Differences in Myocardial Remodeling and Tissue Characteristics in Chronic Isolated Aortic and Mitral Regurgitation.

BACKGROUND: The left ventricular hemodynamic load differs between aortic regurgitation (AR) and primary mitral regurgitation (MR). We used cardiac magnetic resonance to compare left ventricular remodeling patterns, systemic forward stroke volume, and tissue characteristics between patients with isolated AR and isolated MR. METHODS: We assessed remodeling parameters across the spectrum of regurgitant volume. Left ventricular volumes and mass were compared against normal values for age and sex. We calculated forward stroke volume (planimetered left ventricular stroke volume-regurgitant volume) and derived a cardiac magnetic resonance-based systemic cardiac index. We assessed symptom status according to remodeling patterns. We also evaluated the prevalence of myocardial scarring using late gadolinium enhancement imaging, and the extent of interstitial expansion via extracellular volume fraction. RESULTS: We studied 664 patients (240 AR, 424 primary MR), median age of 60.7 (49.5-69.9) years. AR led to more pronounced increases in ventricular volume and mass compared with MR across the spectrum of regurgitant volume (P<0.001). In ≥moderate regurgitation, AR patients had a higher prevalence of eccentric hypertrophy (58.3% versus 17.5% in MR; P<0.001), whereas MR patients had normal geometry (56.7%) followed by myocardial thinning with low mass/volume ratio (18.4%). The patterns of eccentric hypertrophy and myocardial thinning were more common in symptomatic AR and MR patients (P<0.001). Systemic cardiac index remained unchanged across the spectrum of AR, whereas it progressively declined with increasing MR volume. Patients with MR had a higher prevalence of myocardial scarring and higher extracellular volume with increasing regurgitant volume (P value for trend <0.001), whereas they were unchanged across the spectrum of AR (P=0.24 and 0.42, respectively). CONCLUSIONS: Cardiac magnetic resonance identified significant heterogeneity in remodeling patterns and tissue characteristics at matched degrees of AR and MR. Further research is needed to examine if these differences impact reverse remodeling and clinical outcomes after intervention.

Influence of Cardiac Remodeling on Clinical Outcomes in Patients With Aortic Regurgitation.

BACKGROUND: Quantitative cardiac magnetic resonance (CMR) outcome studies in aortic regurgitation (AR) are few. It is unclear if volume measurements are beneficial over diameters. OBJECTIVES: This study sought to evaluate the association of CMR quantitative thresholds and outcomes in AR patients. METHODS: In a multicenter study, asymptomatic patients with moderate or severe AR on CMR with preserved left ventricular ejection fraction (LVEF) were evaluated. Primary outcome was development of symptoms or decrease in LVEF to <50%, development of guideline indications for surgery based on LV dimensions, or death under medical management. Secondary outcome was the same as the primary outcome, excluding surgery for remodeling indications. We excluded patients who underwent surgery within 30 days of CMR. Receiver-operating characteristic analyses for the association with outcomes were performed. RESULTS: We studied 458 patients (median age: 60 years; IQR: 46-70 years). During a median follow-up of 2.4 years (IQR: 0.9-5.3 years), 133 events occurred. Optimal thresholds were regurgitant volume of 47 mL and regurgitant fraction of 43%, indexed LV end-systolic (iLVES) volume of 43 mL/m2, indexed LV end-diastolic volume of 109 mL/m2, and iLVES diameter of 2 cm/m2. In multivariable regression analysis, iLVES volume of ≥43 mL/m2 (HR: 2.53; 95% CI: 1.75-3.66; P < 0.001) and indexed LV end-diastolic volume of ≥109 mL/m2 were independently associated with the outcomes and provided additional discrimination improvement over iLVES diameter, whereas iLVES diameter was independently associated with the primary outcome but not the secondary outcome. CONCLUSIONS: In asymptomatic AR patients with preserved LVEF, CMR findings can be used to guide management. CMR-based LVES volume assessment performed favorably compared to LV diameters.

Identifying Mitral Valve Prolapse at Risk for Arrhythmias and Fibrosis From Electrocardiograms Using Deep Learning.

BACKGROUND: Mitral valve prolapse (MVP) is a common valvulopathy, with a subset developing sudden cardiac death or cardiac arrest. Complex ventricular ectopy (ComVE) is a marker of arrhythmic risk associated with myocardial fibrosis and increased mortality in MVP. OBJECTIVES: The authors sought to evaluate whether electrocardiogram (ECG)-based machine learning can identify MVP at risk for ComVE, death and/or myocardial fibrosis on cardiac magnetic resonance (CMR) imaging. METHODS: A deep convolutional neural network (CNN) was trained to detect ComVE using 6,916 12-lead ECGs from 569 MVP patients from the University of California-San Francisco between 2012 and 2020. A separate CNN was trained to detect late gadolinium enhancement (LGE) using 1,369 ECGs from 87 MVP patients with contrast CMR. RESULTS: The prevalence of ComVE was 28% (160/569). The area under the receiver operating characteristic curve (AUC) of the CNN to detect ComVE was 0.80 (95% CI: 0.77-0.83) and remained high after excluding patients with moderate-severe mitral regurgitation [0.80 (95% CI: 0.77-0.83)] or bileaflet MVP [0.81 (95% CI: 0.76-0.85)]. AUC to detect all-cause mortality was 0.82 (95% CI: 0.77-0.87). ECG segments relevant to ComVE prediction were related to ventricular depolarization/repolarization (early-mid ST-segment and QRS from V1, V3, and III). LGE in the papillary muscles or basal inferolateral wall was present in 24% patients with available CMR; AUC for detection of LGE was 0.75 (95% CI: 0.68-0.82). CONCLUSIONS: CNN-analyzed 12-lead ECGs can detect MVP at risk for ventricular arrhythmias, death and/or fibrosis and can identify novel ECG correlates of arrhythmic risk. ECG-based CNNs may help select those MVP patients requiring closer follow-up and/or a CMR.

Acute and Subclinical Myocardial Injury in COVID-19.

Coronavirus disease 2019 (COVID-19) is a global pandemic that, at the time of this writing, has led to 178,000,000 cases worldwide and more than 3,875,000 deaths. Cardiovascular complications of COVID-19 have become the focus of investigation after many hospitalized COVID-19 patients-with or without established cardiovascular disease-incurred clinical or subclinical myocardial injury, including isolated biomarker elevations, myocardial infarction, arrhythmia, heart failure, myocarditis, and cardiogenic shock. In this review, we highlight the most recent evidence of the prevalence and potential etiologies of acute and subclinical myocardial injury in COVID-19 patients.

Spinal cord compression due to an extra-dural intra-vascular papillary endothelial hyperplasia of the thoracic spine.

We present a case of spinal cord compression in a 33-year-old male due to a T6-T7 paravertebral mass extending through the intervertebral foramen into the vertebral canal. Histopathological feature was consistent with an intra-vascular papillary endothelial hyperplasia. Differential diagnosis of the lesion and review of the literature are presented.

ATR-101, a Selective and Potent Inhibitor of Acyl-CoA Acyltransferase 1, Induces Apoptosis in H295R Adrenocortical Cells and in the Adrenal Cortex of Dogs.

ATR-101 is a novel, oral drug candidate currently in development for the treatment of adrenocortical cancer. ATR-101 is a selective and potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase 1 (ACAT1), an enzyme located in the endoplasmic reticulum (ER) membrane that catalyzes esterification of intracellular free cholesterol (FC). We aimed to identify mechanisms by which ATR-101 induces adrenocortical cell death. In H295R human adrenocortical carcinoma cells, ATR-101 decreases the formation of cholesteryl esters and increases FC levels, demonstrating potent inhibition of ACAT1 activity. Caspase-3/7 levels and terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeled-positive cells are increased by ATR-101 treatment, indicating activation of apoptosis. Exogenous cholesterol markedly potentiates the activity of ATR-101, suggesting that excess FC that cannot be adequately esterified increases caspase-3/7 activation and subsequent cell death. Inhibition of calcium release from the ER or the subsequent uptake of calcium by mitochondria reverses apoptosis induced by ATR-101. ATR-101 also activates multiple components of the unfolded protein response, an indicator of ER stress. Targeted knockdown of ACAT1 in an adrenocortical cell line mimicked the effects of ATR-101, suggesting that ACAT1 mediates the cytotoxic effects of ATR-101. Finally, in vivo treatment of dogs with ATR-101 decreased adrenocortical steroid production and induced cellular apoptosis that was restricted to the adrenal cortex. Together, these studies demonstrate that inhibition of ACAT1 by ATR-101 increases FC, resulting in dysregulation of ER calcium stores that result in ER stress, the unfolded protein response, and ultimately apoptosis.

Hyperaldosteronism: How to Discriminate Among Different Disease Forms?

Primary aldosteronism (PA), characterized by the inappropriate and abnormal adrenal secretion of aldosterone, is the most common cause of secondary hypertension. PA has been shown to increase cardiovasular and cerebrovascular risks in comparison with essential hypertension. PA is a multi-faceted disease, which comprises unilateral forms, benefitting from surgical treatment, and bilateral forms, which are the best managed medically. PA is more frequently sporadic, but in some cases, it displays a familial transmission pattern. For these reasons, it is important to diagnose PA early on and correctly distinguish and manage its different forms. In this review, we analyze the different forms of PA, with attention on the diagnostic pathway and the genetics of the disease.

Diagnosis and treatment of unilateral forms of primary aldosteronism.

Primary aldosteronism (PA) is now recognized as the most frequent form of secondary arterial hypertension. The importance of a correct and prompt diagnosis of PA is determined by its relevant prevalence, its increased cardiovascular risk compared to essential hypertension and by the possibility of reversing this increased risk with a targeted therapy. Surgical treatment of unilateral forms of PA (mainly aldosterone-producing adenomas) is at present recommended in well-selected patients because of its cost-effectiveness. Therefore, subtype differentiation of PA forms is of fundamental importance, and available guidelines recommend contrast-enhanced CT-scanning and adrenal venous sampling (AVS) as the main diagnostic tests for this purpose. In this review, we discuss the value of adrenal non-invasive imaging and AVS, the recent advances in complementary tests and, finally, the available data on the outcome of surgical treatment for PA.

Long-term cardio- and cerebrovascular events in patients with primary aldosteronism.

BACKGROUND: Aldosterone plays a detrimental role on the cardiovascular system and PA patients display a higher risk of events compared with EH. OBJECTIVES: The objectives of the study were to compare cardio- and cerebrovascular events in patients with primary aldosteronism (PA) and matched essential hypertension (EH). METHODS: We retrospectively compared the percentage of patients experiencing events at baseline and during a median follow-up of 12 years in 270 PA patients case-control matched 1:3 with EH patients and in PA subtypes [aldosterone-producing adenoma (n = 57); bilateral adrenal hyperplasia (n = 213)] vs matched EH. RESULTS: A significantly higher number of PA patients experienced cardiovascular events over the entire period of the study (22.6% vs 12.7%, P < .001). At the diagnosis of PA, a higher number of patients had experienced total events (14.1% vs 8.4% EH, P = .007); furthermore, during the follow-up period, PA patients had a higher rate of events (8.5% vs 4.3% EH, P = .008). In particular, stroke and arrhythmias were more frequent in PA patients. During the follow-up, a higher percentage of PA patients developed type 2 diabetes. Parameters that were independently associated with the occurrence of all events were age, duration of hypertension, systolic blood pressure, presence of diabetes mellitus, and PA diagnosis. After division into PA subtypes, patients with either aldosterone-producing adenoma or bilateral adrenal hyperplasia displayed a higher rate of events compared with the matched EH patients. CONCLUSIONS: This study demonstrates in a large population of patients the pathogenetic role of aldosterone excess in the cardiovascular system and thus the importance of early diagnosis and targeted PA treatment.

Visinin-like 1 is upregulated in aldosterone-producing adenomas with KCNJ5 mutations and protects from calcium-induced apoptosis.

Visinin-like 1 (VSNL1) is upregulated in aldosterone-producing adenomas (APAs) compared with normal adrenals. We demonstrate that VSNL1 overexpression in adrenocortical carcinoma cells (NCI H295R) upregulates basal and angiotensin II-stimulated CYP11B2 gene expression 3.2- and 1.5-fold, respectively. Conversely, silencing VSNL1 by RNA interference decreases angiotensin II-stimulated CYP11B2 expression and aldosterone secretion by 41.0% and 34.5%, respectively. Mutations in the potassium channel KCNJ5 have been identified in APAs that result in sodium influx and membrane depolarization and are postulated to result in calcium influx in adrenal glomerulosa cells. VSNL1 and CYP11B2 are 8.1- and 6.0-fold more highly expressed, respectively, in APAs harboring KCNJ5 mutations compared with those without, and the upregulation of VSNL1 in these APAs accounts for the overexpression of VSNL1 in the total APA sample set compared with normal adrenals. Silencing VSNL1 in H295R cells renders them sensitive to ionomycin-induced apoptosis, indicating that VSNL1 protects these cells against calcium-induced cell death. Concomitant expression of mutated KCNJ5 (G151R) and silencing VSNL1 results in apoptosis of H295R cells, an effect that is blocked by nifedipine and is absent using a control small-interfering RNA or when wild-type KCNJ5 is expressed and VSNL1 is silenced. These data demonstrate that VSNL1 plays a dual function in vitro in the regulation of CYP11B2 gene expression and in the inhibition of calcium-induced apoptosis. In addition, VSNL1 may play a role in the pathophysiology of APAs harboring mutations in the potassium channel KCNJ5 via its antiapoptotic function in response to calcium cytotoxicity and its effect on aldosterone production.

Evaluation of primary aldosteronism.

PURPOSE OF REVIEW: The purpose of this review is to briefly summarize current knowledge on diagnosis and treatment of primary aldosteronism, the most frequent cause of endocrine hypertension. RECENT FINDINGS: The prevalence of primary aldosteronism increases with the severity of hypertension, from 2% in patients with grade 1 hypertension to 20% among resistant hypertensives. The detection of primary aldosteronism is of particular importance, not only because it provides an opportunity for a targeted treatment but also because it has been extensively demonstrated that patients affected by primary aldosteronism are more prone to cardiovascular events and target organ damage than patients with essential hypertension. The diagnosis of primary aldosteronism is a three-step process; screening, confirmation and subtype diagnosis. SUMMARY: We review, the strategies to correctly identify primary aldosteronism, highlighting the central role of the new guidelines and the diagnostic aspects still under debate.