Abstract-Studies on genetically manipulated mice suggest a role for -protein kinase C (PKC) in cardiac hypertrophy and in heart failure. The potential clinical relevance of these findings was tested here using a pharmacological inhibitor of PKC activity during the progression to heart failure in hypertensive Dahl rats. Dahl rats, fed an 8% high-salt diet from the age of 6 weeks, exhibited compensatory cardiac hypertrophy by 11 weeks, followed by heart failure at Ϸ17 weeks and death by the age of Ϸ20 weeks (123Ϯ3 days). Sustained treatment between weeks 11 and 17 with the selective PKC inhibitor V1-2 or with an angiotensin II receptor blocker olmesartan prolonged animal survival by Ϸ5 weeks (V1-2: 154Ϯ7 days; olmesartan: 149Ϯ5 days). These treatments resulted in improved fractional shortening (V1-2: 58Ϯ2%; olmesartan: 53Ϯ2%; saline: 41Ϯ6%) and decreased cardiac parenchymal fibrosis when measured at 17 weeks without lowering blood pressure at any time during the treatment. Combined treatment with V1-2, together with olmesartan, prolonged animal survival by 5 weeks (37 days) relative to olmesartan alone (from 160Ϯ5 to 197Ϯ14 days, respectively) and by Ϸ11 weeks (74 days) on average relative to saline-treated animals, suggesting that the pathway inhibited by PKC inhibition is not identical to the olmesartan-induced effect. These data suggest that an PKC-selective inhibitor such as V1-2 may have a potential in augmenting current therapeutic strategies for the treatment of heart failure in humans. Key Words: heart failure Ⅲ protein kinase C Ⅲ ventricular remodeling Ⅲ hypertrophy Ⅲ fibrosis A lthough two-thirds of cases of heart failure in the United States are because of myocardial infarction, hypertension is a major contributor to this morbidity. Therefore, we studied hypertension-induced heart failure using hypertensive salt-sensitive Dahl rats. 1,2 Because many of the signaling events associated with heart failure involve activation of protein kinase C (PKC), 1,3 we determined whether PKC regulation affects disease progression. We focused on PKC, because there are conflicting reports on its role in cardiac hypertrophy and heart failure based on genetic manipulation of mice. 1,4 -6 Because the enzyme may have different roles during heart development, we used a pharmacological approach to selectively inhibit it at a defined time during disease.We previously designed isozyme-selective peptide regulators of PKC, which function by inhibiting or activating PKC translocation. These peptide regulators are linked to membrane-permeable peptides, TAT [47][48][49][50][51][52][53][54][55][56][57] , to enable their effective intracellular delivery and are, therefore, useful pharmacological tools. Using the Dahl salt-sensitive hypertension-induced heart failure rat model, 1,2 we determined here whether sustained pharmacological inhibition of PKC with the abovementioned peptide or with an angiotensin receptor blocker, olmesartan, delays progression to heart failure. Methods Hypertension-Induced Heart Failure ModelAnimal protocols ...

Invasive cardiopulmonary exercise testing (iCPET) combines full central hemodynamic assessment with continuous measurements of pulmonary gas exchange and ventilation to help in understanding the pathophysiology underpinning unexplained exertional intolerance. There is increasing evidence to support the use of iCPET as a key methodology for diagnosing heart failure with preserved ejection fraction and exercise-induced pulmonary hypertension as occult causes of exercise limitation, but there is little information available outlining the methodology to use this diagnostic test in clinical practice. To bridge this knowledge gap, the operational protocol for iCPET at our institution is discussed in detail. In turn, a standardized iCPET protocol may provide a common framework to describe the evolving understanding of mechanism(s) that limit exercise capacity and to facilitate research efforts to define novel treatments in these patients.

IMPORTANCE Questions have recently arisen as to whether 30-day mortality is a reasonable metric for understanding institutional practice differences after transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR).OBJECTIVE To examine the utility of 30-day vs 90-day mortality after TAVR and SAVR as a mortality quality metric. DESIGN, SETTING, AND PARTICIPANTSThis nationally representative, multicenter, cohort study analyzed data from Medicare beneficiaries undergoing TAVR and SAVR procedures from January 1, 2012, to December 31, 2015. Concomitant coronary artery bypass grafting and other heart valve or other major open-heart procedures were excluded. Hospitals that performed fewer than 50 TAVR or 70 SAVR procedures per year were excluded to ensure reliable estimates and to reduce the risks of inflated results because of small institutional sample sizes. Data were analyzed from October 2018 to August 2019.EXPOSURES Hospitals were ranked into top-(10%), middle-(80%), and bottom-performing (10%) groups based on their 4-year mean 30-day mortality. MAIN OUTCOMES AND MEASURESChanges in hospital performance rankings at 90 days and 1 year and correlation of 30-and 90-day mortality with 1-year mortality were examined.RESULTS A total of 30 329 TAVR admissions at 184 hospitals and 26 021 SAVR admissions at 191 hospitals were evaluated. For TAVR, 40 hospitals (21.7%) changed performance rankings at 90 days: 13 (48.1%) in the top-performing group and 8 (29.6%) in the bottom-performing group. At 1 year, 56 hospitals (30.4%), which included 21 (77.8%) in the top-performing group and 12 (44.4%) in the bottom-performing group, changed rankings. Similar findings were observed for SAVR, with an overall 90-day conversion rate of 17.3% and a 1-year rate of 30.3%. These findings persisted after adjusting for the differences in patient risk profiles among the 3 groups. Capturing 90-day events was also more robustly informative regarding expected 1-year outcomes after both TAVR and SAVR, largely owing to the observed plateau in the instantaneous hazard observed beyond this point. CONCLUSIONS AND RELEVANCEThe findings suggest that evaluation of hospital performance based on 30-day mortality may underestimate outcomes and therefore substantially misrepresent institutional performance after TAVR and SAVR compared with 90-day mortality, even after risk adjustment. Although 30-day mortality has been validated, 90-day mortality may be a more reliable outcome metric for measuring hospital performance and capturing procedure-related mortality.