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).

Background: Surgical aortic valve replacement (SAVR) represents a class I indication in symptomatic patients with severe aortic stenosis (AS). However, indications for early SAVR in asymptomatic patients with severe AS and normal left ventricular function remain debated. Methods: The Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR) trial is an investigator-initiated international prospective randomized controlled trial that evaluated the safety and efficacy of early SAVR in the treatment of asymptomatic patients with severe AS, according to common criteria (valve area ≤1 cm 2 with aortic jet velocity >4 m/s or a mean trans-aortic gradient ≥40 mm Hg), and with normal LV function. Negative exercise testing was mandatory for inclusion. The primary hypothesis was that early SAVR would reduce the primary composite endpoint of all-cause death, acute myocardial infarction, stroke or unplanned hospitalization for heart failure, as compared to a conservative strategy according to guidelines. The trial was designed as event-driven to reach a minimum of 35 prespecified events. The study was performed in 9 centers in 7 European countries. Results: Between June 2015 and September 2020, 157 patients (mean age 67 years, 57 % men) were randomly allocated to early surgery (n=78) or conservative treatment (n=79). Follow-up was completed in May 2021. Overall median follow-up was 32 months: 28 months in the early surgery group and 35 months in the conservative treatment group. There was a total of 39 events, 13 in early surgery and 26 in conservative treatment group. In the early surgery group, 72 patients (92.3 %) underwent SAVR with operative mortality of 1.4 %. In an intention-to-treat analysis, patients randomized to early surgery had a significantly lower incidence of primary composite endpoint than those in the conservative arm (HR 0.46, 95 % CI 0.23-0.90, p=0.02). There was no statistical difference in secondary endpoints, including all-cause mortality, first heart failure hospitalizations, major bleeding or thromboembolic complications, but trends were consistent with the primary outcome. Conclusions: In asymptomatic patients with severe AS, early surgery reduced a primary composite of all-cause death, acute myocardial infarction, stroke or unplanned hospitalization for heart failure compared with conservative treatment. This randomized trial provides preliminary support for early SAVR once AS becomes severe, regardless of symptoms.

Background: Heart failure with preserved ejection fraction (HFpEF) is commonly associated with hypertension (HTN). However, resting echocardiography (ECHO) can underestimate the severity of disease. Exercise stress echocardiography (ESE) and the cardiopulmonary exercise testing (CPX) appeared to be useful tests in dynamic assessment of HFpEF. The value of combined exercise stress echocardiography cardiopulmonary testing (ESE-CPX) in the identification of masked HFpEF is still undetermined. Objective: The purpose of this study was to analyse the value of the combined ESE-CPX in the identification of masked HFpEF in patients with HTN, dyspnoea and normal resting left ventricular (LV) systolic and diastolic function. Methodology: We studied 87 patients with HTN, exertional dyspnoea and normal resting LV function. They all underwent ESE-CPX testing (supine bicycle, ramp protocol, 15 W/min). ECHO measurements were performed at rest, and at peak load. Achievement of peak E/e' ratio>15 was a marker for masked HFpEF. Results: Increase of E/e'>15 occurred in 8/87 patients (9.2%) during ESE-CPX. Those patients had the lower peak VO2 (p ¼ 0.012), the lower VO2 at anaerobic threshold (p ¼ 0.025), the lower workload (p ¼ 0.026), the lower peak partial pressure end tidal carbon dioxide (PetCO2) (p < 0.0001), and the higher VE/VCO2 slope (p < 0.0001) which was an independent multivariate predictor of HFpEF (p ¼ 0.021), with the cut-off value of 32.95 according to the receiveroperator characteristic (ROC) curve (sensitivity (Sn) 100%, specificity (Sp) 90%). Conclusion: The combined ESE-CPX test is feasible and reliable test that can unmask HFpEF and may become an important aid in the early diagnosis of HFpEF, excluding the other causes of exertional dyspnoea.

Aortic stenosis and diabetes mellitus are both progressive diseases which, if left untreated, result in significant morbidity and mortality. There is evidence that the prevalence of diabetes is substantially increased in patients with aortic stenosis and those with diabetes have increased rates of progression from mild to severe aortic stenosis. There are good data supporting the hypothesis that aortic stenosis and diabetes mellitus are associated with diabetes mellitus being detrimental towards the quality of life and survival of patients. Thus, a thorough understanding of the pathogenesis of both of these disease processes and the relationship between them aids in designing appropriate preventive and therapeutic approaches. This review aims to give a comprehensive and up-to-date insight into the influence of diabetes mellitus on patients with degenerative aortic stenosis, as well as the prognosis and therapeutic approach to these patients.

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BackgroundInsulin resistance (IR) assessed by the Homeostatic Model Assessment (HOMA) index in the acute phase of myocardial infarction in non-diabetic patients was recently established as an independent predictor of intrahospital mortality. In this study we postulated that acute IR is a dynamic phenomenon associated with the development of myocardial and microvascular injury and larger final infarct size in patients with ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (pPCI).MethodsIn 104 consecutive patients with the first anterior STEMI without diabetes, the HOMA index was determined on the 2nd and 7th day after pPCI. Worst-lead residual ST-segment elevation (ST-E) on postprocedural ECG, coronary flow reserve (CFR) determined by transthoracic Doppler echocardiography on the 2nd day after pPCI and fixed perfusion defect on single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) determined six weeks after pPCI were analyzed according to HOMA indices.ResultsIR was present in 55 % and 58 % of patients on day 2 and day 7, respectively. Incomplete post-procedural ST-E resolution was more frequent in patients with IR compared to patients without IR, both on day 2 (p = 0.001) and day 7 (p < 0.001). The HOMA index on day 7 correlated with SPECT-MPI perfusion defect (r = 0.331), whereas both HOMA indices correlated well with CFR (r = -0.331 to -0.386) (p < 0.01 for all). In multivariable backward logistic regression analysis adjusted for significant univariate predictors and potential confounding variables, IR on day 2 was an independent predictor of residual ST-E ≥ 2 mm (OR 11.70, 95% CI 2.46-55.51, p = 0.002) and CFR < 2 (OR = 5.98, 95% CI 1.88-19.03, p = 0.002), whereas IR on day 7 was an independent predictor of SPECT-MPI perfusion defect > 20% (OR 11.37, 95% CI 1.34-96.21, p = 0.026).ConclusionIR assessed by the HOMA index during the acute phase of the first anterior STEMI in patients without diabetes treated by pPCI is independently associated with poorer myocardial reperfusion, impaired coronary microcirculatory function and potentially with larger final infarct size.

We thank both groups for their letters and interest in the AVATAR trial (Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis). 1 In response to Ennezat et al, individual components of the primary composite outcome were not statistically different among randomized groups. The trial was not adequately powered to detect the difference of each component of composite primary outcome. Individual analyses of all-cause mortality and heart failure hospitalizations showed a strong trend favoring early surgery (ES), making it hypothetically plausible that, if the number of enrolled patients was higher, the difference could reach statistical significance. We believe that the relatively high rates of sudden cardiac death (SCD) further point at the unpredictability of aortic stenosis (AS) and potential hazards of a watchful waiting strategy. Two patients randomly assigned to the conservative treatment group unfortunately had SCD several months after the surgery. Accordingly, the death of these patients should not be viewed in the context of the risk of SCD associated with untreated asymptomatic AS.Serial exercise testing (ET) during follow-up was not performed in our trial. As suggested, it would be the most optimal solution for adequate implementation of a watchful waiting strategy. It is unfortunate that ET is seldom performed in a real-world clinical setting for symptom evaluation for AS. 2 It is even more unlikely that serial ET could be performed for routine follow-up of asymptomatic patients. We performed ET in each patient for symptom evaluation at the beginning of the trial, and, to include truly asymptomatic patients with AS, each patient needed to reach the age-predicted heart rate followed by the implementation of regular clinical and echocardiographic follow-up per guidelines recommendations. 3 Although the exclusion criterion was a fall in systolic blood pressure ≥20 mm Hg, among those included, no patient experienced a fall in systolic blood pressure.

Background Functional assessment of myocardial bridging (MB) remains clinically challenging because of the dynamic nature of the extravascular coronary compression with a certain degree of intraluminal coronary reduction. The aim of our study was to assess performance and diagnostic value of diastolic‐fractional flow reserve (d‐FFR) during dobutamine provocation versus conventional‐FFR during adenosine provocation with exercise‐induced myocardial ischemia as reference. Methods and Results This prospective study includes 60 symptomatic patients (45 men, mean age 57±9 years) with MB on the left anterior descending artery and systolic compression ≥50% diameter stenosis. Patients were evaluated by exercise stress‐echocardiography test, and both conventional‐FFR and d‐FFR in the distal segment of left anterior descending artery during intravenous infusion of adenosine (140 μg/kg per minute) and dobutamine (10–50 μg/kg per minute), separately. Exercise–stress‐echocardiography test was positive for myocardial ischemia in 19/60 patients (32%). Conventional‐FFR during adenosine and peak dobutamine had similar values (0.84±0.04 versus 0.84±0.06, P =0.852), but d‐FFR during peak dobutamine was significantly lower than d‐FFR during adenosine (0.76±0.08 versus 0.79±0.08, P =0.018). Diastolic‐FFR during peak dobutamine was significantly lower in the exercise‐stress‐echocardiography test –positive group compared with the exercise‐ stress‐echocardiography test –negative group (0.70±0.07 versus 0.79±0.06, P <0.001), but not during adenosine (0.79±0.07 versus 0.78±0.09, P =0.613). Among physiological indices, d‐FFR during peak dobutamine was the only independent predictor of functionally significant MB (odds ratio, 0.870; 95% CI, 0.767–0.986, P =0.03). Receiver‐operating characteristics curve analysis identifies the optimal d‐FFR during peak dobutamine cut‐off ≤0.76 (area under curve, 0.927; 95% CI, 0.833–1.000; P <0.001) with a sensitivity, specificity, and positive and negative predictive value of 95%, 95%, 90%, and 98%, respectively, for identifying MB associated with stress‐induced ischemia. Conclusions Diastolic‐FFR, but not conventional‐FFR, during inotropic stimulation with high‐dose dobutamine, in comparison to vasodilatation with adenosine, provides more reliable functional significance of MB in relation to stress‐induced myocardial ischemia.