Marko Banovic

Reply: The C-CURE Randomized Clinical Trial (Cardiopoietic stem Cell therapy in heart failURE).

We appreciate the interest of Dr. Mielewczik and colleagues in the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial. As outlined in our paper [(1)][1], feasibility and safety were the primary endpoints in this first-in-man study that assessed cardiogenically-oriented, autologous bone

Prognostic Value of Coronary Flow Reserve in Asymptomatic Moderate or Severe Aortic Stenosis with Preserved Ejection Fraction and Nonobstructed Coronary Arteries

Aim: Patients with moderate and severe aortic stenosis (AS) and without obstructive epicardial coronary disease have been shown to have an impairment of coronary flow reserve (CFR). We investigated the prognostic significance of CFR in predicting death during mid‐to‐long‐term follow‐up in asymptomatic patients with moderate/severe AS, preserved ejection fraction (EF), and with nonobstructed coronary arteries. Method and Result: A total of 127 patients with moderate or severe AS (effective orifice area of 1.5 cm2 or less), mean age 66 ± 11 were enrolled in this prospective study. The median follow‐up was 32 ± 7 months. All patients had standard Doppler echo study, coronary angiography, and adenosine‐stress transthoracic Doppler echo for CFR measurement. Univariate analysis showed that diabetes mellitus, CFR, aortic valve area (AVA), maximal velocity (Vmax), mean pressure gradient (Pmean), energy loss index (ELI), aortic valve resistance (AVR), NT‐proBNP, E/E′, valvulo‐arterial impedance (Zva), and stroke work loss (SWL) were associated (P < 0.05) with death. Multivariable logistic regression analysis revealed that only Zva and CFR were independent predictors of death, with the CFR being the single strongest predictor (Table 2). Using receiver operating characteristics (ROC) analysis, the CFR value of 1.85 had the highest accuracy in predicting the death during mid‐to‐long‐term follow‐up (area under the curve; AUC 0.890, P = 0.009, sensitivity 96.3%, specificity 75%; 95% CI 0.287–0.946; Fig. 1). The Zva value of 5.52 Hg/mL per m had a sensitivity 70.0% and specificity 72.0% (AUC 0.766, 95% CI 0.587–0.946; P = 0.005). Conclusion: This study demonstrates that CFR has a prognostic value in patients with asymptomatic moderate or severe AS with preserved EF and nonobstructed coronary arteries.

Diagnostic value of NT-proBNP in identifying impaired coronary flow reserve in asymptomatic moderate or severe aortic stenosis

AIM NT-proBNP has been shown to be a reliable biochemical marker for left ventricular wall stress. The relationship between NT-proBNP and coronary flow reserve (CFR) was evaluated in patients with significant asymptomatic aortic stenosis (AS). METHODS A total of 74 patients with moderate or severe AS, mean age 66.68 ± 10.02 years (56.75% males), were enrolled in this prospective study. All patients underwent coronary angiography and had no obstructive coronary disease (defined as having no stenosis >50% in diameter). They had all undergone standard transthoracic Doppler-echo study and adenosine stress transthoracic-echo for CFR measurement and laboratory analysis for NT-proBNP measurement. RESULTS The median NT-proBNP value was significantly increased (417.0 pg/ml; interquartile range [IQR]: 176.8-962.2 pg/ml). NT-proBNP was significantly higher in the group with CFR ≤2.5 (median: 549.0 pg/ml; IQR: 311.5-1131.0 pg/ml; as opposed to median: 291.5 pg/ml; IQR: 123.0-636.2 pg/ml; W = 452; p = 0.012). NT-proBNP showed significant negative correlation with CFR (ρ = -0.377, p = 0.001). There was also significant correlation between NT-proBNP and E/E´, S´ and aortic valve resistance. The NT-proBNP value of 334.00 pg/ml was determined as the best cut-off value for the diagnosis of CFR ≤2.5 (area under the curve: 0.67; 95%CI: 0.54-0.79; p < 0.01) and the sensitivity and specificity were 74 and 64%, respectively. CONCLUSION Elevated NT-proBNP can indicate patients with impaired CFR in asymptomatic moderate or severe AS patients with preserved ejection fraction and nonobstructive coronary arteries.

Endpoints in stem cell trials in ischemic heart failure

Despite multimodal regimens and diverse treatment options alleviating disease symptoms, morbidity and mortality associated with advanced ischemic heart failure remain high. Recently, technological innovation has led to the development of regenerative therapeutic interventions aimed at halting or reversing the vicious cycle of heart failure progression. Driven by the unmet patient need and fueled by encouraging experimental studies, stem cell-based clinical trials have been launched over the past decade. Collectively, these trials have enrolled several thousand patients and demonstrated the clinical feasibility and safety of cell-based interventions. However, the totality of evidence supporting their efficacy in ischemic heart failure remains limited. Experience from the early randomized stem cell clinical trials underscores the key points in trial design ranging from adequate hypothesis formulation to selection of the optimal patient population, cell type and delivery route. Importantly, to translate the unprecedented promise of regenerative biotherapies into clinical benefit, it is crucial to ensure the appropriate choice of endpoints along the regulatory path. Accordingly, we here provide considerations relevant to the choice of endpoints for regenerative clinical trials in the ischemic heart failure setting.

Time-dependent changes of plasma adiponectin concentration in relation to coronary microcirculatory function in patients with acute myocardial infarction treated by primary percutaneous coronary intervention

BACKGROUND AND PURPOSE To analyze plasma adiponectin kinetics in patients with ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (pPCI) and its association with coronary flow reserve (CFR), an index of coronary microcirculatory function. METHODS A total of 96 consecutive patients with the first anterior STEMI treated by pPCI without heart failure were included. CFR was assessed on the 7th day after pPCI. Plasma adiponectin was measured on admission before pPCI, and on the 2nd and 7th day after pPCI. RESULTS Adiponectin concentration was the highest on admission, declined to the lowest level on the 2nd day, and rose on the 7th day remaining below admission values. Impaired coronary microcirculatory function (CFR<2) was observed in 41% of the patients. Adiponectin concentrations significantly positively correlated with CFR, and the strongest correlation was with the 2nd day adiponectin (r=0.489, p<0.001). In multivariate models, adiponectin concentrations were independent predictors of impaired CFR [on admission: odds ratio (OR) 0.175, confidence interval (CI): 0.047-0.654, p=0.010; 2nd day: OR 0.146, 95% CI: 0.044-0.485, p=0.002; 7th day: OR 0.198, CI: 0.064-0.611, p=0.005]. The best power to predict impaired CFR was the 2nd day adiponectin. Delta values of adiponectin (differences between adiponectin concentrations) did not correlate with CFR. CONCLUSIONS In patients with the first anterior STEMI treated by pPCI plasma adiponectin concentrations before and after pPCI are strongly associated with CFR. Our results support the hypothesis that low adiponectin, especially during the early post-pPCI period, carries the risk for impaired coronary microcirculatory function in STEMI patients.

The interface of hypothalamic–pituitary–adrenocortical axis and circulating brain natriuretic peptide in prediction of cardiopulmonary performance during physical stress

Brain natriuretic peptide (NT-pro-BNP) was implicated in the regulation of hypothalamic-pituitary-adrenocortical (HPA) responses to psychological stressors. However, HPA axis activation in different physical stress models and its interface with NT-pro-BNP in the prediction of cardiopulmonary performance is unclear. Cardiopulmonary test on a treadmill was used to assess cardiopulmonary parameters in 16 elite male wrestlers (W), 21 water polo player (WP) and 20 sedentary age-matched subjects (C). Plasma levels of NT-pro-BNP, cortisol and adrenocorticotropic hormone (ACTH) were measured using immunoassay sandwich technique, radioimmunoassay and radioimmunometric techniques, respectively, 10min before test (1), at beginning (2), at maximal effort (3), at 3rdmin of recovery (4). In all groups, NT-pro-BNP decreased between 1 and 2; increased from 2 to 3; and remained unchanged until 4. ACTH increased from 1 to 4, whereas cortisol increased from 1 to 3 and stayed elevated at 4. In all groups together, ΔNT-pro-BNP2/1 predicted peak oxygen consumption (B=37.40, r=0.38, p=0.007); cortisol at 3 predicted heart rate increase between 2 and 3 (r=-0.38,B=-0.06, p=0.005); cortisol at 2 predicted peak carbon-dioxide output (B=2.27, r=0.35, p<0.001); ΔACTH3/2 predicted peak ventilatory equivalent for carbon-dioxide (B=0.03, r=0.33, p=0.003). The relation of cortisol at 1 with NT-pro-BNP at 1 and 3 was demonstrated using logistic function in all the participants together (for 1/cortisol at 1 B=63.40, 58.52; r=0.41, 0.34; p=0.003, 0.013, respectively). ΔNT-pro-BNP2/1 linearly correlated with ΔACTH4/3 in WP and W (r=-0.45, -0.48; p=0.04, 0.04, respectively). These results demonstrate for the first time that HPA axis and NT-pro-BNP interface in physical stress probably contribute to integrative regulation of cardiopulmonary performance.

Prediction of a good response to cardiac resynchronization therapy in patients with severe dilated cardyomyopathy: could conventional echocardiography be the answer after all?

Objectives: The aim of this study was to assess the performance of echocardiographic parameters to predict response to cardiac resynchronization therapy (CRT). Background: CRT reduces morbidity and mortality due to the proper selection of candidates for CRT. Methods: The 12‐month trial was performed on 70 optimally medicated patients with standard inclusion criteria: NYHA class III or IV heart failure, left ventricular ejection fraction (LVEF) ≤ 35%, and QRS ≥ 120 ms. All parameters were evaluated by conventional and tissue Doppler‐based methods. Indicator of positive CRT response was more than 20% in improvement of LVEF. Results: LVEF increased >20% in 42 patients. Out of 43 tested baseline echocardiographic parameters, 12 showed statistical difference between responders and nonresponders. Out of these 12 parameters, six (LVSV, LVSI, LVFS, RVd, VPMR, and PISA) had modest to moderately good ability to predict LVEF response with sensitivity ranging from 62.2% to 82.4%, and specificity ranging from 56.5% to 81.2%. For those parameters, the area under the receiver‐operating characteristic curve for positive response to CRT was ≤0.76. Multivariate regression analysis resulted in selection of LVSI and LVFS as possible predictive independent parameters for a good response. The cutoff value for LVSI was 38.7 mL/m2 (P = 0.045) and for LVFS was 13% (P = 0.032). Conclusions: Contribution of LVSI and LVFS is to be confirmed in larger trials. Simplicity of their assessment by conventional echocardiography could be an argument for adding them to the inclusion criteria for CRT in severe heart failure patients. (Echocardiography 2012;29:267‐275)

Myocardial regeneration therapy in heart failure: Current status and future therapeutic implications in clinical practice

Despite multiple treatment regimens the morbidity and mortality of patients with advanced heart failure (HF) have reached pandemic proportions. In an effort to address the root cause of the problem, curative strategies are increasingly being considered. A case in point is the evolution of regenerative medicine technologies aiming to halt or even reverse progressive organ deterioration in the HF setting. The prevailing unmet clinical needs in HF therapy have provided a major incentive for the development of cell-based treatment strategies, which have shown encouraging results in experimental studies. In turn, this has led to a significant international effort in cell-based clinical trials. In order to translate the promise of biotherapies into clinical benefit many more questions need to be addressed. In this review we analyze current clinical experience regarding cell therapy in the setting of ischemic/nonischemic HF and address key issues that could be a guide for future successful cell-based therapeutic application in HF patients in clinical practice.

Percutaneous Treatment of Aortic Valve Disease: Contemporary Overview and Future Trends

Efforts to develop and refine percutaneous approaches to cardiac valve repair and replacement have advanced rapidly over the past several years, having exceeded even the most optimistic expectations. New innovations have been predominantly directed toward the most frequent form of valvular heart disease (VHD) in the industrialized world; aortic stenosis (AS). Approximately 250,000 transcatheter aortic valve implantation (TAVI) procedures have been done so far addressing this significant medical need. Because of the predominance of degenerative etiologies, the prevalence of VHD increases markedly in population above the age of 65 years, in particular with regard to severe AS. As the populations of the industrialized countries continue to be older, the need for less invasive and safer methods of treating severe AS will continue to grow. In this review we provide comprehensive and up-to-date overview of TAVI in current clinical practice. We have also addressed dilemmas and unanswered questions related to TAVI procedures in different groups of patients and highlighted opportunities and trends related to future TAVI implementation.

Noninvasive assessment of myocardial bridging by coronary flow velocity reserve with transthoracic Doppler echocardiography: vasodilator vs. inotropic stimulation

BACKGROUND To consider hemodynamic assessment of myocardial bridging (MB) adequate, it is believed that inotropic stimulation with dobutamine should be estimated because its dynamic nature depends on the degree of extravascular coronary compression. This study evaluated comparative assessment of hemodynamic relevance of MB using coronary flow velocity reserve (CFVR) measurements by transthoracic Doppler echocardiography (TTDE) with vasodilatative and inotropic challenges. METHODS This prospective study included forty-four patients with angiographic evidence of isolated MB of the left anterior descending coronary artery (LAD) and systolic compression of ≥50% diameter stenosis. All patients were evaluated by exercise stress-echocardiography (ExSE) test for signs of myocardial ischemia, and CFVR of the distal segment of LAD during iv.infusion of adenosine (ADO:140μg/kg/min) and iv.infusion of dobutamine (DOB:10-40μg/kg/min), separately. RESULTS Exercise-SE was positive for myocardial ischemia in 8/44 (18%) of patients. CFVR during ADO was significantly higher than CFVR during peak DOB (2.85±0.68 vs. 2.44±0.48, p=0.002). CFVR during peak DOB was significantly lower in SE-positive group in comparison to SE-negative group (2.01±0.16 vs. 2.54±0.47, p<0.001), but not for ADO (2.47±0.51 vs. 2.89±0.70, p=0.168), respectively. Multivariable logistic analysis showed that CFVR peak DOB was the most significant predictor of functional significant MB (OR 0.011, 95%CI: 0.001-0.507, p=0.021). Receiver-operating characteristic curves have shown that TTDE-CFVR obtained by high-dose of dobutamine infusion is better than those by adenosine regarding to functional status of MB (AUC 0.861, p=0.004; AUC 0.674, p=0.179, respectively). CONCLUSIONS Non-invasive CFVR measurement by TTDE during inotropic stimulation, in comparison to vasodilation, provides more reliable functional evaluation of MB.