Cp2TiCl2-Catalyzed Photoredox Allylation of Aldehydes with Visible Light

A Barbier-type Cp2TiCl2-mediated (10 mol %) photoredox allylation of aldehydes under irradiation with visible light (blue light-emitting diodes (LEDs), 450 nm) and in the presence of an organic dye (3DPAFIPN, 5 mol %) with allylbromides is described

Exercise-induced mitral regurgitation and right ventricle to pulmonary circulation uncoupling across the heart failure phenotypes

Exercise-induced mitral regurgitation (Ex-MR) is one of the mechanisms that contribute to reduced functional capacity in heart failure (HF). Its prevalence is not well defined across different HF subtypes. The aim of the present study was to describe functional phenotypes and cardiac response to exercise in HFrEF, HFmrEF, and HFpEF, according to Ex-MR prevalence. A total of 218 patients with HF [146 men, 68 (59–78) yr], 137 HFrEF, 41 HFmrEF, 40 HFpEF, and 23 controls were tested with cardiopulmonary exercise test combined with exercise echocardiography. Ex-MR was defined as development of at least moderate (≥2+/4+) regurgitation during exercise. Ex-MR was highly prevalent in the overall population (52%) although differed in the subgroups as follows: 82/137 (60%) in HFrEF, 17/41 (41%) in HFmrEF, and 14/40 (35%) in HFpEF (P < 0.05). Ex-MR was associated with a high rate of ventilation (VE) to carbon dioxide production (VCO2) in all HF subtypes [31.2 (26.6–35.6) vs. 33.4 (29.6–40.5), P = 0.004; 28.1 (24.5–31.9) vs. 34.4 (28.2–36.7), P = 0.01; 28.8 (26.6–32.4) vs. 32.2 (29.2–36.7), P = 0.01] and with lower peak VO2 in HFrEF and HFmrEF. Exercise right ventricle to pulmonary circulation (RV-PC) uncoupling was observed in HFrEF and HFpEF patients with Ex-MR [peak TAPSE/SPAP: HFrEF 0.40 (0.30–0.57) vs. 0.29 (0.23–0.39), P = 0.006; HFpEF 0.44 (0.28–0.62) vs. 0.31 (0.27–0.33), P = 0.05]. HFpEF with Ex-MR showed a distinct phenotype characterized by better chronotropic reserve and peripheral O2 extraction

Aspirin inhibits the acute venodilator response to furosemide in patients with chronic heart failure

OBJECTIVES: We sought to determine the effect of aspirin on the venodilator effect of furosemide in patients with chronic heart failure (CHF) BACKGROUND: Furosemide has an acute venodilator effect preceding its diuretic action, which is blocked by nonsteroidal anti-inflammatory drugs. The ability of therapeutic doses of aspirin to block this effect of furosemide in patients with CHF has not been studied. For comparison, the venodilator response to nitroglycerin (NTG) was also studied. METHODS: Eleven patients with CHF were randomized to receive placebo, aspirin at 75 mg/day or aspirin at 300 mg/day for 14 days in a double-blind, crossover study. The effect of these pretreatments on the change in forearm venous capacitance (FVC) after 20 mg of intravenous furosemide was measured over 20 min by using venous occlusion plethysmography. In a second study, the effect of 400 μg of sublingual NTG on FVC was documented in 11 similar patients (nine participated in the first study). RESULTS: Mean arterial pressure, heart rate and forearm blood flow did not change in response to furosemide. After placebo pretreatment, furosemide caused an increase in FVC of 2.2% (95% confidence interval [CI] −0.9% to 5.2%; mean response over 20 min). By comparison, FVC fell by −1.1% (95% CI −4.2% to 1.9%) after pretreatment with aspirin at 75 mg/day, and by −3.7% (95% CI −6.8% to −0.7%) after aspirin at 300 mg/day (p = 0.020). In the second study, NTG increased FVC by 2.1% (95% CI −1.6% to 5.8%) (p = 0.95 vs. furosemide). CONCLUSIONS: In patients with CHF, venodilation occurs within minutes of the administration of intravenous dose of furosemide. Our observation that aspirin inhibits this effect further questions the use of aspirin in patients with CHF

Sacubitril/Valsartan in heart failure with reduced ejection fraction: clinical and echocardiographic insights from a real world population

Abstract Background Following the PARADIGM trial, some studies have identified cardiac remodeling as major background for hard end point benefits of Sacubitril/Valsartan (S/V), but few adopted a well described definition in the literature. Purpose We aimed at a comprehensive evaluation of the effects of S/V on echo-derived measures of cardiac remodeling along with clinical and laboratory data over a medium-term follow-up pointing to a real-world HFrEF population. Methods This is a prospective observational study of HFrEF patients on optimal medical therapy (OMT) initiated with S/V at Heart Failure Clinic of our institute (January 2017-January 2020). In 62 HFrEF, echocardiographic, laboratory and clinical data were collected at baseline and over 10 (Q1-Q3 8–13) months after S/V initiation. Mean age was 68±12 years, 79% men. Left ventricular reverse remodeling (LVRR) was defined as: 1) an absolute increase in LVEF ≥10 points or a LVEF ≥50% at follow-up and 2) a relative decrease in indexed left ventricular end-diastolic diameter of at least 10% or an indexed left ventricular end-diastolic diameter ≤33 mm/m2. Results Compared to baseline, S/V promoted a significant improvement of LV ejection fraction (LVEF, from 30% to 37%; p&lt;0,0001) with an absolute median increase in LVEF of 8 points. Parallel significant reductions in left ventricular and atrial volumes, lower mitral regurgitation degree and a better diastolic dysfunction along with clinical improvement (NYHA class and NT-proBNP values) were observed at follow up. sPAP (systolic Pulmonary Arterial Pressure) was significantly decreased at follow-up evaluation (37 mmHg vs 31 mmHg p=0,005) (Table 1). Overall, LVRR as defined above was observed in 30% of patients. Younger age (64 vs 74 years, p=0,007), a shorter duration of the disease (7 vs 23 months, p=0,009), and non ischaemic etiology (79% vs 33% p=0,003), along with a smaller baseline LAESVi (Left Atrial End Systolic Volume, 41 vs 48 ml/m2 p=0,012) were more common in patients with LVRR. sPAP and Right Ventricular (RV) function estimated by tricuspid annular plane systolic excursion (TAPSE) were significantly better in LVRR patients along with TAPSE/sPAP ratio (Table 2). Conclusions Our data point to a remarkable medium-term reverse remodeling effect by S/V in HFrEF. Findings reinforce the concept that the main benefits of S/V on hard end-points are mediated by its cardiac-related effects. Both a left and right reverse remodeling occur in HFrEF patients who start S/V in the most adaptable phase of the disease supporting an early administration. Funding Acknowledgement Type of funding sources: None

Reduced functional measure of cardiovascular reserve predicts admission to critical care unit following kidney transplantation

Background: There is currently no effective preoperative assessment for patients undergoing kidney transplantation that is able to identify those at high perioperative risk requiring admission to critical care unit (CCU). We sought to determine if functional measures of cardiovascular reserve, in particular the anaerobic threshold (VO2AT) could identify these patients. Methods: Adult patients were assessed within 4 weeks prior to kidney transplantation in a University hospital with a 37-bed CCU, between April 2010 and June 2012. Cardiopulmonary exercise testing (CPET), echocardiography and arterial applanation tonometry were performed. Results: There were 70 participants (age 41.7614.5 years, 60% male, 91.4% living donor kidney recipients, 23.4% were desensitized). 14 patients (20%) required escalation of care from the ward to CCU following transplantation. Reduced anaerobic threshold (VO2AT) was the most significant predictor, independently (OR = 0.43; 95% CI 0.27–0.68; p,0.001) and in the multivariate logistic regression analysis (adjusted OR = 0.26; 95% CI 0.12–0.59; p = 0.001). The area under the receiveroperating- characteristic curve was 0.93, based on a risk prediction model that incorporated VO2AT, body mass index and desensitization status. Neither echocardiographic nor measures of aortic compliance were significantly associated with CCU admission. Conclusions: To our knowledge, this is the first prospective observational study to demonstrate the usefulness of CPET as a preoperative risk stratification tool for patients undergoing kidney transplantation. The study suggests that VO2AT has the potential to predict perioperative morbidity in kidney transplant recipients

Effects of Physical Exercise on Endothelial Function and DNA Methylation

Essential hypertension is the leading preventable cause of death in the world. Epidemiological studies have shown that physical training can reduce blood pressure ( BP), both in hypertensive and healthy individuals. Increasing evidence is emerging that DNA methylation is involved in alteration of the phenotype and of vascular function in response to environmental stimuli. We evaluated repetitive element and gene-specific DNA methylation in peripheral blood leukocytes of 68 volunteers, taken before ( T0) and after ( T1) a three-month intervention protocol of continuative aerobic physical exercise. DNA methylation was assessed by bisulfite-PCR and pyrosequencing. Comparing T0 and T1 measurements, we found an increase in oxygen consumption at peak of exercise ( VO2peak) and a decrease in diastolic BP at rest. Exercise increased the levels of ALU and Long Interspersed Nuclear Element 1 ( LINE-1) repetitive elements methylation, and of Endothelin-1 ( EDN1), Inducible Nitric Oxide Synthase ( NOS2), and Tumour Necrosis Factor Alpha ( TNF) gene-specific methylation. VO2peak was positively associated with methylation of ALU, EDN1, NOS2, and TNF; systolic BP at rest was inversely associated with LINE-1, EDN1, and NOS2 methylation; diastolic BP was inversely associated with EDN1 and NOS2 methylation. Our findings suggest a possible role of DNA methylation for lowering systemic BP induced by the continuative aerobic physical training program

Phosphodiesterase-5 Inhibition Mimics Intermittent Reoxygenation and Improves Cardioprotection in the Hypoxic Myocardium

Although chronic hypoxia is a claimed myocardial risk factor reducing tolerance to ischemia/reperfusion (I/R), intermittent reoxygenation has beneficial effects and enhances heart tolerance to I/R. Aim of the study: To test the hypothesis that, by mimicking intermittent reoxygenation, selective inhibition of phosphodiesterase-5 activity improves ischemia tolerance during hypoxia. Adult male Sprague-Dawley rats were exposed to hypoxia for 15 days (10% O2) and treated with placebo, sildenafil (1.4 mg/kg/day, i. p.), intermittent reoxygenation (1 h/day exposure to room air) or both. Controls were normoxic hearts. To assess tolerance to I/R all hearts were subjected to 30-min regional ischemia by left anterior descending coronary artery ligation followed by 3 h-reperfusion. Whereas hypoxia depressed tolerance to I/R, both sildenafil and intermittent reoxygenation reduced the infarct size without exhibiting cumulative effects. The changes in myocardial cGMP, apoptosis (DNA fragmentation), caspase-3 activity (alternative marker for cardiomyocyte apoptosis), eNOS phosphorylation and Akt activity paralleled the changes in cardioprotection. However, the level of plasma nitrates and nitrites was higher in the sildenafil+intermittent reoxygenation than sildenafil and intermittent reoxygenation groups, whereas total eNOS and Akt proteins were unchanged throughout. Conclusions: Sildenafil administration has the potential to mimic the cardioprotective effects led by intermittent reoxygenation, thereby opening the possibility to treat patients unable to be reoxygenated through a pharmacological modulation of NO-dependent mechanisms

Right and left ventricles: as inseparable as the twin brothers ‘Castor and Pollux’

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A case for assessment of oscillatory breathing during cardiopulmonary exercise test in risk stratification of elderly patients with chronic heart failure

The prognostic value of exercise oscillatory breathing (EOB) during cardiopulmonary test (CPX) has been described in young chronic heart failure (HF) patients. We assessed the prognostic role of EOB vs other clinical and ventilatory parameters in elderly HF patients performing a maximal CPX. Methods and results: We prospectively followed-up 370 HF outpatients >= 65 years after a symptom limited CPX. We tested the predictive value of clinical and ventilatory parameters for all-cause mortality and a composite of all-cause mortality and HF hospitalizations. Median age was 74 years, 51% had ischemic heart disease, 25% NYHA class III; ejection fraction was 41% [34-50]. Peak oxygen consumption (PVO2) was 11.9 [9.9-14] mL/kg/min, the slope of the regression line relating ventilation to CO2 output, (VE/VCO2 slope) was 33.9 [29.8-39.2]. EOB was found in 58% of patients. At follow-up, 84 patients died and overall 158, using a time-to-first event approach, met the composite end-point. Independent predictors of all-cause mortality were CPX EOB and the ratio of VE/VCO2 slope to peak VO2, hemoglobin, creatinine and body mass index. The area under the ROC curve (AUC) of the Cox multivariable model was 0.80 (95% CI 0.73 to 0.87). Independent predictors of the composite end-point were EOB, VE/VCO2 slope, hemoglobin and HF admissions in the previous year (Model AUC 0.75) (95% CI 0.69 to 0.81). Conclusions: Among elderly HF patients, EOB prevalence is higher than middle-aged cohorts. EOB and the ratio of VE/VCO2 slope to peak VO2 resulted the strongest ventilatory predictor of all-cause mortality, independent of ventricular function

Echocardiographic phenotype and prognosis in transthyretin cardiac amyloidosis

AIMS: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. We sought to characterize the structural and functional echocardiographic phenotype across the spectrum of wild-type (wtATTR-CM) and hereditary (hATTR-CM) transthyretin cardiomyopathy and the echocardiographic features predicting prognosis. METHODS AND RESULTS: We studied 1240 patients with ATTR-CM who underwent prospective protocolized evaluations comprising full echocardiographic assessment and survival between 2000 and 2019, comprising 766 with wtATTR-CM and 474 with hATTR-CM, of whom 314 had the V122I variant and 127 the T60A variant. At diagnosis, patients with V122I-hATTR-CM had the most severe degree of systolic and diastolic dysfunction across all echocardiographic parameters and patients with T60AhATTR-CM the least; patients with wtATTR-CM had intermediate features. Stroke volume index, right atrial area index, longitudinal strain, and E/e' were all independently associated with mortality (P < 0.05 for all). Severe aortic stenosis (AS) was also independently associated with prognosis, conferring a significantly shorter survival (median survival 22 vs. 53 months, P = 0.001). CONCLUSION: The three distinct genotypes present with varying degrees of severity. Echocardiography indicates a complex pathophysiology in which both systolic and diastolic function are independently associated with mortality. The presence of severe AS was independently associated with significantly reduced patient survival