key: cord-0798818-9gbel3pq
authors: Kim, Jiwon; Volodarskiy, Alexander; Sultana, Razia; Pollie, Meridith P.; Yum, Brian; Nambiar, Lakshmi; Tafreshi, Romina; Mitlak, Hannah W.; RoyChoudhury, Arindam; Horn, Evelyn M.; Hriljac, Ingrid; Narula, Nupoor; Kim, Sijun; Ndhlovu, Lishomwa; Goyal, Parag; Safford, Monika M.; Shaw, Leslee; Devereux, Richard B.; Weinsaft, Jonathan W.
title: Prognostic Utility of Right Ventricular Remodeling Over Conventional Risk Stratification in Patients With COVID-19
date: 2020-10-27
journal: J Am Coll Cardiol
DOI: 10.1016/j.jacc.2020.08.066
sha: 8a1cb4bb9223d5c5a9328e447e64793f3ff417b7
doc_id: 798818
cord_uid: 9gbel3pq

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a growing pandemic that confers augmented risk for right ventricular (RV) dysfunction and dilation; the prognostic utility of adverse RV remodeling in COVID-19 patients is uncertain. OBJECTIVES: The purpose of this study was to test whether adverse RV remodeling (dysfunction/dilation) predicts COVID-19 prognosis independent of clinical and biomarker risk stratification. METHODS: Consecutive COVID-19 inpatients undergoing clinical transthoracic echocardiography at 3 New York City hospitals were studied; images were analyzed by a central core laboratory blinded to clinical and biomarker data. RESULTS: In total, 510 patients (age 64 ± 14 years, 66% men) were studied; RV dilation and dysfunction were present in 35% and 15%, respectively. RV dysfunction increased stepwise in relation to RV chamber size (p = 0.007). During inpatient follow-up (median 20 days), 77% of patients had a study-related endpoint (death 32%, discharge 45%). RV dysfunction (hazard ratio [HR]: 2.57; 95% confidence interval [CI]: 1.49 to 4.43; p = 0.001) and dilation (HR: 1.43; 95% CI: 1.05 to 1.96; p = 0.02) each independently conferred mortality risk. Patients without adverse RV remodeling were more likely to survive to hospital discharge (HR: 1.39; 95% CI: 1.01 to 1.90; p = 0.041). RV indices provided additional risk stratification beyond biomarker strata; risk for death was greatest among patients with adverse RV remodeling and positive biomarkers and was lesser among patients with isolated biomarker elevations (p ≤ 0.001). In multivariate analysis, adverse RV remodeling conferred a >2-fold increase in mortality risk, which remained significant (p < 0.01) when controlling for age and biomarker elevations; the predictive value of adverse RV remodeling was similar irrespective of whether analyses were performed using troponin, D-dimer, or ferritin. CONCLUSIONS: Adverse RV remodeling predicts mortality in COVID-19 independent of standard clinical and biomarker-based assessment.

C oronavirus disease 2019 (COVID- 19) is an evolving global pandemic.

More than 15 million people have been diagnosed with COVID-19 worldwide (1) . In the United States, >142,000 people have died with COVID-19, and >23,000 deaths have occurred in the New York City area (2) . Given high rates of infection and the substantial morbidity and mortality risks conferred by this condition, evidence-based data regarding risk stratification of patients with COVID-19 is critical.

Emerging data suggests that cardiovascular injury occurs in the setting of COVID-19 infection. In an initial study of hospitalized patients with COVID-19, suspected cardiac injury was present in 7.2%, including nearly one-quarter (22%) of COVID-19infected patients who required intensive care unitlevel care (3) . In another study, almost 12% of COVID-19-infected patients without known cardiovascular disease had elevated troponin levels or cardiac arrest during index hospitalization (4) . Cardiac injury has also been reported to predict prognosis among COVID-19-infected patients, as evidenced by outcomes data that troponin elevation was present in 46% of nonsurvivors as opposed to 1% of survivors (5) and was associated with a >10-fold increased risk of mortality among hospitalized COVID-19 patients (6) .

Adverse cardiac chamber remodeling has been reported in patients with COVID-19. Given that this condition confers high risk for lung involvement, a key area of focus has been adverse right ventricular remodeling. Single-center studies have shown both RV dilation and dysfunction to commonly occur with COVID-19 infection, and to confer adverse prognosis (7, 8) . However, mechanistic determinants and incremental prognostic utility of RV remodeling to that of clinical or biomarker assessment are uncertain.

This study encompassed a multicenter cohort of (TAPSE <1.6 cm, Sʹ <10 mm/s) were used for each parameter (11) . Concordant with prior methods by our group (12) , RV dysfunction was defined by impairment of both TAPSE and Sʹ so as to reduce false positive classification. RV size was quantified based on end-diastolic diameter, which was measured at the RV base (septumfree wall) in apical 4-chamber orientation. RV dilation was defined using a binary cutoff (>4.1 cm) in accordance with consensus guidelines (13) .

LV systolic function, chamber size, and myocardial mass were quantified based on linear dimensions measured in parasternal long-axis, consistent with established quantitative methods validated in necropsy comparisons and epidemiological outcomes studies (14) (15) (16) (17) (18) . A semiquantitative regional wall motion score was calculated in accordance with established criteria (13) . Sex-specific binary cutoffs for LV chamber dilation and hypertrophy were derived from consensus guidelines and normative data samples (19, 20) .

Additional analyses were performed to assess sequelae of ventricular remodeling that could potentially affect prognosis. Left atrial size was measured based on diameter, as well as planimetered chamber volume using a modified biplane area-length method. Mitral and tricuspid regurgitation were graded in accordance with consensus guidelines (21 Values are median (interquartile range) or % (count). Bold p values are statistically significant. *Abnormal biomarker cutoffs defined in accordance with bioassays at participatory study sites (troponin-I >0.5 ng/ml, troponin-T >0.1 ng/ml, ferritin >274 ng/ml, D-dimer >229 mg/ml, C-reactive protein (CRP) >0.9 mg/dl, AST >34 U/l, ALT >49 U/l).

ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; ULN ¼ upper limit of normal; WBC ¼ white blood cells. based on poor echo image quality-raising uncertainty as to whether findings from this study reflect data that can be routinely acquired in clinical practice or large-scale epidemiological research. Regarding generalizability, it should also be noted that mortality in this prior study (15%) was lower than that in our cohort (32%)-and that mortality in our study was within the range (24% to 32%) reported among patients of similar age and intensive care unit-level acuity in prior epidemiological studies in the United States (23) (24) (25) and Europe (26, 27) . In a subsequent U.S. study of 101 patients, Argulian et al. (7) assessed RV size using an equivalent approach to our study and reported RV dilation to predict mortality in patients with COVID-19. Whereas this study supports premise of our study, limited sample size and laboratory data prohibited assessment of whether the predictive utility of adverse RV remodeling dysfunction was additive to that of biomarker derived prognostic markers, which was a focus of the current research.

Regarding mechanism, our observed link between adverse RV remodeling and death may stem from hemodynamic stimuli in which RV dilation is an initially compensatory adaptation to increased RV afterload and/or augmented pulmonary circulatory requirements in context of COVID-mediated hypoxia, but ultimately leads to increased RV wall stress and subsequent dysfunction. Consistent with this notion, our findings demonstrated that RV dysfunction was 2-fold less common than dilation and typically occurred in patients in whom dilation was greatest. More specifically, hypercoagulability and high rates of thrombotic events are known to occur in COVID-19 patients among whom coagulopathy can involve the venous, arterial, and microcirculatory systems (28) (29) (30) . Thromboembolism and microthrombi due to COVID-19 infection-related inflammation, hypoxia, and diffuse intravascular coagulation has the potential to augment RV afterload leading to RV dilation and ultimately resulting in RV dysfunction/failure.

It is also possible that our observed association between RV dysfunction and elevated troponin reflects RV myocardial injury stemming from hypoxia or inflammatory myocarditis. Consistent with the latter, myocarditis has been reported in patients with acute COVID-19 infection (31) , and it is possible that such pathology could affect both LV and RV myocardium. It is also plausible that COVID-mediated systemic inflammation activates molecular pathways that depress myocardial contractility. For example, prior animal studies have shown inflammatory cytokines impair cardiac systolic function (32, 33 (9, 34) , and that both TAPSE and Sʹ predict clinical outcomes, including impaired effort tolerance (12) and mortality (35) . More broadly, given that the echo indices tested in our study can be rapidly acquired and require no specialized software for data analysis, our finding that they strongly impacted clinical prognosis supports the notion that such RV-focused analyses should be incorporated into echo-based triage and risk stratification of patients with known or suspected COVID-19 infection.

Finally, whereas our study demonstrated adverse RV remodeling to be linked to LV dysfunction as well as elevated troponin and systemic inflammatory biomarkers, further studies are warranted to test whether the physiological basis of these associations stems from alterations in RV loading conditions or direct cardiotoxic effects on the RV. Related to this, it is important to note that whereas our results demonstrate adverse RV remodeling to strongly predict mortality in critically ill patients with COVID-19, available study data was insufficient to establish the mechanism for RV dilation or dysfunction. For example, given that COVID-19 can induce a prothrombotic milieu, it is possible that RV dilation resulted from augmented afterload and/or hypoxia due to pulmonary emboli. Whereas critical illness and transmission risks prohibited referral for imaging assessment for thromboembolic events and/or preexisting lung disease (e.g., chronic obstructive pulmonary disease) in a systematic manner, further research is warranted to test these issues as well as whether prognosis in patients with COVID-19 varies based on quantitative methods employed for RV assessment or mechanism of RV dilation or dysfunction. 

World Health Organization. WHO coronavirus disease (COVID-19) dashboard

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

COVID-19 and the cardiovascular system

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China

Right ventricular dilation in hospitalized patients with COVID-19 Infection

Prognostic value of right ventricular longitudinal strain in patients with COVID-19

Echocardiographic linear dimensions for assessment of right ventricular chamber volume as demonstrated by cardiac magnetic resonance

Reliability of echocardiographic assessment of left ventricular structure and function: the PRESERVE study. Prospective Randomized Study Evaluating Regression of Ventricular Enlargement

Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography

Right ventricular dysfunction impairs effort tolerance independent of left ventricular function among patients undergoing exercise stress myocardial perfusion imaging

Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings

Echocardiographic determination of left ventricular mass in man

Prognostic implications of ejection fraction from linear echocardiographic dimensions: the Strong Heart Study

Prognostic implications of relations of left ventricular systolic dysfunction with body composition and myocardial energy expenditure: the Strong Heart Study

Prognostic significance of left ventricular mass change during treatment of hypertension

Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology

Normal limits in relation to age, body size and gender of two-dimensional echocardiographic aortic root dimensions in persons >/¼15 years of age

Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography Developed in Collaboration with the Society for Cardiovascular Magnetic Resonance

Clinical characteristics of Covid-19 in New York City

Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study

Hospitalization and mortality among black patients and white patients with Covid-19

Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area

Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study

Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Supporting colleagues-but how?

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Myocarditis in a patient with COVID-19: a cause of raised troponin and ECG changes

Dilated cardiomyopathy in transgenic mice with cardiacspecific overexpression of tumor necrosis factoralpha

Interleukin-1beta induces a reversible cardiomyopathy in the mouse

Left ventricular stroke volume quantification by contrast echocardiography -comparison of linear and flow-based methods to cardiac magnetic resonance

Incremental utility of right ventricular dysfunction in patients with myeloproliferative neoplasm-associated pulmonary hypertension