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Background-Recent studies have demonstrated that lesions of aortic sclerosis and stenosis share several similarities with lesions of atherosclerosis. In atherosclerosis, angiotensin-converting enzyme (ACE) is expressed by a subset of macrophages. This study was undertaken to determine whether ACE might be present in aortic sclerosis or stenosis lesions. Methods and Results-Immunohistochemistry was performed on 26 paraffin-embedded human aortic valves. Monospecific antibodies were used to identify ACE, macrophages, angiotensin II type 1 receptor (AT-1 receptor), angiotensin II, and apolipoprotein B. Human low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were isolated from plasma of normal volunteers by sequential density-gradient ultracentrifugation. ACE was not present in normal valves but was present in all valves with aortic sclerosis or stenosis lesions. ACE was detected on a subset of lesion macrophages but was present primarily in an extracellular distribution, where it colocalized with apolipoprotein B. ACE was detected by Western blotting on plasma LDL but not on HDL isolated from normal volunteers. Angiotensin II, the enzymatic product of ACE, was colocalized with ACE in valve lesions. ACE also was colocalized with apolipoprotein B in an adjacent coronary atherosclerotic plaque. Conclusions-ACE is present in aortic sclerosis and stenosis lesions, where it may participate in lesion development, as is evidenced by the presence of its enzymatic product, angiotensin II. The observation of an association of ACE with LDL in both lesions and plasma suggests that LDL may deliver ACE to lesions and has implications for the role of ACE-containing LDL in other diseases, such as atherosclerosis.

Background-Calcific aortic valve disease is common in the elderly, is correlated with common cardiovascular risk factors, and is associated with increased cardiovascular event risk; however, whether metabolic syndrome is associated with an increased prevalence of aortic valve calcium (AVC) is not known.

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Background: Sodium glucose cotransporter 2 inhibitors (SGLT2i) prevent heart failure (HF) hospitalizations in patients with Type 2 Diabetes (T2D), and improve outcomes in those with HF and reduced ejection fraction (EF), regardless of T2D. Mechanisms of HF benefits remain unclear, and effects of SGLT2i on hemodynamics (filling pressures) are not known. EMBRACE-HF Trial was designed to address this knowledge gap. Methods: EMBRACE-HF is an investigator-initiated, randomized, multi-center, double-blind, placebo-controlled trial. From July 2017 to November 2019, patients with HF (regardless of EF, with or without T2D) and previously implanted pulmonary artery (PA) pressure sensor (CardioMEMS) were randomized across 10 US centers to empagliflozin 10 mg daily or placebo and treated for 12 weeks. The primary endpoint was change in PA diastolic pressure (PADP) from baseline to end of treatment (average PADP weeks 8-12). Secondary endpoints included health status (Kansas City Cardiomyopathy Questionnaire (KCCQ)), natriuretic peptides and 6-minute walking distance. Results: Overall, 93 patients were screened, and 65 were randomized (33 empagliflozin, 32 placebo). Mean age was 66 years, 63% were male, 52% had T2D, 54% NYHA class III/IV; mean EF 44%, median NT-proBNP 637 pg/mL and mean PADP 22 mmHg. Empagliflozin significantly reduced PADP, with effects beginning at week 1, and amplified over time; average PADP (weeks 8-12) was 1.5 mmHg lower (95% CI (0.2, 2.8); p = 0.02); and at week 12, PADP was 1.7 mmHg lower (95% CI (0.3, 3.2); p = 0.02) with empagliflozin vs placebo. Results were consistent for PA systolic and PA mean pressures. There was no difference in mean loop diuretic management (daily furosemide equivalents) between treatment groups. No significant differences between treatment groups were observed in KCCQ, natriuretic peptide levels and 6-minute walking distance. Conclusions: In patients with HF and CardioMEMS PA pressure sensor, empagliflozin produced rapid reductions in PA pressures that were amplified over time and appeared to be independent of loop diuretic management. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03030222.

Objective This study aimed to test whether aortic valve calcium (AVC) is independently associated with coronary and cardiovascular events in a primary-prevention population. Background Aortic sclerosis is associated with increased cardiovascular morbidity and mortality among the elderly, but the mechanisms underlying this association remain controversial and it is unknown if this association extends to younger individuals. Methods We performed a prospective analysis of 6,685 participants in the Multi-Ethnic Study of Atherosclerosis. All subjects, aged 45-84 years and free of clinical cardiovascular disease at baseline, underwent computed tomography for AVC and coronary artery calcium (CAC) scoring. The primary, pre-specified combined endpoint of cardiovascular events included myocardial infarctions, fatal and non-fatal strokes, resuscitated cardiac arrest and cardiovascular death, while a secondary combined endpoint of coronary events excluded strokes. The association between AVC and clinical events was assessed using Cox proportional hazards regression with incremental adjustments for demographics, cardiovascular risk factors, inflammatory biomarkers and subclinical coronary atherosclerosis. Results Over a median follow up of 5.8 [IQR 5.6, 5.9] years, adjusting for demographics and cardiovascular risk factors, subjects with AVC (n=894, 13.4%) had higher risks of cardiovascular (HR, 1.50; 95% CI, 1.10-2.03) and coronary (HR, 1.72; 95% CI, 1.19-2.49) events compared to those without AVC. Adjustments for inflammatory biomarkers did not alter these associations, but adjustment for CAC substantially attenuated both cardiovascular (HR, 1.32; 95% CI: 0.98-1.78) and coronary (HR, 1.41; 95% CI, 0.98-2.02) event risk. AVC remained predictive of cardiovascular mortality even after full adjustment (HR, 2.51; 95% CI, 1.22-5.21). Conclusions In this multiethnic MESA cohort, free of clinical cardiovascular disease, AVC predicts cardiovascular and coronary event risk independent of traditional risk factors and inflammatory biomarkers, likely due to the strong correlation between AVC and subclinical atherosclerosis. The association of AVC with excess cardiovascular mortality beyond coronary atherosclerosis risk merits further investigation.

Background: Ambulatory hemodynamic monitoring with an implantable pulmonary artery (PA) sensor is approved for patients with New York Heart Association Class III heart failure (HF) and a prior HF hospitalization (HFH) within 12 months. The objective of this study was to assess the efficacy and safety of PA pressure-guided therapy in routine clinical practice with special focus on subgroups defined by sex, race, and ejection fraction. Methods: This multi-center, prospective, open-label, observational, single-arm trial of 1200 patients across 104 centers within the United States with New York Heart Association class III HF and a prior HFH within 12 months evaluated patients undergoing PA pressure sensor implantation between September 1, 2014, and October 11, 2017. The primary efficacy outcome was the difference between rates of adjudicated HFH 1 year after compared with the 1 year before sensor implantation. Safety end points were freedom from device- or system-related complications at 2 years and freedom from pressure sensor failure at 2 years. Results: Mean age for the population was 69 years, 37.7% were women, 17.2% were non-White, and 46.8% had preserved ejection fraction. During the year after sensor implantation, the mean rate of daily pressure transmission was 76±24% and PA pressures declined significantly. The rate of HFH was significantly lower at 1 year compared with the year before implantation (0.54 versus 1.25 events/patient-years, hazard ratio 0.43 [95% CI, 0.39–0.47], P <0.0001). The rate of all-cause hospitalization was also lower following sensor implantation (1.67 versus 2.28 events/patient-years, hazard ratio 0.73 [95% CI, 0.68–0.78], P <0.0001). Results were consistent across subgroups defined by ejection fraction, sex, race, cause of cardiomyopathy, presence/absence of implantable cardiac defibrillator or cardiac resynchronization therapy and ejection fraction. Freedom from device- or system-related complications was 99.6%, and freedom from pressure sensor failure was 99.9% at 1 year. Conclusions: In routine clinical practice as in clinical trials, PA pressure-guided therapy for HF was associated with lower PA pressures, lower rates of HFH and all-cause hospitalization, and low rates of adverse events across a broad range of patients with symptomatic HF and prior HFH. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02279888.

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