Andrzej Mysiak

A randomized study of the beneficial effects of aldosterone antagonism on LV function, structure, and fibrosis markers in metabolic syndrome

OBJECTIVES The purpose of this study was to identify the effects of spironolactone on left ventricular (LV) structure and function, and serological fibrosis markers in patients with metabolic syndrome (MS) taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. BACKGROUND Myocardial fibrosis may be an important contributor to myocardial impairment in MS, and aldosterone antagonism may reduce fibrosis. METHODS Eighty patients (age 59 ± 11 years) with MS, already being treated with angiotensin II inhibition, were randomized to spironolactone 25 mg/day or placebo for 6 months. Each patient underwent baseline and follow-up conventional echocardiography and color tissue Doppler imaging. Raw data files were used to measure calibrated integrated backscatter and to calculate radial and longitudinal strain. Blood was obtained at baseline and follow-up to measure fibrosis markers (procollagen type III amino-terminal propeptide and procollagen type I carboxy-terminal propeptide [PICP]). RESULTS The spironolactone group showed significant improvement of LV function, myocardial reflectivity, and LV hypertrophy, with a parallel decrease in levels of PICP and procollagen type III amino-terminal propeptide. No analogous changes were seen in the placebo group. Baseline strain (β = 0.47, p < 0.0001), spironolactone therapy (β = -0.38, p < 0.0001), and change in PICP level (β = -0.19, p < 0.03) were independently associated with LV systolic function improvement (increase in strain). Correlates of LV diastolic function improvement (increase in early diastolic mitral annular velocity) were baseline early diastolic mitral annular velocity (β = 0.47, p < 0.0001), spironolactone therapy (β = -0.21, p < 0.03), change in PICP level (β = -0.23, p < 0.02), and age (β = 0.22, p < 0.04). Favorable effects of spironolactone on cardiac function were not demonstrated in patients with less fibrosis (the lower baseline PICP tertile) or preserved function (the upper baseline strain tertile). CONCLUSIONS Addition of spironolactone to standard angiotensin II inhibition improved myocardial abnormalities and decreased fibrotic markers in MS. The magnitude of benefit on cardiac performance is determined mainly by baseline LV dysfunction and collagen turnover as well its response to intervention.

Fibrosis and cardiac function in obesity: a randomised controlled trial of aldosterone blockade

Objectives As myocardial fibrosis might be an important contributor to the association of obesity with left ventricular (LV) dysfunction and heart failure, we investigated the effects of spironolactone on LV function and serological fibrosis markers (procollagen type III N-terminal propeptide (PIIINP) and procollagen type I C-terminal propeptide (PICP)) in patients with obesity and abnormal LV performance. Design A prospective, randomised, double-blind, placebo-controlled study. Setting A university hospital. Patients and intervention 113 patients (mean±SD age 58±8 years) with body mass index≥30, without any comorbidities, with impaired early diastolic mitral annular velocity, randomised to spironolactone 25 mg/day or placebo for 6 months. Main outcome measures Echocardiographically derived indices of LV systolic (strain and strain rate) and diastolic (E velocity, tissue e′ and E/e′ ratio) function, myocardial reflectivity (calibrated integrated backscatter (IB)), and serum PICP and PIIINP. Results In the spironolactone group, significant improvements in myocardial deformation, peak early diastolic velocity (Em), E/e′ and IB were noted with a simultaneous decrease in PICP and PIIINP. No corresponding alterations were found with placebo. Improvement in LV systolic function (increase in strain) was independently associated with baseline strain (β=−0.43, p<0.001), change in IB (β=0.26, p<0.02) and baseline PICP (β=0.24, p<0.04). Among the independent determinants of LV diastolic improvement were for increase in Em – baseline Em (β=−0.44, p<0.001) and baseline PICP (β=0.35, p<0.002), and for decrease in E/e′ – baseline E/e′ (β=−0.35, p<0.005) and change in PICP (β=0.25, p<0.04). Conclusions In patients with obesity without other comorbidities, aldosterone antagonism improves LV function and myocardial acoustic properties, and reduces circulating procollagen levels. Beneficial changes in cardiac performance are independently predicted by baseline LV dysfunction and baseline disturbances, as well as treatment-induced improvements in fibrosis markers. Clinical Trial Registration http://www.anzctr.org.au ACTRN12609000655246.

Reduced circulating apelin in essential hypertension and its association with cardiac dysfunction

Objective Apelin – a novel multifunction peptide implicated in regulation of the cardiovascular system, including blood pressure and cardiac function control – has been postulated to be involved in the pathophysiology of hypertension and hypertensive heart disease. We investigated the circulating apelin level and its relationship to left ventricular function in patients with essential hypertension. Methods We enrolled 232 hypertensive patients without concomitant diseases affecting cardiovascular functions and 76 healthy controls. Each patient underwent plasma apelin measurement and echocardiographic assessment of left ventricular systolic and diastolic function using myocardial velocities and deformation parameters, and myocardial reflectivity using calibrated integrated backscatter. Results Hypertensive patients demonstrated lower plasma apelin than the controls (265 ± 127 vs. 330 ± 159 pg/ml; P < 0.001). Patients with the lowest plasma apelin, that is, from the first tertile, exhibited more severe left ventricular systolic and diastolic function abnormalities than their peers from the other two tertiles. In multivariable regression analysis, apelin was, in addition to patient age, BMI, blood pressure, left ventricular mass index and calibrated integrated backscatter in the basal septum, an independent correlate of left ventricular systolic function parameters (β = 0.18; P < 0.001 for strain and β = 0.12; P < 0.03 for systolic strain rate) and diastolic function parameters (β = 0.13; P < 0.01 for early diastolic strain rate, β = 0.11; P < 0.04 for early diastolic myocardial velocity, and β = −0.11; P < 0.04 for the ratio of mitral inflow to mitral annular early diastolic velocity). Conclusion In patients with essential hypertension, circulating apelin levels are reduced, and lower plasma apelin is independently associated with more profound left ventricular systolic and diastolic function impairment.

Left Ventricular Function Impairment in Patients With Normal-Weight Obesity Contribution of Abdominal Fat Deposition, Profibrotic State, Reduced Insulin Sensitivity, and Proinflammatory Activation

Background— Obesity predisposes to left ventricular (LV) dysfunction and heart failure; however, the risk of these complications has not been assessed in patients with a normal body mass index (BMI) but increased body fat content (normal-weight obesity, NWO). We hypothesized that LV performance in NWO may be impaired and sought to investigate potential contributors to cardiac functional abnormalities. Methods and Results— One hundred sixty-eight subjects (age, 38±7 years) with BMI <25kg/m2 and no history of any disease affecting the myocardium were classified on the basis of body fat content into 2 groups: with NWO and without NWO. Echocardiographic indices of LV systolic and diastolic function, including myocardial velocities and deformation, serological fibrosis markers, indicators of proinflammatory activation, and metabolic control, were evaluated. Subjects with NWO demonstrated impaired LV systolic and diastolic function, increased fibrosis intensity (assessed by procollagen type I carboxy-terminal propeptide [PICP]), impaired insulin sensitivity, and increased proinflammatory activation as compared with individuals with normal body fat. The independent correlates of LV systolic and diastolic function variables were as follows: for strain, IL-18 (&bgr;=−0.17, P<0.006), C-reactive protein (&bgr;=−0.20, P<0.002) and abdominal fat deposit (&bgr;=−0.20, P<0.003); for tissue S velocity, PICP (&bgr;=−0.21, P<0.002) and abdominal fat deposit (&bgr;=−0.43, P<0.0001); for tissue E velocity, abdominal fat deposit (&bgr;=−0.30, P<0.0001), PICP (&bgr;=−0.31, P<0.0001) and homeostasis model assessment of insulin resistance index (HOMA IR; &bgr;=−0.20, P<0.002); and for E/e′-PICP, IL-18 (both &bgr;=0.18, P<0.01) and HOMA IR (&bgr;=0.16, P<0.04). Conclusions— In patients with NWO, subclinical disturbances of LV function are independently associated with the extent of abdominal fat deposit, profibrotic state (as reflected by circulating PICP), reduced insulin sensitivity, and proinflammatory activation.

Expression of Proinflammatory Factors, Proangiogenic Factors and Endostatin in Patients with Heart Failure and Different Grades of Collateral Circulation Development*

BACKGROUND The process of collateral vessel maturation is stimulated by numerous factors affecting the endothelium and smooth muscle cells building the vessel wall. Looking for arteriogenesis stimulating factors means looking for a potential innovative heart failure treatment method in the patients unresponsive to traditional therapies. OBJECTIVES The purpose of this study was to assess the changes in serum concentrations of pro-inflammatory factor IL-6, growth factors FGF (FGFa, FGFb, FGFbH), HGF, VEGF and endostatin in heart failure patients in relation to the coronary collaterals development stage. MATERIAL AND METHODS This study included 22 patients with chronic heart failure NYHA II or III (mean age 62.5 ± 11.6 years) and 8 control patients (mean age 58.4 ± 10.7 years). Coronary angiography was performed and the presence and grade of collateral circulation was assessed by a four-level scale proposed by Rentrop and Cohen. The level of the studied factors was determined in the blood samples collected during the angiographic procedure. RESULTS The concentration of IL-6 was significantly higher in the heart failure patients than in the control group (p < 0.001) and in NYHA III vs. NYHA II patients (p < 0.02). Patients with heart failure and collaterals grade 1 or 2 exhibited higher serum concentrations of FGFbH (from p < 0.03 to p < 0.01). The serum VEGF level in NYHA III patients was significantly higher than in NYHA II individuals (from p < 0.03 to p < 0.01). CONCLUSIONS Higher levels of IL-6 and FGFbH were observed in patients with heart failure. Collaterals formation seems to be associated with the activation of pro-inflammatory factors, growth factors and endostatin.

Cardiac arrest due to left circumflex coronary artery embolism as a complication of subtherapeutic oral anticoagulation in a patient with mitral and aortic mechanical valve prostheses.

We report a case of a 65-year-old female patient after replacement of aortic and mitral valve with mechanical prostheses and implantation of a pacemaker hospitalized in our clinic due to acute coronary syndrome complicated with cardiac arrest due to ventricular fibrillation. The electrocardiogram performed on admission showed signs of myocardial infarction with concomitant ventricular pacing. After successful resuscitation the coronary angiography was performed, which showed occlusion of the left circumflex artery (LCx) by thrombus. On the basis of intravascular ultrasound imaging the presence of vulnerable plaque, parietal thrombus and dissection of LCx were excluded. It suggested that occlusion of the LCx resulted from its embolism by left-sided heart thrombus due to subtherapeutic oral anticoagulation. In this case suboptimal anticoagulation was partially iatrogenic. Two weeks before the patient had been given vitamin K intravenously due to indeterminable international normalized ratio (INR) level, which caused transient resistance to oral anticoagulants. This case report illustrates tragic difficulties in the treatment with vitamin K antagonists, which concern as many as 2/3 of anticoagulated patients. These troubles contributed to the search for new, more efficient and safer anticoagulants. There are two classes of new oral anticoagulant drugs, which do not require monitoring of coagulation: direct thrombin inhibitors (e.g. dabigatran) and factor Xa inhibitors (e.g. rivaroxaban). In spite of their proven efficacy in the prevention of ischaemic stroke related to atrial fibrillation and prevention or treatment of deep vein thrombosis and pulmonary embolism, the use of new oral anticoagulants for the treatment of patients with mechanical valve prostheses needs further research.

MMP-2, MMP-9, and TIMP-4 and Response to Aspirin in Diabetic and Nondiabetic Patients with Stable Coronary Artery Disease: A Pilot Study

Background High on-aspirin treatment platelets reactivity (HPR) is a significant problem in long-term secondary prevention of cardiovascular events. We hypothesize that imbalance between platelets MMPs/TIMPs results in cardiovascular disorders. We also explored whether chronically elevated blood glucose affects MMP-2/TIMP-4 release from platelets. Materials and Methods Seventy patients with stable coronary artery disease, supplemented with aspirin, participated in this pilot study. The presence of HPR and/or diabetes mellitus was considered as the differentiating factor. Light aggregometry, impedance aggregometry, and ELISA tests for TXB2, MMP-2, MMP-9, and TIMP-4 were performed in serum, plasma, platelet-rich plasma, and platelets-poor plasma, as appropriate. Results Aspirin-HPR did not affect plasma MMP-2, MMP-9, and TIMP-4. Arachidonic acid-induced aggregation of platelets from aspirin-HPR patients did not lead to increased release of MMP-2, MMP-9, and TIMP-4. Studying patients at the lowest TXB2 serum concentration quartile revealed that high concentration of plasma TIMP-4 and TIMP-4 negatively correlated with TXB2 and platelet aggregation. Diabetics showed an increased plasma MMP-2 as well as an increased MMP-2 in supernatants after platelet aggregation. However, diabetes mellitus did not affect MMP-9 and TIMP-4. Conclusion Aspirin-HPR did not affect the translocation and release of MMPs and TIMP-4 from platelets. TIMP-4 may serve as a marker of TXA2-mediated platelet aggregation. Chronically elevated plasma glucose increases plasma MMP-2, and HPR potentiates this phenomenon.

Left main aneurysm and what's next?

The purpose of the case report is to present a case of a 65-year-old male, referred for coronary angiography because of a typical chest pain. The coronary angiography showed an aneurysm of the left main coronary artery. Despite the absence of obvious ischemic symptoms and because of the potential complications of the aneurysm with a width of 15 mm, the patient underwent surgery.

Renal artery denervation due to refractory hypertension in a patient after kidney transplantation – 3 years of observation - Case Report

INTRODUCTION Hypertension is prevalent in most patients after renal transplantation, and it is the main factor contributing to cardiovascular diseases that cause death of a significant number of these patients. Up to 95% of patients after transplantation have hypertension, and among them are patients with refractory hypertension. Elevated blood pressure is one of the causes of deterioration of transplant function and may accelerate transplant loss. CASE REPORT We present the first case in the world of a patient (who was 61 years old) in whom denervation of native renal arteries was performed after renal transplantation (2004). The patient was suffering from uncontrolled refractory hypertension. Antihypertensive therapy was used but the effect was not satisfactory. The patient received amlodipine, bisoprolol, clonidine, furosemide, and doxazosin in high doses. Clinical assessments with ambulatory blood pressure monitoring revealed a predominant blood pressure 149/96 with incidents of hypertensive crises. High blood pressure is a cardiovascular risk factor and it also has a significant influence on transplant failure, which was the reason for performing the denervation. The procedure was carried out through the femoral artery with the use of a 6F guiding catheter. During a 3-year observation, significant decreases in ambulatory blood pressure monitoring systolic and diastolic blood pressures were observed after the procedure (149/96 mm Hg vs 134/91 mm Hg before and after the denervation, respectively). There was a significant regression of left ventricle mass (577 g before denervation vs 470 g after 3 years). The functioning of the renal transplant became stable after 3 years of observation (38 mL/min before denervation and 38 mL/min after 3 years). CONCLUSIONS The first case in the world of a renal transplant patient who had denervation of native renal arteries has demonstrated a positive effect in controlling blood pressure over a 3-year observation. Three years after denervation, a reduction of heart hypertrophy and stabilization of renal function were noted. The presented case shows that denervation of native renal arteries denervation may be successful and safe in kidney transplant recipients.

Plasma level of YKL-40 correlates with the severity of coronary atherosclerosis assessed with SYNTAX score

Introduction YKL‑40 is a protein released locally by inflammatory cells. Thus, it may constitute a biomarker of inflammatory conditions, such as atherosclerosis. Objectives The aim of the study was to determine YKL‑40 levels in patients with ischemic heart disease and to analyze the correlation of this biomarker with the severity of coronary atherosclerosis. Patients and methods The study included 158 patients: 52 with stable ischemic heart disease and 67 with acute coronary syndrome: ST‑segment elevation myocardial infarction (STEMI; n = 47) or non-ST‑segment elevation myocardial infarction (NSTEMI; n = 20). The control group included 39 individuals without abnormalities in coronary vessels. We evaluated plasma YKL‑40 levels and their correlation with the severity of coronary atherosclerosis assessed with the SYNTAX score. Results Patients with myocardial infarction had higher plasma YKL‑40 levels than those with stable ischemic disease (median [range], 235.3 [161.6-366.1] ng/ml vs 61.2 [53.1-83.1] ng/ml; P <0.001) or controls (median [range], 235.3 [161.6-366.1] ng/ml vs 55.7 [51.2-75.2] ng/ml; P <0.001). No differences were found in YKL‑40 concentrations between STEMI and NSTEMI patients (median [range], 263 [150.3-363.7] ng/ml and 214.9 [163.4-367.6] ng/ml, respectively; P = 0.7). The SYNTAX score in patients with ischemic heart disease correlated positively with YKL‑40 concentrations (R = 0.34; P <0.001). Conclusions YKL‑40 can be considered a potential biomarker of coronary atherosclerosis severity.