Early triage echocardiography to predict outcomes in patients admitted with COVID-19: a multicenter study.

INTRODUCTION: Cardiac involvement seems to impact prognosis of COVID-19, especially in critically ill patients. We aimed to assess the prognostic value of right ventricular (RV) and left ventricular (LV) dysfunction, evaluated by bedside triage echocardiography (echo), in patients admitted to emergency departments (ED) in the US with COVID-19. We also assessed the feasibility of using cloud imaging for sharing and interpreting echocardiograms. METHODS: Patients admitted to three reference EDs with confirmed COVID-19 underwent triage echo within 72 h of symptom onset with remote interpretation. Clinical and laboratory data, as well as COVID-19 symptoms, were collected. The association between echo variables, demographics and clinical data with all-cause hospital mortality and intensive care unit (ICU) admission was assessed using logistic regression. RESULTS: Three hundred ninety-nine patients were enrolled, 41% women, with a mean age of 62±16 years. Mean oxygen saturation on presentation was 92.3± 9.2%. Compared to in-hospital survivors, non-survivors were older, had lower oxygen saturation on presentation, were more likely to have a chronic condition and had lower LV ejection fraction (50.3±19.7% vs. 58.0±13.6%) (P < .05). In the cohort, 101 (25%) patients had moderate/severe LV dysfunction, 131 (33%) had moderate/severe RV dysfunction. Advanced age and lower oxygen saturation were independently associated with death and ICU admission. LV and RV function, or other echo variables, were not independent predictors of outcomes. CONCLUSION: In patients admitted with COVID-19 undergoing early echo triage, the independent predictors of death and ICU admission were age and oxygen saturation. The inclusion of echo variables did not improve prediction of unfavorable outcomes.

Cardiac microstructural alterations in immune-inflammatory myocardial disease: a retrospective case-control study.

BACKGROUND: Immune-inflammatory myocardial disease contributes to multiple chronic cardiac processes, but access to non-invasive screening is limited. We have previously developed a method of echocardiographic texture analysis, called the high-spectrum signal intensity coefficient (HS-SIC) which assesses myocardial microstructure and previously associated with myocardial fibrosis. We aimed to determine whether this echocardiographic texture analysis of cardiac microstructure can identify inflammatory cardiac disease in the clinical setting. METHODS: We conducted a retrospective case-control study of 318 patients with distinct clinical myocardial pathologies and 20 healthy controls. Populations included myocarditis, atypical chest pain/palpitations, STEMI, severe aortic stenosis, acute COVID infection, amyloidosis, and cardiac transplantation with acute rejection, without current rejection but with prior rejection, and with no history of rejection. We assessed the HS-SIC's ability to differentiate between a broader diversity of clinical groups and healthy controls. We used Kruskal-Wallis tests to compare HS-SIC values measured in each of the clinical populations with those in the healthy control group and compared HS-SIC values between the subgroups of cardiac transplantation rejection status. RESULTS: For the total sample of N = 338, the mean age was 49.6 ± 20.9 years and 50% were women. The mean ± standard error of the mean of HS-SIC were: 0.668 ± 0.074 for controls, 0.552 ± 0.049 for atypical chest pain/palpitations, 0.425 ± 0.058 for myocarditis, 0.881 ± 0.129 for STEMI, 1.116 ± 0.196 for severe aortic stenosis, 0.904 ± 0.116 for acute COVID, and 0.698 ± 0.103 for amyloidosis. Among cardiac transplant recipients, HS-SIC values were 0.478 ± 0.999 for active rejection, 0.594 ± 0.091 for prior rejection, and 1.191 ± 0.442 for never rejection. We observed significant differences in HS-SIC between controls and myocarditis (P = 0.0014), active rejection (P = 0.0076), and atypical chest pain or palpitations (P = 0.0014); as well as between transplant patients with active rejection and those without current or prior rejection (P = 0.031). CONCLUSIONS: An echocardiographic method can be used to characterize tissue signatures of microstructural changes across a spectrum of cardiac disease including immune-inflammatory conditions.

Cardiac target organ damage in hypertension: insights from epidemiology.

Hypertension is an important risk factor implicated in the development of multiple common cardiac conditions, including coronary atherosclerosis, heart failure, and atrial fibrillation. Epidemiologic studies have provided insights into the shared pathogenesis of hypertension and subclinical as well as clinically evident cardiac diseases. The mechanistic common ground between chronic blood pressure elevation and cardiac disease likely begins early in life. Understanding these connections will aid ongoing efforts to identify individuals at risk, develop targeted therapeutics, and improve overall outcomes for individuals with elevated blood pressure in the population at large.

Sex Differences in Health Status and Clinical Outcomes After Nonprimary Percutaneous Coronary Intervention.

BACKGROUND: Greater insight into sex-based differences in health status can lay the foundation for more equitable health care. This study compares differences in health status of women and men in the CPORT-E trial (Cardiovascular Patient Outcomes Research Team Non-Primary Percutaneous Coronary Intervention) undergoing nonprimary percutaneous coronary intervention. METHODS: We compared Seattle Angina Questionnaire scores at baseline, 6 weeks, and 9 months for 6851 women and 12 016 men undergoing nonprimary percutaneous coronary intervention. RESULTS: Proportions of angina-free patients increased from 26.2% and 29.8% at baseline to 71.6% and 78.7% at 6 weeks to 78.1% and 83.0% at 9 months in women and men, respectively (P<0.001 for all). After adjusting for clinical and procedural characteristics as well as baseline angina, freedom from angina in women was 34% less likely at 6 weeks (odds ratio, 0.66 [95% CI, 0.61-0.71]; P<0.001) and 32% less likely at 9 months (odds ratio, 0.68 [95% CI, 0.62-0.74]; P<0.001) compared with men. CONCLUSIONS: Although health status increased significantly after percutaneous coronary intervention in both women and men, women had poorer health status outcomes than men before and after percutaneous coronary intervention. Additional investigation into therapies that address the causes of poorer health status in women with coronary artery disease is needed. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00549796.

Cardiac microstructural alterations measured by echocardiography identify sex-specific risk for heart failure.

OBJECTIVE: Established preclinical imaging assessments of heart failure (HF) risk are based on macrostructural cardiac remodelling. Given that microstructural alterations may also influence HF risk, particularly in women, we examined associations between microstructural alterations and incident HF. METHODS: We studied N=2511 adult participants (mean age 65.7±8.8 years, 56% women) of the Framingham Offspring Study who were free of cardiovascular disease at baseline. We employed texture analysis of echocardiography to quantify microstructural alteration, based on the high spectrum signal intensity coefficient (HS-SIC). We examined its relations to incident HF in sex-pooled and sex-specific Cox models accounting for traditional HF risk factors and macrostructural alterations. RESULTS: We observed 94 new HF events over 7.4±1.7 years. Individuals with higher HS-SIC had increased risk for incident HF (HR 1.67 per 1-SD in HS-SIC, 95% CI 1.31 to 2.13; p<0.0001). Adjusting for age and antihypertensive medication use, this association was significant in women (p=0.02) but not men (p=0.78). Adjusting for traditional risk factors (including body mass index, total/high-density lipoprotein cholesterol, blood pressure traits, diabetes and smoking) attenuated the association in women (HR 1.30, p=0.07), with mediation of HF risk by the HS-SIC seen for a majority of these risk factors. However, the HS-SIC association with HF in women remained significant after adjusting for relative wall thickness (representing macrostructure alteration) in addition to these risk factors (HR 1.47, p=0.02). CONCLUSIONS: Cardiac microstructural alterations are associated with elevated risk for HF, particularly in women. Microstructural alteration may identify sex-specific pathways by which individuals progress from risk factors to clinical HF.

Opportunities to improve cardiovascular health in the new American workplace.

Adult working-class Americans spend on average 50% of their workday awake time at their jobs. The vast majority of these jobs involve mostly physically inactive tasks and frequent exposure to unhealthy food options. Traditionally, the workplace has been a challenging environment for cardiovascular prevention, where cardiovascular guidelines have had limited implementation. Despite the impact that unhealthy lifestyles at the workplace may have on the cardiovascular health of U.S. workers, there is currently no policy in place aimed at improving this. In this review, we discuss recent evidence on the prevalence of physical inactivity among Americans, with a special focus on the time spent at the workplace; and the invaluable opportunity that workplace-based lifestyle interventions may represent for improving the prevention of cardiovascular disease. We describe the current regulatory context, the key stakeholders involved, and present specific, guideline-inspired initiatives to be considered by both Congress and employers to improve the "cardiovascular safety" of US jobs. Additionally, we discuss how the COVID-19 pandemic has forever altered the workplace, and what lessons can be taken from this experience and applied to cardiovascular disease prevention in the new American workplace. For many Americans, long sitting hours at their job represent a risk to their cardiovascular health. We discuss how a paradigm shift in how we approach cardiovascular health, from focusing on leisure time to also focusing on work time, may help curtail the epidemic of cardiovascular disease in this country.

Runx2/Cbfa1, but not loss of myocardin, is required for smooth muscle cell lineage reprogramming toward osteochondrogenesis.

Vascular calcification is a major risk factor for cardiovascular morbidity and mortality. Smooth muscle cells (SMCs) may play an important role in vascular cartilaginous metaplasia and calcification via reprogramming to the osteochondrogenic state. To study whether SM lineage reprogramming and thus matrix calcification is reversible and what the necessary regulatory factors are to reverse this process, we used cells isolated from calcifying arterial medias of 4-week-old matrix Gla protein knockout mice (MGP-/-SMCs). We found that vascular cells with an osteochondrogenic phenotype regained SMC properties (positive for SM22alpha and SM alpha-actin) and down-regulated osteochondrogenic gene expression (Runx2/Cbfa1 and osteopontin) upon culture in medium that favors SMC differentiation. Over time, the MGP-/- SMCs no longer expressed osteochondrogenic proteins and became indistinguishable from wild-type SMCs. Moreover, phenotypic switch of the restored SMCs to the osteochondrogenic state was re-induced by the pro-calcific factor, inorganic phosphate. Finally, loss- and gain-of-function studies of myocardin, a SM-specific transcription co-activator, and Runx2/Cbfa1, an osteochondrogenic transcription factor, revealed that upregulation of Runx2/Cbfa1, but not loss of myocardin, played a critical role in phosphate-induced SMC lineage reprogramming and calcification. These results are the first to demonstrate reversibility of vascular SMCs in the osteochondrogenic state in response to local environmental cues, and that myocardin-enforced SMC lineage allocation was not sufficient to block vascular calcification. On the other hand, Runx2/Cbfa1 was found to be a decisive factor identified in the process.

Early Transcatheter Aortic Valve Function With and Without Therapeutic Anticoagulation.

OBJECTIVES: Prosthetic leaflet thrombosis is a growing concern in transcatheter aortic valve replacement (TAVR). Given the uncertainty of best practices for antiplatelet and anticoagulation therapies in the post-TAVR period, additional evidence regarding the impact of anticoagulation on prosthetic valve function after TAVR is needed. METHODS: Patients undergoing native-valve TAVR at a single academic institution between 2012 and 2015 were analyzed based on any anticoagulant use at hospital discharge post TAVR. Changes in prosthetic valve peak velocity and mean gradient were assessed based on transthoracic echocardiograms performed immediately following valve implant and at 4-week follow-up. Multivariate regression analyses were performed to explore the impact of anticoagulation status on early TAVR valve performance. RESULTS: For 403 patients, there were no available data to analyze. Of those, 29.6% were discharged on anticoagulation. Following TAVR, the average mean prosthetic valve gradient was 11.8 ± 5.6 mm Hg and peak velocity was 2.33 ± 0.52 m/s. There were no significant differences between anticoagulated and non-anticoagulated groups in the mean or peak gradients or velocity immediately following implant or at 4 weeks, which remained true following multivariate adjustment (P=.80 for delta mean gradient; P=.91 for delta peak velocity). CONCLUSION: Our data suggest that the absence of anticoagulation is not associated with short-term degradation in TAVR performance and do not support the routine use of anticoagulation following native-valve TAVR.

Preclinical Alterations in Myocardial Microstructure in People with Metabolic Syndrome.

OBJECTIVE: Metabolic syndrome (MetS) can lead to myocardial fibrosis, diastolic dysfunction, and eventual heart failure. This study evaluated alterations in myocardial microstructure in people with MetS by using a novel algorithm to characterize ultrasonic signal intensity variation. METHODS: Among 254 participants without existing cardiovascular disease (mean age 42 ± 11 years, 75% women), there were 162 with MetS, 47 with obesity without MetS, and 45 nonobese controls. Standard echocardiography was performed, and a novel validated computational algorithm was used to investigate myocardial microstructure based on sonographic signal intensity and distribution. The signal intensity coefficient (SIC [left ventricular microstructure]) was examined. RESULTS: The SIC was significantly higher in people with MetS compared with people with (P < 0.001) and without obesity (P = 0.04), even after adjustment for age, sex, body mass index, hypertension, diabetes mellitus, and the ratio of triglyceride (TG) to high-density lipoprotein (HDL) cholesterol (P < 0.05 for all). Clinical correlates of SIC included TG concentrations (r = 0.21, P = 0.0007) and the TG/HDL ratio (r = 0.2, P = 0.001). CONCLUSIONS: This study's findings suggest that preclinical MetS and dyslipidemia in particular are associated with altered myocardial signal intensity variation. Future studies are needed to determine whether the SIC may help detect subclinical diseases in people with metabolic disease, with the ultimate goal of targeting preventive efforts.

Ultrasonic Assessment of Myocardial Microstructure in Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers With and Without Left Ventricular Hypertrophy.

BACKGROUND: The noninvasive assessment of altered myocardium in patients with genetic mutations that are associated with hypertrophic cardiomyopathy (HCM) remains challenging. In this pilot study, we evaluated whether a novel echocardiography-based assessment of myocardial microstructure, the signal intensity coefficient (SIC), could detect tissue-level alterations in HCM sarcomere mutation carriers with and without left ventricular hypertrophy. METHODS AND RESULTS: We studied 3 groups of genotyped individuals: sarcomere mutation carriers with left ventricular hypertrophy (clinical HCM; n=36), mutation carriers with normal left ventricular wall thickness (subclinical HCM; n=28), and healthy controls (n=10). We compared measurements of echocardiographic SIC with validated assessments of cardiac microstructural alteration, including cardiac magnetic resonance measures of interstitial fibrosis (extracellular volume fraction), as well as serum biomarkers (NTproBNP, hs-cTnI, and PICP). In age-, sex-, and familial relation-adjusted analyses, the SIC was quantitatively different across subjects with overt HCM, subclinical HCM, and healthy controls (P<0.001). Compared with controls, the SIC was 61% higher in overt HCM and 47% higher in subclinical HCM (P<0.001 for both). The SIC was significantly correlated with extracellular volume (r=0.72; P<0.01), with left ventricular mass and E' velocity (r=0.45, -0.60, respectively; P<0.01 for both), and with serum NTproBNP levels (r=0.36; P<0.001). CONCLUSIONS: Our findings suggest that the SIC could serve as a noninvasive quantitative tool for assessing altered myocardial tissue characteristics in patients with genetic mutations associated with HCM. Further studies are needed to determine whether the SIC could be used to identify subclinical changes in patients at risk for HCM and to evaluate the effects of interventions.

Ultrasonic assessment of myocardial microstructure.

Echocardiography is a widely accessible imaging modality that is commonly used to noninvasively characterize and quantify changes in cardiac structure and function. Ultrasonic assessments of cardiac tissue can include analyses of backscatter signal intensity within a given region of interest. Previously established techniques have relied predominantly on the integrated or mean value of backscatter signal intensities, which may be susceptible to variability from aliased data from low frame rates and time delays for algorithms based on cyclic variation. Herein, we describe an ultrasound-based imaging algorithm that extends from previous methods, can be applied to a single image frame and accounts for the full distribution of signal intensity values derived from a given myocardial sample. When applied to representative mouse and human imaging data, the algorithm distinguishes between subjects with and without exposure to chronic afterload resistance. The algorithm offers an enhanced surrogate measure of myocardial microstructure and can be performed using open-access image analysis software.

Identifying early changes in myocardial microstructure in hypertensive heart disease.

The transition from healthy myocardium to hypertensive heart disease is characterized by a series of poorly understood changes in myocardial tissue microstructure. Incremental alterations in the orientation and integrity of myocardial fibers can be assessed using advanced ultrasonic image analysis. We used a modified algorithm to investigate left ventricular myocardial microstructure based on analysis of the reflection intensity at the myocardial-pericardial interface on B-mode echocardiographic images. We evaluated the extent to which the novel algorithm can differentiate between normal myocardium and hypertensive heart disease in humans as well as in a mouse model of afterload resistance. The algorithm significantly differentiated between individuals with uncomplicated essential hypertension (N = 30) and healthy controls (N = 28), even after adjusting for age and sex (P = 0.025). There was a trend in higher relative wall thickness in hypertensive individuals compared to controls (P = 0.08), but no difference between groups in left ventricular mass (P = 0.98) or total wall thickness (P = 0.37). In mice, algorithm measurements (P = 0.026) compared with left ventricular mass (P = 0.053) more clearly differentiated between animal groups that underwent fixed aortic banding, temporary aortic banding, or sham procedure, on echocardiography at 7 weeks after surgery. Based on sonographic signal intensity analysis, a novel imaging algorithm provides an accessible, non-invasive measure that appears to differentiate normal left ventricular microstructure from myocardium exposed to chronic afterload stress. The algorithm may represent a particularly sensitive measure of the myocardial changes that occur early in the course of disease progression.