Extracellular Matrix Instability and Chronic Inflammation Underlie Maladaptive Right Ventricular Pressure Overload Remodeling and Failure in Male Mice.

Background: Right ventricular dysfunction (RVD) portends increased death risk for heart failure (HF) and pulmonary arterial hypertension (PAH) patients, regardless of left ventricular function or etiology. In both, RVD arises from the chronic RV pressure overload, and represents advanced cardiopulmonary disease. RV remodeling responses and survival rates of HF and PAH patients, however, differ by sex. Men develop more severe RVD and die at younger ages than do women. Mechanistic details of this sexual dimorphism in RV remodeling are incompletely understood. We sought to elucidate the cardiac pathophysiology underlying the sex-specific RV remodeling phenotypes, RV failure (RVF) versus compensated RVD. Methods: We subjected male (M-) and female (F-) adult mice to moderate pulmonary artery banding (PAB) for 9wks. Mice underwent serial echocardiography, cardiac MRI, RV pressure-volume loop recordings, histologic and molecular analyses. Results: M-PAB developed severe RVD with RVF, increased RV collagen deposition and degradation, extracellular matrix (ECM) instability, and activation and recruitment of macrophages. Despite the same severity and chronicity of RV pressure overload, F-PAB had more stable ECM, lacked chronic inflammation, and developed mild RVD without RVF. Conclusions: ECM destabilization and chronic activation of recruited macrophages are associated with maladaptive RV remodeling and RVF in male PAB mice. Adaptive RV remodeling of female PAB mice lacked these histopathologic changes. Our findings suggest that these two pathophysiologic processes likely contribute to the sexual dimorphism of RV pressure overload remodeling. Further mechanistic studies are needed to assess their pathogenic roles and potential as targets for RVD therapy and RVF prevention. CLINICAL PERSPECTIVE: What is new?: In a mouse model of pure PH, males but not females showed an association between ECM instability, chronic inflammation with activation of recruited macrophages, and severe RV dysfunction and failure.What are the clinical implications?: In male HF and PH patients, enhancing ECM stability and countering the recruitment and activation of macrophages may help preserve RV function such that RVF can be prevented or delayed. Further preclinical mechanistic studies are needed to assess the therapeutic potential of such approaches. RESEARCH PERSPECTIVE: What new question does this study raise? What question should be addressed next?: What mechanisms regulate RV ECM stability and macrophage recruitment and activation in response to chronic RV pressure overload? Are these regulatory mechanisms dependent upon or independent of sex hormone signaling?

Tie2-Cre-Induced Inactivation of Non-Nuclear Estrogen Receptor-α Signaling Abrogates Estrogen Protection Against Vascular Injury.

Using the Cre-loxP system, we generated the first mouse model in which estrogen receptor-α non-nuclear signaling was inactivated in endothelial cells. Estrogen protection against mechanical vascular injury was impaired in this model. This result indicates the pivotal role of endothelial estrogen receptor-α non-nuclear signaling in the vasculoprotective effects of estrogen.

Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19.

Acute cardiac injury is prevalent in critical COVID-19 and associated with increased mortality. Its etiology remains debated, as initially presumed causes - myocarditis and cardiac necrosis - have proved uncommon. To elucidate the pathophysiology of COVID-19-associated cardiac injury, we conducted a prospective study of the first 69 consecutive COVID-19 decedents at CUIMC in New York City. Of 6 acute cardiac histopathologic features, presence of microthrombi was the most commonly detected among our cohort. We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak erythrocyte sedimentation rate and C-reactive protein were independently associated with increased odds of microthrombi, supporting an immunothrombotic etiology. Using single-nuclei RNA-sequencing analysis on 3 patients with and 4 patients without cardiac microthrombi, we discovered an enrichment of prothrombotic/antifibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling among cardiac fibroblasts in microthrombi-positive, relative to microthrombi-negative, COVID-19 hearts. Non-COVID-19, nonfailing hearts were used as reference controls. Our study identifies a specific transcriptomic signature in cardiac fibroblasts as a salient feature of microthrombi-positive COVID-19 hearts. Our findings warrant further mechanistic study as cardiac fibroblasts may represent a potential therapeutic target for COVID-19-associated cardiac microthrombi.

Sex Differences and Regulatory Actions of Estrogen in Cardiovascular System.

Great progress has been made in the understanding of the pathophysiology of cardiovascular diseases (CVDs), and this has improved the prevention and prognosis of CVDs. However, while sex differences in CVDs have been well documented and studied for decades, their full extent remains unclear. Results of the latest clinical studies provide strong evidence of sex differences in the efficacy of drug treatment for heart failure, thereby possibly providing new mechanistic insights into sex differences in CVDs. In this review, we discuss the significance of sex differences, as rediscovered by recent studies, in the pathogenesis of CVDs. First, we provide an overview of the results of clinical trials to date regarding sex differences and hormone replacement therapy. Then, we discuss the role of sex differences in the maintenance and disruption of cardiovascular tissue homeostasis.

Molecular Pathophysiology of Cardiac Injury and Cardiac Microthrombi in Fatal COVID-19: Insights from Clinico-histopathologic and Single Nuclei RNA Sequencing Analyses.

Cardiac injury is associated with critical COVID-19, yet its etiology remains debated. To elucidate the pathogenic mechanisms of COVID-19-associated cardiac injury, we conducted a single-center prospective cohort study of 69 COVID-19 decedents. Of six cardiac histopathologic features, microthrombi was the most commonly detected (n=48, 70%). We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak ESR and CRP during hospitalization were independently associated with higher odds of microthrombi. Using single nuclei RNA-sequence analysis, we discovered an enrichment of pro-thrombotic/anti-fibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling amongst cardiac fibroblasts in microthrombi-positive COVID-19 hearts relative to microthrombi-negative COVID-19. Non-COVID-19 non-failing hearts were used as reference controls. Our cumulative findings identify the specific transcriptomic changes in cardiac fibroblasts as salient features of COVID-19-associated cardiac microthrombi.

Estrogen Receptor-α Non-Nuclear Signaling Confers Cardioprotection and Is Essential to cGMP-PDE5 Inhibition Efficacy.

Using genetically engineered mice lacking estrogen receptor-α non-nuclear signaling, this study demonstrated that estrogen receptor-α non-nuclear signaling activated myocardial cyclic guanosine monophosphate-dependent protein kinase G and conferred protection against cardiac remodeling induced by pressure overload. This pathway was indispensable to the therapeutic efficacy of cyclic guanosine monophosphate-phosphodiesterase 5 inhibition but not to that of soluble guanylate cyclase stimulation. These results might partially explain the equivocal results of phosphodiesterase 5 inhibitor efficacy and also provide the molecular basis for the advantage of using a soluble guanylate cyclase simulator as a new therapeutic option in post-menopausal women. This study also highlighted the need for female-specific therapeutic strategies for heart failure.

Feasibility of a T-Shirt-Type Wearable Electrocardiography Monitor for Detection of Covert Atrial Fibrillation in Young Healthy Adults.

Covert atrial fibrillation (AF) accounts for cryptogenic stroke aetiology in elderly patients and in younger populations. However, asymptomatic AF is difficult to diagnose based on a short electrocardiography (ECG) recording. We evaluated the feasibility of a self-applied continuous ECG monitoring device that can record automatically, easily, and noninvasively in a younger population. We investigated community screening for asymptomatic AF using a wireless single-lead ECG with an electrode embedded in a T-shirt. One hundred men with a CHADS2 score ≥1 who were free from AF and <65 years of age were enrolled. We instructed the participants to wear ECG monitoring devices for at least 4 days/week over 2 months. The proportion of participants with newly detected AF (NDAF) and the monitoring time were evaluated. The mean CHADS2 score was 1.43 ± 0.62. The mean patient age was 52.5 ± 5.4 years. The mean monitoring time was 222 ± 199 hours. NDAF continuing for >30 seconds was detected in 10 participants (10.0%). AF continuing for >6 minutes was detected in 2 participants (2.0%). The T-shirt-type wearable ECG monitoring system was suitable for continuous, daily long-term use among young people with high physical activity, and it had the distinct capability of identifying covert AF.

Regulatory Actions of Estrogen Receptor Signaling in the Cardiovascular System.

Premenopausal females have a lower incidence of death from cardiovascular disease (CVD) than male counterparts, supporting the notion that estrogen is protective against the development and progression of CVD. Although large-scale randomized trials of postmenopausal hormone replacement therapy failed to show cardiovascular benefits, recent ELITE study demonstrated anti-atherosclerotic benefits of exogenous estrogen depending on the initiation timing of the therapy. These results have urged us to better understand the mechanisms for actions of estrogens on CVD. Here, we review experimental and human studies, highlighting the emerging role of estrogen's non-nuclear actions linking to NO-cGMP signaling pathways.

Membrane-Initiated Estrogen Receptor Signaling Mediates Metabolic Homeostasis via Central Activation of Protein Phosphatase 2A.

Women gain weight and their diabetes risk increases as they transition through menopause; these changes can be partly reversed by hormone therapy. However, the underlying molecular mechanisms mediating these effects are unknown. A novel knock-in mouse line with the selective blockade of the membrane-initiated estrogen receptor (ER) pathway was used, and we found that the lack of this pathway precipitated excessive weight gain and glucose intolerance independent of food intake and that this was accompanied by impaired adaptive thermogenesis and reduced physical activity. Notably, the central activation of protein phosphatase (PP) 2A improved metabolic disorders induced by the lack of membrane-initiated ER signaling. Furthermore, the antiobesity effect of estrogen replacement in a murine menopause model was abolished by central PP2A inactivation. These findings define a critical role for membrane-initiated ER signaling in metabolic homeostasis via the central action of PP2A.

A Case of a Cardiac Resynchronization Therapy-Defibrillator Exhibiting a Lower and Alternately Variable Basic Rate.

A cardiac resynchronization therapy defibrillator (CRT-D) (Medtronic Inc. Protecta XT) was implanted in a 67-year-old man who had cardiac sarcoidosis with extremely low cardiac function. He had ventricular tachycardia which was controlled by catheter ablation, medication and pacing. The programmed mode was DDI, lower rate was 90 beats/minute, paced AV delay was 150 ms, and the noncompetitive atrial pacing (NCAP) function was programmed as 300 ms.After his admission for pneumonia and heart failure, we changed his DDI mode to a DDD mode because he had atrial tachycardia, which led to inadequate bi-ventricular pacing. After a while, there were cycle lengths which were longer than his device setting and alternately varied. We were able to avoid this phenomenon with AV delay of 120 ms and NCAP of 200 ms.NCAP is an algorithm which creates a gap above a certain period after the detection of an atrial signal during the postventricular atrial refractory period of the pacemaker. This is to prevent atrial tachycardia and repetitive non-reentrant ventriculoatrial (VA) synchrony in the presence of retrograde VA conduction. But in this case, NCAP algorithm induced much lower rate than the programmed basic lower rate. This situation produced some arrhythmias and exacerbated symptoms of heart failure. This had to be paid attention to, especially when the device was programmed at high basic heart rate.

Periprocedural Complications in Patients Undergoing Catheter Ablation of Atrial Fibrillation Without Discontinuation of a Vitamin K Antagonist and Direct Oral Anticoagulants.

BACKGROUND: Periprocedural anticoagulation is important in catheter ablation (CA) of atrial fibrillation (AF) and there is increasing evidence that uninterrupted vitamin K antagonist (VKA) therapy is superior to interrupted anticoagulation strategies. Since the emergence of direct oral anticoagulants (DOACs), numerous studies have shown promising results for their use in uninterrupted strategies. However, further studies are needed to further define the efficacy and safety of performing AF ablation with uninterrupted factor XA inhibitors or direct thrombin inhibitors.Methods and Results:We have performed CA of AF without discontinuation of either VKA or DOAC therapy since April 2014. A total of 376 patients with AF underwent CA including pulmonary vein isolation. All of the patients were divided into 2 groups (uninterrupted VKA or uninterrupted DOACs). Anticoagulation with DOACs was associated with fewer complications than uninterrupted VKA therapy (P=0.04). There were significant differences between groups in the rates of congestive heart failure, left ventricular ejection fraction, body weight, and estimated glomerular filtration rate and of the CHADS2, CHA2DS2-VASc and HAS-BLED scores. Therefore, we also analyzed the results using the propensity score-matching method. We found no significant difference in periprocedural complications between uninterrupted VKA or DOACs therapy (P=0.65). CONCLUSIONS: CA of AF without discontinuation of DOACs is not inferior to CA without discontinuation of a VKA, with regard to ischemic or hemorrhagic complications.

Heart Failure Complicated by Alveolar Hemorrhage due to Vascular Collapse and Amyloid Deposits in Wild-Type Transthyretin Amyloidosis.

The main clinical manifestations of wild-type transthyretin (TTR)-related amyloidosis are progressive heart failure and neuropathy. There have been some reports on cerebral hemorrhage due to cerebral amyloid angiopathy in patients with TTR-related amyloidosis, but little is known about the vascular involvement in other organs. A 77-year-old woman experienced heart failure and was admitted for deteriorating heart failure status. Echocardiography showed diffuse hypokinesis of the left ventricle with biventricular wall thickness. On the 12th hospital day, the blood oxygen saturation level suddenly dropped and, despite oxygen supplementation and intensive care, the patient died. An autopsy revealed systemic deposition of amyloids which were immunolabeled by an anti-TTR antibody. Furthermore, gene-sequencing analysis showed no evidence of TTR gene mutations. The patient was diagnosed postmortem with wild-type TTR-related amyloidosis. Pathological findings revealed alveolar hemorrhage of the lung. Massive amyloid deposits were present in the vessels, and collapsed internal elastic laminae with lymphocyte infiltration were observed at the site of amyloid deposits in the bronchial artery, suggesting that deposits with inflammation might cause the collapse of the bronchial artery and lead to hemorrhage. In amyloidosis patients who suffer heart failure, there is the potential for vascular collapse caused by the accumulation of amyloid deposits with inflammation.