Wojciech Kosmala

Effect of If-channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: a randomized trial.

OBJECTIVES The aim of this study was to test the effects of treatment with ivabradine on exercise capacity and left ventricular filling in patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND Because symptoms of HFpEF are typically exertional, optimization of diastolic filling time by controlling heart rate may delay the onset of symptoms. METHODS Sixty-one patients with HFpEF were randomly assigned to ivabradine 5 mg twice daily (n = 30) or placebo (n = 31) for 7 days in this double-blind trial. Cardiopulmonary exercise testing with echocardiographic assessment of myocardial function and left ventricular filling were undertaken at rest and after exercise. RESULTS The ivabradine group demonstrated significant improvement between baseline and follow-up exercise capacity (4.2 ± 1.8 METs vs. 5.7 ± 1.9 METs, p = 0.001) and peak oxygen uptake (14.0 ± 6.1 ml/min/kg vs. 17.0 ± 3.3 ml/min/kg, p = 0.001), with simultaneous reduction in exercise-induced increase in the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity (3.1 ± 2.7 vs. 1.3 ± 2.0, p = 0.004). Work load-corrected chronotropic response (the difference in heart rate at the same exercise time at the baseline and follow-up tests) showed a slower increase in heart rate during exercise than in the placebo-treated group. Therapy with ivabradine (β = 0.34, p = 0.04) and change with treatment in exertional increase in the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity (β = -0.30, p = 0.02) were independent correlates of increase in exercise capacity, and therapy with ivabradine (β = 0.32, p = 0.007) was independently correlated with increase in peak oxygen uptake. CONCLUSIONS In patients with HFpEF, short-term treatment with ivabradine increased exercise capacity, with a contribution from improved left ventricular filling pressure response to exercise as reflected by the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity. Because this patient population is symptomatic on exertion, therapeutic treatments targeting abnormal exercise hemodynamic status may prove useful. (Use of Exercise and Medical Therapies to Improve Cardiac Function Among Patients With Exertional Shortness of Breath Due to Lung Congestion; ACTRN12610001087044).

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.

Relation of circulating markers of fibrosis and progression of left and right ventricular dysfunction in hypertensive patients with heart failure.

Objective To study the association of circulating markers of fibrosis: procollagen type III amino-terminal propeptide (PIIINP), procollagen type I carboxy-terminal propeptide (PIP) and collagen type I carboxy-terminal telopeptide (CITP): with left (LV) and right ventricular (RV) longitudinal and LV radial systolic function in patients with heart failure in the course of essential hypertension. Methods The study population consisted of 81 patients with hypertension divided into four groups according to NYHA classification and 20 healthy controls. Cardiac function was estimated by myocardial deformation indices assessed by tissue Doppler imaging. Serum PIIINP, PIP and CITP levels were quantified by radioimmunoassay. Results Progressive LV longitudinal function impairment was demonstrated in all hypertension groups as indicated by reduced peak systolic strain and strain rate and increased postsystolic strain index. The respective indicators of LV radial function were deteriorated only in NYHA classes III-IV. Concurrently, RV longitudinal function was found abnormal in NYHA classes II-IV. PIIINP concentration was higher in NYHA class III and IV, whereas CITP level was increased and PIP/CITP ratio was decreased in the NYHA IV individuals. PIIINP was an independent correlate of LV and RV longitudinal strain (R2 = 0.52, β = −0.34, P < 0.001; R2 = 0.25, β = −0.27, P < 0.01, respectively). PIP/CITP ratio independently determined LV radial strain in patients with LV ejection fraction less than 50% (R2 = 0.44, β = 0.52, P < 0.008). Conclusion In hypertensive patients, the progressive decline in cardiac longitudinal function is related to increased collagen III synthesis, whereas the changes in collagen I turnover favoring its increased degradation might contribute to LV radial and global systolic dysfunction seen in the advanced hypertensive heart disease.

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.

Plasma levels of Tnf-α, Il-6, and Il-10 and their relationship with left ventricular diastolic function in patients with stable angina pectoris and preserved left ventricular systolic performance

AimsThe role of inflammation – a key factor underlying coronary artery disease (CAD) and systolic heart failure – in promotion of left ventricular (LV) diastolic dysfunction has not been investigated extensively so far. The aim of this study was: (i) to evaluate plasma levels of TNF-&agr;, IL-6, and IL-10 in patients with stable CAD and preserved LV systolic function and (ii) to assess their relationships with LV diastolic function. MethodsThe study population consisted of 126 patients with single vessel and 58 patients with multivessel stable CAD and LV ejection fraction >50%, and 39 healthy controls. Each participant underwent echocardiographic study including estimation of LV diastolic function indices: peak velocities of early (E) and late (A) transmitral flows, deceleration time of E wave, isovolumic relaxation time, E wave (ETT) and A wave (ATT) transit time to the LV outflow tract, and flow propagation velocity of E wave (Ep). Plasma TNF-&agr;, IL-6, and IL-10 levels were evaluated by radioimmunometric method. ResultsPatients with CAD presented higher TNF-&agr; and IL-6 levels and higher values of IL-6/IL-10 and TNF-&agr;/IL-10 ratio than the controls. IL-6 levels were higher in patients with multivessel disease than in those with single vessel disease. Significant correlations (all P<0.001) were found for TNF-&agr; and Ep (r=−0.41), E/Ep (r=0.45), and ETT (r=0.38). IL-6 correlated with Ep (r=−0.39) and E/A (r=−0.33), whereas IL-10 with ETT (r=0.37), Ep (r=−0.44), and E/Ep (r=0.46). ConclusionIn patients with stable CAD and preserved LV systolic performance, plasma levels of TNF-&agr; and IL-6 are elevated and there is association between immunoinflammatory activation reflected by plasma levels of cytokines and LV diastolic dysfunction.

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.

Subclinical impairment of left ventricular function in young obese women: contributions of polycystic ovary disease and insulin resistance.

CONTEXT Obesity and insulin resistance (IR) may produce disturbances of left ventricular (LV) function. Obese women with polycystic ovary syndrome (PCO), characterized by hormonal and metabolic abnormalities, are thought to be at particularly increased cardiovascular risk. OBJECTIVES We sought to determine the influence of IR on LV function in obese young women with and without PCO and without other comorbidities. DESIGN This was a cross-sectional study. SETTING The study was performed at a university hospital. PATIENTS A total of 150 women aged younger than 40 yr with a body mass index (BMI) of 30 kg/m(2) or more was classified into three groups: with both PCO and IR, without PCO and with IR, and without either PCO or IR. MAIN OUTCOME MEASURES Tissue Doppler-derived myocardial velocities, strain-rate and strain, and metabolic and hormonal measurements were calculated. RESULTS Subclinical impairment of LV systolic and diastolic function as indicated by lower peak strain (P < 0.001), peak systolic strain rate (P < 0.001), peak early diastolic strain rate (P < 0.001), and peak early diastolic velocity (P < 0.01) was demonstrated in both groups with IR. IR subjects with and without PCO did not differ in any LV function indices. Strain was independently associated with fasting insulin (beta = -0.39; P < 0.001), urinary albumin excretion (UAE) (beta = -0.36; P < 0.001), and BMI (beta = -0.22; P < 0.03), and peak early diastolic strain rate was associated with UAE (beta = -0.35; P < 0.001), fasting insulin (beta = -0.24; P < 0.02), BMI (beta = -0.23; P < 0.02), and SHBG (beta = 0.20; P < 0.04). CONCLUSIONS In obese young women, fasting insulin, BMI, SHBG, and UAE are independent correlates of impaired LV performance. The contribution of PCO to LV function abnormalities is linked to IR, but not to other hormonal aberrations associated with this condition.

Use of Body Weight and Insulin Resistance to Select Obese Patients for Echocardiographic Assessment of Subclinical Left Ventricular Dysfunction

Obesity is associated with heart failure. Recognition of subclinical left ventricular (LV) dysfunction may permit the initiation of therapy to prevent the development of heart failure. In this study of anthropometric, biochemical, and echocardiographic measurements in 295 healthy overweight subjects, we sought to investigate the effect of insulin resistance and severity of obesity on LV function and to establish a strategy for detection of LV dysfunction using metabolic and echocardiographic measurements. Correlates of subclinical dysfunction (defined from myocardial deformation in a matched group of 98 slim controls) were sought, and receiver operator characteristic curves for clinical and laboratory parameters were performed to identify optimal cutoffs to permit an effective diagnostic strategy. Subclinical impairment of LV function (average strain<18%) was present in 124 subjects (42%), and 52% of severely obese patients (body mass index [BMI]>35 kg/m2). Independent correlates of strain were BMI (beta=-0.25, p<0.0001), fasting insulin (beta=-0.22, p<0.001), and age (beta=-0.18, p<0.003). In patients with a BMI<35 kg/m2, subclinical impairment was uncommon in the absence of hyperinsulinemia. Using a BMI<35 kg/m2 and an insulin level<13 mIU/L to select patients for further testing allowed echocardiography to be avoided in 35% of subjects in whom the prevalence of LV dysfunction was low. In conclusion, obesity and insulin resistance are important contributors to LV dysfunction, a deleterious effect of hyperinsulinemia on LV performance is particularly seen in overweight and moderately obese subjects, and the combination of BMI, fasting insulin, and echocardiography appears optimal for efficient identification of subclinical LV dysfunction in overweight and obese subjects.

Incremental value of left atrial structural and functional characteristics for prediction of atrial fibrillation in patients receiving cardiac pacing

Background—Better prediction of cardiac pacing patients at risk of atrial fibrillation (AF) would enable more effective prophylaxis. We sought whether left atrial (LA) electromechanical conduction time (EMT) and myocardial mechanics were associated with incident AF in patients undergoing dual chamber pacemaker implantation, independent of left atrial volume (LAV). Methods and Results—Clinical data were obtained prospectively in 146 enrollees (73±10 years) undergoing dual chamber pacemaker implantation in the Protect-Pace study. Echocardiograms and 2-dimensional strain analysis were obtained post implantation and at 2 years. Complete ascertainment of AF during follow-up was identified from interrogation of permanent pacemakers. Cox regression was used to identify correlates of AF. Incident AF (n=29, 20%) was associated with higher systolic blood pressure (P=0.01), lower left ventricular ejection fraction (P=0.03), lower LA strain at atrial contraction (LASac; P<0.001), higher LAV (P<0.003), and longer septal electromechanical conduction time (P<0.01). The associations of LAV and LASac with incident AF were independent of age, sex, systolic blood pressure, and left ventricular size and function. However, the combination of the 3 strongest predictors showed LASac (P=0.02) and systolic blood pressure (P=0.01) were independently associated with incident AF, but LAV was not (P=0.07). Using the optimal cut points from receiver operator characteristic curves (62 mL for LAV and 8.6% for LASac), we demonstrated that a significantly greater rate of AF was associated with both lower LASac at higher LAV and with lower LASac at lower LAV. Conclusions—The risk of AF in patients receiving dual chamber pacing is independently associated with LA size and function, not left ventricular structural and functional characteristics or right ventricular lead location. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00461734.