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Introduction: Recent efforts to increase CRT response by multiSPOT pacing (MSP) from multiple bipols on the same left ventricular lead are still inconclusive. Aim: The Left Ventricular (LV) MultiSPOTpacing for CRT (iSPOT) study compared the acute hemodynamic response of MSP pacing by using 3 electrodes on a quadripolar lead compared with conventional biventricular pacing (BiV). Methods: Patients with left bundle branch block (LBBB) underwent an acute hemodynamic study to determine the %change in LV+dP/dtmax from baseline atrial pacing compared to the following configurations: BiV pacing with the LV lead in a one of lateral veins, while pacing from the distal, mid, or proximal electrode and all 3 electrodes together (i.e. MSP). All measurements were repeated 4 times at 5 different atrioventricular delays. We also measured QRS-width and individual Q-LV durations. Results: Protocol was completed in 24 patients, all with LBBB (QRS width 171±20 ms) and 58% ischemic aetiology. The percentage change in LV+dP/dtmax for MSP pacing was 31.0±3.3% (Mean±SE), which was not significantly superior to any BiV pacing configuration: 28.9±3.2% (LV-distal), 28.3±2.7% (LV-mid), and 29.5±3.0% (LV-prox), respectively. Correlation between LV+dP/dtmax and either QRS-width or Q-LV ratio was poor. Conclusions: In patients with LBBB MultiSPOT LV pacing demonstrated comparable improvement in contractility to best conventional BiV pacing. Optimization of atrioventricular delay is important for the best performance for both BiV and MultiSPOT pacing configurations. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background: The fractional flow reserve (FFR) value of 0.75 has been validated against ischemic testing, whereas the FFR value of 0.80 has been widely accepted to guide clinical decision making. However, revascularization when FFR is 0.76 to 0.80, within the so-called gray zone, is still debatable.Methods and Results: From February 1997 to June 2013, all patients with single-segment disease and an FFR value within the gray zone or within the 2 neighboring FFR strata (0.70-0.75 and 0.81-0.85) were included. Study end points consisted of major adverse cardiovascular events (death, myocardial infarction, and any revascularization) up to 5 years. Of 17 380 FFR measurements, 1459 patients were included. Of them, 449 patients were treated with revascularization and 1010 patients were treated with medical therapy. In the gray zone, the major adverse cardiovascular events rate was similar (37 [13.9%] versus 21 [11.2%], respectively; P=0.3) between medical therapy and revascularization, whereas a strong trend toward a higher rate of death or myocardial infarction (25 [9.4] versus 9 [4.8], P=0.06) and overall death (20 [7.5] versus 6 [3.2], P=0.059) was observed in the medical therapy group. Among medical therapy patients, a significant step-up increase in major adverse cardiovascular events rate was observed across the 3 FFR strata, especially with proximal lesion location. In revascularization patients, the major adverse cardiovascular events rate was not different across the 3 FFR strata.Conclusions: FFR in and around the gray zone bears a major prognostic value, especially in proximal lesions. These data confirm that FFR≤0.80 is valid to guide clinical decision making. [ABSTRACT FROM AUTHOR]

Background The present study involved both human cohorts and animal experiments to explore the performance of soluble CD146 (sCD146), a marker of endothelial function, as a diagnostic marker of acutely decompensated heart failure (ADHF), to determine the influence of patients' characteristics on that performance and to explore the potential application of CD146 in the pathophysiology of ADHF. Methods and results NT-proBNP and sCD146 were measured in three hundred ninety-one patients admitted to the emergency department for acute dyspnea. ROC curve analysis demonstrated that AUCs for ADHF diagnosis in dyspneic patients were 0.86 (95% CI: 0.82–0.90) for sCD146 and 0.90 (95% CI: 0.86–0.92) for NT-proBNP. Subgroup analyses demonstrated that adding sCD146 to NT-proBNP improved the diagnostic performance for patients lying in the gray zone of NT-proBNP (p = 0.02) and could be especially useful for ruling-out ADHF. An experimental model of ADHF in rats using thoracic aortic constriction suggests that CD146 is expressed in the intima of large arteries and associated with both left ventricular function and organ congestion. Conclusions sCD146, a marker of endothelial function, seems to be as powerful as NT-proBNP is used to detect the cardiac origin of an acute dyspnea. The combination of sCD146 and NT-proBNP may have better performance than NT-proBNP used alone in particular for patients underlying in the “gray” zone and could therefore be an improved option for ruling-out ADHF. Both experimental and human data suggest that CD146 is related to systolic left ventricular function and to organ congestion. [ABSTRACT FROM AUTHOR]

Background: The chemokine Stromal cell-derived factor 1α (SDF1α, CXCL12) is currently under investigation as a biomarker for various cardiac diseases. The correct interpretation of SDF1α levels is complicated by the occurrence of truncated forms that possess an altered biological activity. Methodology: We studied the immunoreactivities of SDF1α forms and evaluated the effect of adding a DPP4 inhibitor in sampling tubes on measured SDF1α levels. Using optimized sampling, we measured DPP4 activity and SDF1α levels in patients with varying degrees of heart failure. Results: The immunoreactivities of SDF1α and its degradation products were determined with three immunoassays. A one hour incubation of SDF1α with DPP4 at 37°C resulted in 2/3 loss of immunoreactivity in each of the assays. Incubation with serum gave a similar result. Using appropriate sampling, SDF1α levels were found to be significantly higher in those heart failure patients with a severe loss of left ventricular function. DPP4 activity in serum was not altered in the heart failure population. However, the DPP4 activity was found to be significantly decreased in patients with high SDF1α levels Conclusions: We propose that all samples for SDF1α analysis should be collected in the presence of at least a DPP4 inhibitor. In doing so, we found higher SDF1α levels in subgroups of patients with heart failure. Our work supports the need for further research on the clinical relevance of SDF1α levels in cardiac disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Information on exercise capacity and training in patients who underwent valvular surgery is scarce. The aim of this study is to evaluate postoperative exercise capacity and functional improvement after exercise training according to the preoperative risk and type of surgery. In this prospective study, 145 patients who underwent aortic valve surgery (AVS) or mitral valve surgery (MVS) and who were referred for cardiac rehabilitation were stratified according to the preoperative risk (European System for Cardiac Operative Risk Evaluation [EuroSCORE]) and type of surgery (sternotomy vs ministernotomy or port access). Exercise capacity was evaluated at the start and end of cardiac rehabilitation. Postoperative exercise capacity and the benefit from exercise training were compared between the groups. Patients with a higher preoperative risk had a worse postoperative exercise capacity, with a lower load, peak VO2, anaerobic threshold and 6-minute walking distance (all p <0.001), and a higher VE/VCO2 slope (p [ 0.01). In MVS, port access patients performed significantlybetter at baseline (all p <0.05), but in AVS, ministernotomy patients performed better thansternotomy patients with a concomitant coronary artery bypass graft (p <0.05). Trainingresulted in an improvement in exercise capacity in each risk group and each type of surgery(all p <0.05). This gain in exercise capacity was comparable for the EuroSCORE riskgroups and for the types of surgery, for patients after AVS or MVS. In conclusion, exercisecapacity after cardiac surgery is related to the preoperative risk and the type of surgery. Despite these differences in postoperative exercise capacity, a similar benefit from exercisetraining is obtained, regardless of their preoperative risk or type of surgery. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to evaluate the feasibility and safety of autologous bone marrow–derived and cardiogenically oriented mesenchymal stem cell therapy and to probe for signs of efficacy in patients with chronic heart failure. Background: In pre-clinical heart failure models, cardiopoietic stem cell therapy improves left ventricular function and blunts pathological remodeling. Methods: The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial, a prospective, multicenter, randomized trial, was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. In the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy. Results: Mesenchymal stem cell cocktail–based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p < 0.0001) and was associated with a reduction in left ventricular end-systolic volume (−24.8 ± 3.0 ml vs. −8.8 ± 3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 ± 18 m vs. −15 ± 20 m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival. Conclusions: The C-CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. (C-Cure Clinical Trial; NCT00810238). [Copyright &y& Elsevier]

Aims Recent studies indicate that brain natriuretic peptide (BNP1–32) may be truncated into BNP3–32 by dipeptidyl peptidase IV (DPP4) and that BNP3–32 has reduced biological activities compared with BNP1–32. We investigated if DPP4 contributes to the cardiorenal alterations and to the attenuated response to BNP seen in heart failure. Methods and results Haemodynamic and renal assessment was performed in 12 pigs at baseline, 4 weeks after pacing-induced heart failure, and during BNP infusion. They were randomized to either placebo or treatment with a DPP4 inhibitor, sitagliptin. After 4 weeks of pacing, heart rate was reduced compared with baseline in the sitagliptin group (60 ± 2 vs. 95 ± 16 b.p.m., P < 0.01), and an increase in stroke volume was observed in the sitagliptin group compared with placebo (+24 ± 6% vs. –17 ± 7%, P < 0.01). Glomerular filtration rate declined at week 4 compared with baseline in the placebo group (1.3 ± 0.4 vs. 2.3 ± 0.3 mL/kg/min, P < 0.01) but remained preserved in the sitagliptin group [1.8 ± 0.2 vs. 2.0 ± 0.3 mL/kg/min, P = NS (non-significant)]. In the sitagliptin group, BNP infusion improved end-systolic elastance (68 ± 5 vs. 31 ± 4 mmHg/kg/mL, P < 0.05), ventricular–arterial coupling, and mechanical efficiency. Compared with controls (n = 6), myocardial gene expression of BNP, interleukin-6, Na+–Ca2+ exchanger, and calmodulin was up-regulated in the placebo group, but not in the sitagliptin group. Conclusion In pacing-induced heart failure, DPP4 inhibition preserves the glomerular filtration rate, modulates stroke volume and heart rate, and potentiates the positive inotropic effect of exogenous BNP at no energy expense. [ABSTRACT FROM AUTHOR]

The article focuses on the late adaptive coronary artery remodelling after biodegradable stent implantation. Stenting is considered as a new interventional approach. It aims at adaptive coronary remodelling through the limitation of acute elastic recoil and late neointimal proliferation. The study shows that magnesium alloy provides the mechanical properties' benefit which is comparable with controlled absorption over time.

The aim of the present study was to compare 600- and 300-mg clopidogrel loading doses in patients with ST-segment elevation myocardial infarctions who underwent primary percutaneous coronary intervention (PCI). Two hundred fifty-five consecutive patients presenting with ST-segment elevation myocardial infarctions who underwent primary PCI were enrolled. Patients were divided into 2 groups on the basis of the loading dose of clopidogrel received before the procedure (600 vs 300 mg). Procedural angiographic end points and 1-year major adverse cardiac events were compared between the 2 groups. Major adverse cardiac events were defined as death, nonfatal myocardial infarction, and target vessel revascularization. There were no significant differences in baseline clinical and angiographic features between the 2 groups: 157 (62%) in the clopidogrel 600 mg group and 98 (38%) in the 300 mg group. Patients receiving 600-mg loading dose of clopidogrel showed a significantly lower incidence of post-PCI myocardial blush grade 0 or 1 (odds ratio 0.64, 95% confidence interval 0.43 to 0.96, p = 0.03) and significantly less common no-reflow phenomenon (odds ratio 0.38, 95% confidence interval 0.15 to 0.98, p = 0.04) compared to those in the 300-mg group. Propensity-adjusted Cox analysis showed significantly higher survival free of major adverse cardiac events in patients receiving 600-mg loading dose of clopidogrel compared to those receiving the lower dose (hazard ratio 0.57, 95% confidence interval 0.33 to 0.98, p = 0.04). In conclusion, a 600-mg loading dose of clopidogrel is associated with improvements in procedural angiographic end points and 1-year clinical outcomes in patients with ST-segment elevation myocardial infarction who undergo primary PCI compared to a 300-mg dose. [ABSTRACT FROM AUTHOR]

Acute myocardial infarctions were generally believed to result from plaque rupture and thrombosis at the site of a "mild to moderate" coronary stenosis. To assess the severity of coronary stenoses that predisposed to acute coronary syndrome, the 317 patients prospectively included were (1) 102 patients with acute ST-elevation myocardial infarction (STEMI) referred for primary percutaneous coronary intervention (PCI), (2) 135 patients with non-STEMI or unstable angina pectoris (UAP) referred for semiurgent PCI, and (3) 80 patients with stable angina pectoris (SAP) admitted for elective PCI. Patients with STEMI were included if thrombus aspiration could restore normal antegrade coronary blood flow. After aspiration (but before PCI), a high-quality angiogram was obtained and the reference diameter, minimal luminal diameter, and percentage of diameter stenosis of the culprit lesion were quantified. In patients with non-STEMI/UAP and SAP, aspiration was not performed. Average diameter of stenosis was similar in patients with STEMI and those with SAP (66 +/- 12% vs 65 +/- 10%, respectively; p = NS), but was slightly larger in patients with non-STEMI/UAP (71 +/- 12%; p <0.05 vs both STEMI and SAP). In patients with STEMI, only 11% of culprit stenoses were found to have diameter stenosis <50% after removal of the thrombus. In conclusion, most STEMIs occurred at the site of severe coronary stenosis. Diameter stenosis severity was <50% in a minority of cases. [ABSTRACT FROM AUTHOR]

Background Coronary allograft vasculopathy is a severe complication of heart transplantation. We used virtual histology intravascular ultrasound to characterize plaque burden and tissue composition over time in heart transplant recipients. Methods We recruited patients undergoing heart transplantation in four centers in Europe and the US between 2004 and 2606. We used intravascular ultrasound to obtain morphological plaque measurements and to perform virtual histology in the left anterior descending coronary artery. Data were characterized according to the duration between transplantation and intravascular ultrasound assessment: ≤24, >24-60, >60-120 and >120-192 months. Results We assessed vessels from 152 patients (mean age 58 ± 12 years) a mean of 70 ± 53 months (range 1 week to 16 years) after transplantation. Plaque burden of >40% was observed in 26% of vessels analyzed, with increases from baseline being seen in all time categories. If assessed >24 months after transplantation, necrotic core and dense calcified volumes were significantly greater than at baseline (P = 0.0005 and P = 0.01, respectively). Time since heart transplantation and donor age and recipient age were independent predictive factors of increased necrotic core content. Necrotic core volume >2.01 mm³, diabetes mellitus, donor age older than 40 years, follow-up from transplantation longer than 5 years and recipient age older than 58 years were associated with the need for revascularization. Conclusions In coronary allograft vasculopathy, plaque burden and composition change over time and seem to affect clinical outcome. This relationship might facilitate identification of high-risk patients in whom the value of more aggressive medical therapy should be tested. [ABSTRACT FROM AUTHOR]

Objectives: This study was designed to investigate: 1) relationships between serum ST2 levels and hemodynamic/neurohormonal variables; 2) myocardial ST2 production; and the 3) expression of ST2, membrane-anchored ST2L, and its ligand, interleukin (IL)-33, in myocardium, endothelium, and leukocytes from patients with left ventricular (LV) pressure overload and congestive cardiomyopathy. Background: Serum levels of ST2 are elevated in heart failure. The relationship of ST2 to hemodynamic variables, source of ST2, and expression of ST2L and IL-33 in the cardiovascular system are unknown. Methods: Serum ST2 (pg/ml; median [25th, 75th percentile]) was measured in patients with LV hypertrophy (aortic stenosis) (n = 45), congestive cardiomyopathy (n = 53), and controls (n = 23). ST2 was correlated to N-terminal pro-brain natriuretic peptide, C-reactive protein, and hemodynamic variables. Coronary sinus and arterial blood sampling determined myocardial gradient (production) of ST2. The levels of ST2, ST2L, and IL-33 were measured (reverse transcriptase-polymerase chain reaction) in myocardial biopsies and leukocytes. The ST2 protein production was evaluated in human endothelial cells. The IL-33 protein expression was determined (immunohistochemistry) in coronary artery endothelium. Results: The ST2 protein was elevated in aortic stenosis (103 [65, 165] pg/ml, p < 0.05) and congestive cardiomyopathy (194 [69, 551] pg/ml, p < 0.01) versus controls (49 [4, 89] pg/ml) and correlated with B-type natriuretic peptide (r = 0.5, p < 0.05), C-reactive protein (r = 0.6, p < 0.01), and LV end-diastolic pressure (r = 0.38, p < 0.03). The LV ST2 messenger ribonucleic acid was similar in aortic stenosis and congestive cardiomyopathy versus control (p = NS). No myocardial ST2 protein gradient was observed. Endothelial cells secreted ST2. The IL-33 protein was expressed in coronary artery endothelium. Leukocyte ST2L and IL-33 levels were highly correlated (r = 0.97, p < 0.001). Conclusions: In human hypertrophy and failure, serum ST2 correlates with the diastolic load. Though the heart, endothelium, and leukocytes express components of ST2/ST2L/IL-33 pathway, the source of circulating serum ST2 is extra-myocardial. [Copyright &y& Elsevier]

Impaired responses to antiplatelet therapy assessed by laboratory tests are associated with an increased risk of recurrent ischemic events after percutaneous coronary intervention (PCI). This study was designed to determine the relation between responses to aspirin and clopidogrel as assessed by a point-of-care assay (Verify Now, Accumetrics, San Diego, California) and periprocedural myocardial infarction (PMI) in patients undergoing elective PCI for stable angina. One hundred twenty-two consecutive patients undergoing elective coronary stenting prospectively received aspirin 500 mg and clopidogrel 600 mg ≥12 hours before PCI. Clopidogrel response was measured with P2Y12 reaction units (PRUs) and percent inhibition P2Y12 from baseline (percent inhibition P2Y12) and aspirin response with aspirin reaction units (ARUs). Troponin T level was considered positive if it was >0.03 ng/ml. Responses to aspirin and clopidogrel were correlated (r = 0.42, p <0.0001). PMI occurred in 27 patients (22%) who showed significantly lower percent inhibition P2Y12 (25.3 ± 26 vs 38.3 ± 25, p = 0.01) and a trend toward higher PRU values (221 ± 87 vs 193 ± 94, p = 0.21). We did not find any difference for aspirin response as assessed by ARUs in patients with or without PMI (460 ± 82 vs 454 ± 73, p = 0.82). Stratification of percent inhibition P2Y12 isolated a quartile of clopidogrel nonresponders (inhibition P2Y12 <15%) with significantly higher incidence of PMI (44% vs 15%, odds ratio 4.6, 95% confidence interval 1.9 to 11.5, p = 0.001). In conclusion, point-of-care assessment of clopidogrel response reliably predicted PMI after low- to medium-risk elective PCI for stable angina. [Copyright &y& Elsevier]

Objectives: We studied whether functional improvement after cardiac resynchronization therapy (CRT) is associated with reversal of the heart failure (HF) gene program. Background: Cardiac resynchronization therapy improves exercise tolerance and survival in patients with advanced congestive HF and dyssynchrony. Methods: Twenty-four patients referred for CRT underwent left ventricular (LV) endomyocardial biopsies immediately before CRT implantation (baseline). In addition, 17 of them underwent LV endomyocardial biopsy procurement 4 months later (follow-up). In 6 control patients with normal LV function, LV biopsies were obtained at the time of coronary artery bypass grafting. The LV messenger ribonucleic acid (mRNA) levels of contractile and calcium regulatory genes were measured by quantitative real time polymerase chain reaction and normalized for glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The HF patients showing an improvement in New York Heart Association (NYHA) functional class by >1 score and a relative increase in LV ejection fraction > or =25% at 4 months after CRT were considered as responders. Results: The HF patients were characterized by lower LV mRNA levels of alpha-myosin heavy chain (alpha-MHC), beta-myosin heavy chain (beta-MHC), sarcoplasmic reticulum calcium ATPase 2alpha (SERCA), phospholamban (PLN), and higher brain natriuretic peptide (BNP) mRNA levels as compared with control subjects. Responders to CRT (n = 11) showed an increase in LVEF (p < 0.001), a decrease in left ventricular end-diastolic diameter (p = 0.003), and NYHA functional class (p = 0.002), and a reduction in N-terminal proBNP levels (p = 0.032) as compared with baseline. This was associated with an increase in mRNA levels of alpha-MHC (p = 0.035), SERCA (p = 0.032), a decrease in BNP mRNA levels (p = 0.002), and an increase in the ratio of alpha-/beta-MHC (p = 0.018) and SERCA/PLN (p = 0.012). No significant changes in molecular profile were observed in nonresponders. Conclusions: In HF patients with electromechanical cardiac dyssynchrony, functional improvement related to CRT is associated with favorable changes in established molecular markers of HF, including genes that regulate contractile function and pathologic hypertrophy. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to perform a meta-analysis of clinical trials on intracoronary cell therapy after acute myocardial infarction (AMI). Background: Intracoronary cell therapy continues to be evaluated in the setting of AMI with variable impact on left ventricular ejection fraction (LVEF). Methods: We searched the CENTRAL, mRCT, and PubMed databases for controlled trials reporting on intracoronary cell therapy performed in patients with a recent AMI (≤14 days), revascularized percutaneously, with follow-up of ≥3 months. The primary end point was change in LVEF, and secondary end points were changes in infarct size, cardiac dimensions, and dichotomous clinical outcomes. Results: Ten studies were retrieved (698 patients, median follow-up 6 months), and pooling was performed with random effect. Subjects that received intracoronary cell therapy had a significant improvement in LVEF (3.0% increase [95% confidence interval (CI) 1.9 to 4.1]; p < 0.001), as well as a reduction in infarct size (−5.6% [95% CI −8.7 to −2.5]; p < 0.001) and end-systolic volume (−7.4 ml [95% CI −12.2 to −2.7]; p = 0.002), and a trend toward reduced end-diastolic volume (−4.6 ml [95% CI −10.4 to 1.1]; p = 0.11). Intracoronary cell therapy was also associated with a nominally significant reduction in recurrent AMI (p = 0.04) and with trends toward reduced death, rehospitalization for heart failure, and repeat revascularization. Meta-regression suggested the existence of a dose-response association between injected cell volume and LVEF change (p = 0.066). Conclusions: Intracoronary cell therapy following percutaneous coronary intervention for AMI appears to provide statistically and clinically relevant benefits on cardiac function and remodeling. These data confirm the beneficial impact of this novel therapy and support further multicenter randomized trials targeted to address the impact of intracoronary cell therapy on overall and event-free long-term survival. [Copyright &y& Elsevier]

Objectives: The objective of the present study was to assess the relationship between the presence of left ventricular (LV) dyssynchrony and clinical outcome in patients with moderate systolic heart failure undergoing coronary artery bypass graft (CABG) surgery. Background: The presence of LV dyssynchrony is associated with poor prognosis in patients with LV dysfunction. Methods: The study consisted of 215 consecutive patients with ischemic cardiomyopathy and dyspnea (age 65 ± 9 years, 81% male) undergoing CABG. Dyssynchrony was calculated by tissue Doppler imaging from regional time intervals in basal LV segments before and 1 month after CABG. Myocardial viability was assessed using single-photon emission computed tomography (SPECT) before CABG. Results: Twenty-five patients (11.6%) died within 30 days (in-hospital mortality) of CABG. The presence of pre-CABG dyssynchrony ≥119 ms had the highest predictive accuracy for in-hospital mortality, with a sensitivity of 84% and a specificity of 71%. During the median follow-up period of 359 days (interquartile range 219 to 561), an additional 19 patients (10.3%) died and 34 patients (18.5%) were hospitalized for worsening heart failure. At Cox regression analysis, post-CABG dyssynchrony ≥72 ms and ≥5 viable segments were identified as independent predictors of clinical events, with a hazard ratio (HR) of 5.02, 95% confidence interval (CI) 2.57 to 10.02 (p < 0.001), and an HR of 0.63, 95% CI 0.55 to 0.75 (p < 0.001), respectively. Patients without post-CABG dyssynchrony and with viable myocardium had excellent prognosis compared with patients with severe post-CABG dyssynchrony and nonviable myocardium (event rate 3% vs. 64%; p < 0.001). Conclusions: The presence of severe LV dyssynchrony is associated with poor clinical outcomes despite revascularization. These results advocate a routine assessment of both LV dyssynchrony and viability to predict outcome in systolic heart failure patients undergoing CABG surgery. [Copyright &y& Elsevier]

Stem cell therapy has emerged as a potential therapeutic option for cell death-related heart diseases. Preclinical and a number of early phase human studies suggested that cell therapy may augment perfusion and increase myocardial contractility. The rapid translation into clinical trials has left many issues unresolved, and emphasizes the need for specific techniques to visualize the mechanisms involved. Furthermore, the clinical efficacy of cell therapy remains to be proven. Imaging allows for in vivo tracking of cells and can provide a better understanding in the evaluation of the functional effects of cell-based therapies. In this review, a summary of the most promising imaging techniques for cell tracking is provided. Among these are direct labeling of cells with super-paramagnetic agents, radionuclides, and the use of reporter genes for imaging of transplanted cells. In addition, a comprehensive summary is provided of the currently available studies investigating a cell therapy-related effect on left ventricular function, myocardial perfusion, scar tissue, and myocardial viability. [Copyright &y& Elsevier]

The in vivo cardiac differentiation and functional effects of unmodified adult bone marrow mesenchymal stem cells (MSCs) after myocardial infarction (MI) is controversial. We postulated that ex vivo pretreatment of autologous MSCs using cardiomyogenic growth factors will lead to cardiomyogenic specification and will result in superior biological and functional effects on cardiac regeneration of chronically infarcted myocardium. We used a chronic dog MI model generated by ligation of the coronary artery (n = 30). Autologous dog bone marrow MSCs were isolated, culture expanded, and specified into a cardiac lineage by adding growth factors, including basic FGF, IGF-1, and bone morphogenetic protein-2. Dogs underwent cell injection >8 wk after the infarction and were randomized into two groups. Group A dogs (n = 20) received MSCs specified with growth factors (147 ± 96 X 106), and group B (n = 10) received unmodified MSCs (168 ± 24 X 106). After the growth factor treatment, MSCs stained positive for the early muscle and cardiac markers desmin, antimyocyte enhancer factor-2, and Nkx2-5. In group A dogs, prespecified MSCs colocalized with troponin I and cardiac myosin. At 12 wk, group A dogs showed a significantly larger increase in regional wall thickening of the infarcted territory (from 22 ± 8 to 32 ± 6% in group A; P < 0.05 vs. baseline and group B, and from 19 ± 7 to 21 ± 7% in group B, respectively) and a decrease in the wall motion score index (from 1.60 ± 0.05 to 1.35 ± 0.03 in group A; P < 0.05 vs. baseline and group B, and from 1.58 ± 0.07 vs. 1.56 ± 0.08 in group B, respectively). The biological ex vivo cardiomyogenic specification of adult MSCs before their transplantation is feasible and appears to improve their in vivo cardiac differentiation as well as the functional recovery in a dog model of the chronically infarcted myocardium. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to define “significant” renal artery stenosis (i.e., a stenosis able to induce arterial hypertension). Background: The degree of renal artery stenosis that justifies an attempt at revascularization is unknown. Methods: In 15 patients, transstenotic pressure measurements were obtained before and after unilateral stenting. After stenting, graded stenoses were created in the stented segment by progressive inflation of a balloon catheter. Stenosis severity was expressed as the ratio of distal pressure (P d ) corrected for aortic pressure (P a ). Balloon inflation pressure was adjusted to create 6° of stenosis (P d /P a from 1.0 to 0.5, each step during 10 min). Plasma renin concentration was measured at the end of each step in the aorta and in both renal veins. Results: For a P d /P a ratio >0.90, no significant change in plasma renin concentration was observed. However, when P d /P a became <0.90, a significant increase in renin was observed in the renal vein of the stenotic kidney, finally reaching a maximal increase of 346 ± 145% for P d /P a of 0.50 (p = 0.006). These values returned to baseline when the stenosis was relieved. In addition, plasma renin concentration increased significantly in the vein from the non-stenotic kidney (p = 0.02). Conclusions: In renal artery stenoses, a P d /P a ratio of 0.90 can be considered a threshold value below which the stenosis is likely responsible for an up-regulation of renin production and, thus, for renovascular hypertension. These findings might contribute to better patient selection for renal angioplasty. [Copyright &y& Elsevier]

Cardiac transplant-related vasculopathy remains a leading cause of morbidity and mortality in heart transplant (HTx) recipients. Recently, coronary angiography-derived vessel fractional flow reserve (vFFR) has emerged as a new diagnostic computational tool to functionally evaluate the severity of coronary artery disease. Although vFFR estimates have been shown to perform well against invasive FFR in atherosclerotic coronary artery disease, data on the use of vFFR in heart transplant recipients suffering from cardiac transplant-related arteriopathy are lacking. The aim of the presented study was to validate coronary angiography-derived vessel fractional flow reserve to calculate fractional flow reserve in HTx patients with and without cardiac transplant-related vasculopathy. A prospective, single center study of HTx patients referred for annual check-up, undergoing surveillance coronarography was conducted. Invasive FFR was measured using a motorized device at the speed of 1.0 mm/s in all three major coronary arteries. Angiography-derived pullback FFR was derived from the angiogram and compared with invasive FFR pullback curve. Overall, 18,059 FFR values were extracted from the FFR pullback curves from 23 HTx patients. The mean age was 59.3 ± 9.7 years, the mean time after transplantation was 5.24 years [IQR 1.20, 11.25]. A total of 39 vessels from 23 patients (24 LAD, 11 LCX, 4 RCA) were analyzed. Mean distal vFFR was 0.87 ± 0.14 whereas invasive distal FFR was 0.88 ± 0.17. An excellent correlation was found between invasive distal FFR and vFFR (r = 0.92; p < 0.001). The correlation of the pullback tracing was high, with a correlation coefficient between vFFR and invasive FFR pullback values of 0.72 (95% CI 0.71 to 0.73, p < 0.001). The mean difference between vFFR and invasive FFR pullback values was −0.01 with 0.06 of SD (limits of agreements −0.12 to 0.13). In HTx patients, coronary angiography-derived FFR correlates excellently with invasively measured wire-derived FFR. Therefore, angiography derived FFR could be used as a novel diagnostic tool to quantify the functional severity of graft vasculopathy. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Arg16Gly and Gln27Glu polymorphism of β2-adrenergic receptors (β2AR) have been associated with several risk factors for coronary atherosclerotic disease (CAD). Nevertheless, conflicting data have been reported concerning their influence on CAD and cardiovascular clinical events. Aim: To investigate whether (a) β2AR polymorphisms are associated with CAD; and (b) the potential impact, if any, of these polymorphisms on cardiovascular clinical events in patients presenting with angina-like pain or silent ischemia. Methods and results: We screened 786 consecutive patients referred to cardiac catheterization because of angina-like pain or silent ischemia for Arg16Gly, Gln27Glu, Thr164Ile β2AR polymorphisms. Patients were divided in 2 groups according to the presence or absence of CAD at the angiography. Hundred subjects from blood donor center served as controls. Clinical endpoints were evaluated at baseline and up to 6 years follow-up. Glu-27 homozygous genotype and Glu-27 allele (Glu-27, allele frequency: 47% CAD versus 39% NO CAD, p <0.05) were more frequent in patients with CAD. At multivariate analysis, patients carrying Glu-27 allele showed a significantly higher risk of developing CAD (OR: 1.78, 95% CI: 1.21–2.63, p =0.004). At clinical follow-up, a higher incidence of coronary revascularization was noted in Glu-27 homozygotes as compared with Gln-27 homozygote patients. Conclusions: In patients at high risk for CAD and/or angina-like pain, Glu-27 allele of β2 adrenergic receptor polymorphism is an independent risk factor for CAD and appears to be associated with higher incidence of myocardial revascularization. [Copyright &y& Elsevier]

Background: Discrepancies between stenosis severity assessed at coronary computed tomography angiography (CCTA) and ischemia might depend on vessel type. Coronary plaque features are associated with ischemia. Thus, we evaluated the vessel-specific correlation of CCTA-derived diameter stenosis (DS) and invasive fractional flow reserve (FFR) and explored whether integrating morphological plaque features stratified by vessel might increase the predictive yield in identifying vessel-specific ischemia., Methods: Observational cohort study including patients undergoing CCTA for suspected coronary artery disease, with at least one vessel with DS ​≥ ​50 ​% at CCTA, undergoing invasive coronary angiography and FFR. Plaque analysis was performed using validated semi-automated software. Coronary vessels were stratified in left anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA). Per vessel independent predictors of ischemia among CCTA-derived anatomical and morphologic plaque features were tested at univariable and multivariable logistic regression analysis. The best cut-off to predict ischemia was determined by Youden's index. Ischemia was defined by FFR≤0.80., Results: The study population consisted of 192 patients, of whom 224 vessels (61 ​% LAD, 19 ​% LCX, 20 ​% RCA) had lesions with DS ​≥ ​50 ​% interrogated by FFR. Despite similar DS, the rate of FFR≤0.80 was higher in the LAD compared to LCX and RCA (67.2 ​% vs 43.2 ​% and 44.2 ​%, respectively, p ​= ​0.018). A significant correlation between DS and FFR was observed only in LAD (p ​= ​0.003). At multivariable analysis stratified by vessel, the vessel-specific independent predictors of positive FFR were percent atheroma volume (threshold>17 ​%) for LAD, non-calcified plaque volume (threshold >130 ​mm 3 ) for LCX, and lumen volume (threshold <844 ​mm 3 ) for RCA. Integrating DS and vessel-specific morphological plaque features significantly increased the predictive yield for ischemia compared to DS alone (AUC ranging from 0.51 to 0.63 to 0.76-0.80)., Conclusions: Integrating DS and vessel-specific morphological plaque features significantly increased the predictive yield for vessel-specific ischemia compared to DS alone, potentially improving patients' referral to the catheterization laboratory., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: Severe aortic stenosis (AS) is associated with left ventricular (LV) remodelling, likely causing alterations in coronary blood flow and microvascular resistance., Aims: We aimed to evaluate changes in absolute coronary flow and microvascular resistance in patients with AS undergoing transcatheter aortic valve implantation (TAVI)., Methods: Consecutive patients with AS undergoing TAVI with non-obstructive coronary artery disease in the left anterior descending artery (LAD) were included. Absolute coronary flow (Q) and microvascular resistance (R μ ) were measured in the LAD using continuous intracoronary thermodilution at rest and during hyperaemia before and after TAVI, and at 6-month follow-up. Total myocardial mass and LAD-specific mass were quantified by echocardiography and cardiac computed tomography. Regional myocardial perfusion (Q N ) was calculated by dividing absolute flow by the subtended myocardial mass., Results: In 51 patients, Q and R were measured at rest and during hyperaemia before and after TAVI; in 20 (39%) patients, measurements were also obtained 6 months after TAVI. No changes occurred in resting and hyperaemic flow and resistance before and after TAVI nor after 6 months. However, at 6-month follow-up, a notable reverse LV remodelling resulted in a significant increase in hyperaemic perfusion (Q N,hyper : 0.86 [interquartile range {IQR} 0.691.06] vs 1.20 [IQR 0.99-1.32] mL/min/g; p=0.008; pre-TAVI and follow-up, respectively) but not in resting perfusion (Q N,rest : 0.34 [IQR 0.30-0.48] vs 0.47 [IQR 0.36-0.67] mL/min/g; p=0.06)., Conclusions: Immediately after TAVI, no changes occurred in absolute coronary flow or coronary flow reserve. Over time, the remodelling of the left ventricle is associated with increased hyperaemic perfusion.

Background: One third of patients undergoing transcatheter aortic-valve implantation (TAVI) have an indication for oral anticoagulation owing to concomitant diseases. Interruption of oral anticoagulation during TAVI may decrease the risk of bleeding, whereas continuation may decrease the risk of thromboembolism., Methods: We conducted an international, open-label, randomized, noninferiority trial involving patients who were receiving oral anticoagulants and were planning to undergo TAVI. Patients were randomly assigned in a 1:1 ratio to periprocedural continuation or interruption of oral anticoagulation. The primary outcome was a composite of death from cardiovascular causes, stroke from any cause, myocardial infarction, major vascular complications, or major bleeding within 30 days after TAVI., Results: A total of 858 patients were included in the modified intention-to-treat population: 431 were assigned to continuation and 427 to interruption of oral anticoagulation. A primary-outcome event occurred in 71 patients (16.5%) in the continuation group and in 63 (14.8%) in the interruption group (risk difference, 1.7 percentage points; 95% confidence interval [CI], -3.1 to 6.6; P = 0.18 for noninferiority). Thromboembolic events occurred in 38 patients (8.8%) in the continuation group and in 35 (8.2%) in the interruption group (risk difference, 0.6 percentage points; 95% CI, -3.1 to 4.4). Bleeding occurred in 134 patients (31.1%) in the continuation group and in 91 (21.3%) in the interruption group (risk difference, 9.8 percentage points; 95% CI, 3.9 to 15.6)., Conclusions: In patients undergoing TAVI with a concomitant indication for oral anticoagulation, periprocedural continuation was not noninferior to interruption of oral anticoagulation during TAVI with respect to the incidence of a composite of death from cardiovascular causes, stroke, myocardial infarction, major vascular complications, or major bleeding at 30 days. (Funded by the Netherlands Organization for Health Research and Development and the St. Antonius Research Fund; POPular PAUSE TAVI ClinicalTrials.gov number, NCT04437303.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Approximately half of the patients with angina and nonobstructive coronary artery disease (ANOCA) have evidence of coronary microvascular dysfunction (CMD)., Objectives: This study aims to characterize patients with ANOCA by measuring their minimal microvascular resistance and to examine the pattern of vascular remodeling associated with these measurements., Methods: The authors prospectively included patients with ANOCA undergoing continuous thermodilution assessment. Lumen volume and vessel-specific myocardial mass were quantified using coronary computed tomography angiography (CTA). CMD was defined as coronary flow reserve <2.5 and high minimal microvascular resistance as >470 WU., Results: A total of 153 patients were evaluated; 68 had CMD, and 22 of them showed high microvascular resistance. In patients with CMD, coronary flow reserve was 1.9 ± 0.38 vs 3.2 ± 0.81 in controls (P < 0.001). Lumen volume was significantly correlated with minimal microvascular resistance (r = -0.59 [95% CI: -0.45 to -0.71]; P < 0.001). In patients with CMD and high microvascular resistance, lumen volume was 40% smaller than in controls (512.8 ± 130.3 mm 3 vs 853.2 ± 341.2 mm 3 ; P < 0.001). Epicardial lumen volume assessed by coronary CTA was independently associated with minimal microvascular resistance (P < 0.001). The predictive capacity of lumen volume from coronary CTA for detecting high microvascular resistance showed an area under the curve of 0.79 (95% CI: 0.69-0.88)., Conclusions: Patients with CMD and high minimal microvascular resistance have smaller epicardial vessels than those without CMD. Coronary CTA detected high minimal microvascular resistance with very good diagnostic capacity. Coronary CTA could potentially aid in the diagnostic pathway for patients with ANOCA., Competing Interests: Funding Support and Author Disclosures Dr Collet has received research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and consultancy fees from HeartFlow Inc, OpSens, Abbott Vascular, and Philips Volcano. Dr Mizukami has received consultancy fees from Zeon Medical Inc, research grants from Boston Scientific, and speaker fees from Abbott Vascular, Cath works, and Boston Scientific. Drs Buytaert and Munhoz have received research grants provided by the Cardiopath PhD program. Dr De Bruyne has received consultancy fees from Boston Scientific and Abbott Vascular; research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and owns equity in Siemens, GE, Philips, HeartFlow Inc, Edwards Life Sciences, Bayer, Sanofi, and Celyad. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Transcatheter aortic valve replacement(TAVR) has shown clear survival benefits in severe aortic valve stenosis(AS). However, patients unable to recover left ventricle function remain at risk with poor long-term survival. This single-center prospective study aims to analyze the supplementary benefits of myocardial work(MW) assessment for baseline risk stratification in patients with severe AS referred for TAVR., Methods: A total of 110 patients with severe AS referred for TAVR were included in the study. Baseline ECG data, transthoracic echocardiographic(TTE) images and blood samples were obtained. The TTE examination was repeated one day and one month after valve replacement. The primary outcome of the study was a composite endpoint consisting of all-cause mortality and HF hospitalization., Results: During a mean follow-up period of 521 ± 343 days, 29patients(26.4 %) reached the composite endpoint. Baseline troponins, NT-proBNP, sST2, GWI and GCW showed statistically significant differences between groups. Patients with a baseline GWI<2323 mmHg% (sensitivity 0.63 and specificity 0.76)had significantly worse outcome following TAVR. A basic predictive model included QRS-length, TAPSE, LAVI and E/e'. The addition of biomarkers did not yield any further advantages whereas incorporating the GWI cut-off value of 2323 mmHg% significantly enhanced the predictive value. Although there were no significant changes in LVEF and GLS, all patients exhibited a significant reduction in GWI and GCW immediately after TAVR., Conclusion: Our findings provide evidence for the enhanced usefulness of MW analysis in the initial risk stratification of patients with severe AS referred for TAVR. Specifically, a baseline GWI<2323 mmHg% demonstrates an independent predictor associated with increased incidence of all-cause mortality and HF hospitalization following TAVR., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Importance: Although the results of A Study to Evaluate the Corvia Medical Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF II) trial were neutral overall, atrial shunt therapy demonstrated potential efficacy in responders (no latent pulmonary vascular disease and no cardiac rhythm management device). Post hoc analyses were conducted to evaluate the effect of shunt vs sham stratified by responder status., Objective: To evaluate the effect of atrial shunt vs sham control on cardiac structure/function in the overall study and stratified by responder status., Design, Setting, and Participants: This was a sham-controlled randomized clinical trial of an atrial shunt device in heart failure with preserved ejection fraction (HFpEF)/HF with mildly reduced EF (HFmrEF). Trial participants with evaluable echocardiography scans were recruited from 89 international medical centers. Data were analyzed from April 2023 to January 2024., Interventions: Atrial shunt device or sham control., Main Outcome Measures: Changes in echocardiographic measures from baseline to 1, 6, 12, and 24 months after index procedure., Results: The modified intention-to-treat analysis of the REDUCE LAP-HF II trial included 621 randomized patients (median [IQR] age, 72.0 [66.0-77.0] years; 382 female [61.5%]; shunt arm, 309 [49.8%]; sham control arm, 312 [50.2%]). Through 24 months, 212 of 217 patients (98%) in the shunt arm with evaluable echocardiograms had patent shunts. In the overall trial population, the shunt reduced left ventricular (LV) end-diastolic volume (mean difference, -5.65 mL; P <.001), left atrial (LA) minimal volume (mean difference, -2.8 mL; P =.01), and improved LV systolic tissue Doppler velocity (mean difference, 0.69 cm/s; P <.001) and LA emptying fraction (mean difference, 1.88 percentage units; P =.02) compared with sham. Shunt treatment also increased right ventricular (RV; mean difference, 9.58 mL; P <.001) and right atrial (RA; mean difference, 9.71 mL; P <.001) volumes but had no effect on RV systolic function, pulmonary artery pressure, or RA pressure compared with sham. In the shunt arm, responders had smaller increases in RV end-diastolic volume (mean difference, 5.71 mL vs 15.18 mL; interaction P =.01), RV end-systolic volume (mean difference, 1.58 mL vs 7.89 mL; interaction P =.002), and RV/LV ratio (mean difference, 0.07 vs 0.20; interaction P <.001) and larger increases in transmitral A wave velocity (mean difference, 5.08 cm/s vs -1.97 cm/s; interaction P =.02) compared with nonresponders randomized to the shunt, suggesting greater ability to accommodate shunted blood through the pulmonary circulation enabling LA unloading., Conclusions and Relevance: In this post hoc analysis of the REDUCE LAP-HF II trial, over 2 years of follow-up, atrial shunting led to reverse remodeling of left-sided chambers and increases in volume of right-sided chambers consistent with the shunt flow but no change in RV systolic function compared with sham. Changes in cardiac structure/function were more favorable in responders compared with nonresponders treated with the shunt, supporting the previously identified responder group hypothesis and mechanism, although further evaluation with longer follow-up is needed., Trial Registration: ClinicalTrials.gov Identifier: NCT03088033.