programming of the devices neither adverse ICD-cardiostimulator interactions nor device malfunction were observed. Thus, the combined implantation of a cardiostimulator and an ICD is a feasible and safe therapeutic option.

Leptin serum levels in cachectic heart failure patients. Relationship with tumor necrosis factor-alpha system.

Cachexia is a strong predictor for mortality in patients with congestive heart failure. To investigate the role of leptin and regulators of apoptosis in cardiac cachexia we compared leptin concentrations and their relation to the TNF system, interleukin 1-beta (IL-1b), and soluble Fas in patients with heart failure with and without cachexia. Patients with cardiac cachexia have increased levels of interleukin-1b compared to non-cachectic heart failure patients [mean(S.E.)=1.11(0.62) vs. 0.02(0.02), P=0.01] and decreased concentrations of leptin [10.79(3.93) vs. 23.24 (8.35), P=0.1]. Leptin levels correlate with TNF-RI in cachectic heart failure patients (r=0.58, P=0.018). The TNF-RI levels were also correlated with Fas, both in all the patients taken together (r=0.5, P=0.006) and in those with cachexia (r=0.52, P=0.036). Our data indicate that more prospective studies are needed to clarify the role of leptin in the pathophysiology of heart failure cachexia.

Non-invasive evaluation of coronary reserve. Assessment of coronary reserve in patients with coronary artery disease by transesophageal-Doppler echocardiography.

We assessed coronary flow reserve using transesophageal Doppler echocardiography in patients with coronary artery disease. The study included 33 coronary artery disease patients who were undergoing coronary arteriography. The blood flow velocities of the left anterior descending artery before and after intravenous infusion (0.56 mg/min for 4 min) of dipyridamole were recorded using transesophageal Doppler echocardiography. Fourteen normal healthy individuals, matched for age, served as a control group. The index of coronary flow reserve, i.e. the ratio of dipyridamole to baseline maximum diastolic velocity, was calculated. Maximal coronary flow reserve in coronary artery disease patients was significantly lower than in the control group (1.4+/-0.2 vs. 2.8+/-0.3, P<0.001). The coronary artery disease patients were classified into three groups: Group A included 10 patients with <50% left anterior descending artery stenosis; Group B included seven patients with 50-69% left anterior descending artery stenosis; 16 patients with >70% left anterior descending artery stenosis constituted Group C. The maximum coronary flow reserve was significantly different for A vs. B and A vs. C. (A, 1.77+/-0.18; B, 1.51+/-0.1; C, 1.28+/-0.24). A strong and significant correlation was found between the maximum coronary flow reserve and the degree of proximal left anterior descending artery stenosis (r=0.78, P<0.001). Coronary artery disease patients without left anterior descending artery stenosis on the arteriogram exhibited lower maximum coronary flow reserve compared to the control subjects (1.78+/-0.19 vs. 2.8+/-0.3, P=0.000).

Successful management of right coronary air embolus after intracoronary administration of verapamil.

A case of a 50 year-old male with a coronary air embolism is described. The case was successfully treated with intracoronary administration of verapamil.

Mitral regurgitation from papillary muscle rupture: role of transesophageal echocardiography.

A case of a 61 year old male with lateral myocardial infarction, congestive heart failure and fever of days is presented. The exact etiology of this patient's heart failure was established with the application of transesophageal echocardiography. The transthoracic two-dimensional and Doppler echo showed a mobile echogenic density attached to the tip of the anterior mitral leaflet accompanied by moderate mitral regurgitation. Transesophageal echocardiography attributed this echogenic density to a ruptured head of the anterolateral papillary muscle, resulting in severe mitral regurgitation. Cardiac catheterization confirmed the severe mitral regurgitation and uncovered significant stenotic lesions of the coronary arteries. The resultant surgical treatment for the replacement of the mitral valve and coronary artery by-pass confirmed the rupture of the head of the anterolateral papillary muscle. It is suggested that transesophageal echocardiography is particularly capable of providing a definitive and prompt diagnosis of papillary muscle rupture.

Doppler echocardiographic study of pulmonary venous flow in mitral stenosis and early after mitral valve replacement.

The aim of the study was Doppler echocardiographic assessment of the effect of mitral stenosis (MS) on pulmonary venous flow (PVF), and of any changes occurring after mitral valve replacement. Fifty patients with MS (22 in atrial fibrillation (AF)) and 28 healthy subjects (control group) underwent transthoracic echocardiographic evaluation of PVF. Fourteen of the 22 patients in AF were submitted in addition to transesophageal echo study before and after mitral valve replacement. Pulmonary wedge pressure was measured in 18 patients. Patients in sinus rhythm (SR) and more than mild MS showed significantly decreased peak velocity and flow velocity time integral of the systolic forward PVF. This finding was more exaggerated in MS with AF. Concerning diastolic forward PVF, patients in SR showed significantly decreased peak velocity and velocity time integral, irrelevant of the degree of MS, while patients with AF exhibited adequate signs of flow. In all patients duration, deceleration time (D-DT) and pressure half-time (D-PHT) of the diastolic forward PVF were significantly increased. The last two parameters correlated with the corresponding variables of mitral flow and with echocardiographically determined mitral valve area and the D-DT of the pulmonary wedge pressure. Concerning reversed PVF, patients with more than mild MS exhibited significantly increased peak velocity and velocity time integral. After mitral valve replacement, a significant increase of diastolic forward peak velocity and velocity time of the PVF were detected. The duration of diastolic forward peak velocity of PVF, D-DT and D-PHT decreased. The systolic forward phase did not change significntly after the valve replacement.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of atrial pressure increase on effective refractory period and vulnerability to atrial fibrillation in patients with lone atrial fibrillation.

BACKGROUND: There is evidence suggesting that atrial fibrillation (AF) may be induced by acute increase of atrial pressure. The aim of the present study was to investigate the effect of alterations in atrial pressure, induced by varying the atrioventricular (AV) interval, on atrial refractoriness, and on the frequency of induction of (AF), in patients with a history of lone atrial fibrillation (LAF). METHODS AND RESULTS: Twenty-five patients were included in this study. The patients were divided in two groups: the LAF group, and the control group. None of the patients in either group had organic heart disease. Effective refractory period (ERP) and duration of atrial extrastimulus electrogram (A(2)) were measured at two right atrial sites (high lateral wall, atrial appendage) during AV pacing (cycle length: 500 msec) with different AV intervals. Peak, minimal and mean atrial pressure increased from 8.57 +/- 2.37 to 18.14 +/- 4.74 mm Hg, 2 +/- 2.23 to 5.14 +/- 2.60 mm Hg (p = 0.0001) and from 4.28 +/- 1.6 mm Hg to 9.77 +/- 2.9 mm Hg (p = 0.001), respectively during AV interval modification. During lateral and atrial appendage pacing, with a progressive decrease of AV interval to 160, 100, 80, 40, 0 msec, the ERP, the dispersion of ERP, functional refractory period (FRP), A2 and latency period (LP) did not change significantly, in both groups. The frequency of induction of AF was not statistically different in both lateral atrial wall and appendage, during pacing in different AV intervals. CONCLUSIONS: This study demonstrates that alterations in the intraatrial pressure does not have important effects on atrial refractoriness and does not increase vulnerability to AF in patients with a history of LAF.

Mechanisms of liquid flux across pulmonary alveolar epithelial cell monolayers.

Active transport of sodium by pulmonary alveolar epithelial cells (AEC) is believed to be an important component of edema clearance in the normal and injured lung. Data supporting this premise have come from measurements of sodium movement across AEC monolayers or from perfused lung model systems. However, direct measurement of fluid flux across AEC monolayers has not been reported. In the present work, AEC were studied with an experimental system for the measurement of fluid flux (Jv) across functionally intact cell monolayers. Primary adult rat type II alveolar epithelial cells were cultured on 0.8 micron nuleopore filters previously coated with gelatin and fibronectin. Intact monolayers were verified by high electrical resistance (> 1000 omega) at 4-5 d of primary culture. At the same time interval, transmission electron microscopy revealed cells with type I cell-like morphology throughout the monolayer. These were characterized by both adherens and tight junctional attachments. Fluid flux across the monolayers was measured volumetrically over a period of 2 h in the presence of HEPES-buffered DMEM containing 3% fatty acid-free bovine serum albumin. Flux (Jv) was inhibited 39% by 1 X 10(-4) M ouabain (P < 0.01) and 27% by 5 X 10(-4) M amiloride (P < 0.05). These data support the concept that AEC Na+/K(+)-ATPase and Na+ transport systems are important determinants of AEC transepithelial fluid movement in vitro.

Posterior right diagonal artery. An angiographic study.

The purpose of this prospectively performed study was the angiographic visualization of the posterior right diagonal artery (PRDA) and its differentiation from the epicardial branches of the right coronary artery (RCA), that is, the right marginal artery and the posterior descending artery (PDA). The authors prospectively studied the angiographic findings of 607 patients who underwent coronary angiography. The incidence of the angiographically demonstrated PRDA and its distinction from other epicardial branches arising from the distal third of the RCA was the main point of interest. Two types of PDA in those cases where PRDA was present were also demonstrated. Of the patients examined, 535 had dominant right coronary circulation, 59 had left dominant coronary circulation, and 13 had balanced coronary circulation. PRDA was present in 81 patients with right dominant coronary circulation (15.1%), in 2 patients with balanced coronary circulation (15.4%), and in none with left dominant coronary circulation. PRDA was revealed in 48 (40%) of 120 patients with a short PDA and in only 33 (8%) of 415 patients having long PDA. It is imperative to search always for the PRDA, when one is studying coronary arteriographies, bearing in mind that this artery may perfuse the inferior part of the posterior interventricular septum and the adjoining are, depending on the type of PDA.

Detection of coronary artery disease in patients with severe aortic stenosis with noninvasive methods.

Exercise stress ECG testing is not generally recommended in patients with severe aortic stenosis. Analysis of the utility of exercise testing, both with and without the use of myocardial thallium-201 scintigraphy for the diagnosis of coronary artery disease (CAD), yielded low specificity. A noninvasive, safe, and accurate diagnostic modality to ascertain the presence of CAD is not available to date for patients with severe aortic stenosis. The aim of this study was to assess the safety and diagnostic accuracy of adenosine stress echocardiography (A-Stress-Echo) and of adenosine stress myocardial perfusion scintigraphy (A-SPECT), for the detection of CAD in patients with severe aortic stenosis. The study included 50 patients with severe aortic stenosis (maximal instantaneous aortic valve gradient >80 mmHg, range 81 to 144 mmHg, and aortic valve area <0.75 cm2). All patients were submitted to A-Stress-Echo, after a 6-minute infusion of adenosine (140 microg/kg body weight/min), and then (>3 days later) A-SPECT with the same dosage of adenosine as above. Coronary angiography was performed in all patients. No major complications were observed. The unpleasant symptoms were brief and did not necessitate cessation of the test. Both modalities showed the same sensitivity (85% for A-SPECT and 85% for A-Stress-Echo) angiographically diagnosed CAD while A-Stress-Echo yielded much higher specificity (96.7% vs 76.7%). Concordance of the two methods was found in 40 cases and the specificity for those patients was 100%. A-Stress-Echo and A-SPECT, either separately or in combination, constitute excellent and safe noninvasive diagnostic methods in detecting CAD in patients with severe aortic stenosis.