COVID-19 in Adults With Hypertrophic Cardiomyopathy

Background: Individuals with cardiovascular disease are considered high risk for severe COVID-19. However, the clinical impact of COVID-19 in patients with hypertrophic cardiomyopathy (HCM) is unknown. The purpose of this study was to describe the clinical course and outcomes of COVID-19 in patients with HCM. Methods: This retrospective observational study included adults with HCM and positive PCR/antibody test for SARS-CoV-2 at a large urban hospital system in the New York from January, 2020 to January, 2021. Results: Seventy individuals were included, with a mean (SD) age of 60.1 (15.1) years, 39 (55.7%) of whom were male, and 42 (60%) white. Forty-five (65.3%) patients had obstructive HCM. Hypertension and obesity (BMI ≥ 30) were present in 45 (64.3%) and 37 (52.9%) patients, and the prevalence of atrial fibrillation, obstructive sleep apnea and diabetes was high. Common symptoms of COVID-19 were fever, cough, shortness of breath and fatigue, affecting 33 (47.1%), 33 (47.1%), 28 (40.0%), and 28 (40.0%) patients, respectively. Fourteen (20%) patients were hospitalized. The majority (45 [64.3%] patients) recovered without intervention. Two patients had non-fatal pulmonary embolisms, 1 had atrial fibrillation requiring electrical cardioversion and 1 had acute decompensated heart failure. Three (4.3%) patients required mechanical ventilation, two of whom died (case fatality rate 2.9%). A total of 15 (21.4%) patients were asymptomatic. Conclusions: Our data suggest that in this diverse and high-risk group of patients with HCM, established risk factors for severe COVID-19, such as obesity, may be more important drivers of morbidity and mortality than the presence of HCM alone.


INTRODUCTION
Since the beginning of the COVID-19 pandemic, over 200 million cases with over 4 million deaths worldwide have been recorded (1). Cardiovascular disease has emerged as risk factor for increased morbidity and mortality (2)(3)(4). Heart failure in particular was shown to be associated with worse outcomes (5). Hypertrophic cardiomyopathy is the most common inherited cardiac disorder and is characterized by cardiac hypertrophy, left ventricular outflow obstruction in the majority of cases, and diastolic dysfunction (6). We were particularly concerned about outcomes of patients with hypertrophic cardiomyopathy (HCM) due to reports of ACE2 gene upregulation in septal myectomy specimens (7) -the ACE2 receptor being the entry point for the SARS-CoV-2 virus. However, the impact of preexisting HCM on the clinical course of COVID-19 is currently unknown. This study aimed to examine the outcomes of COVID-19 in patients with HCM.

MATERIALS AND METHODS
To address this question, we performed a retrospective cohort study of consecutive adult patients, age ≥18 years with HCM who underwent testing for COVID-19 PCR or antibodies at NYU Langone Health, a large urban healthcare system in the New York City area with hospitals in Manhattan, Brooklyn, and Nassau County between January 1, 2020 and January 6, 2021. Individuals were included in the study if they had either positive SARS-CoV-2 PCR or antibody testing. The study was approved by the NYU Grossman School of Medicine's Institutional Review Board and informed consent was waived.
Imaging studies were reviewed by one cardiologist (D.M.) to confirm HCM diagnosis by current guidelines (6) and to identify HCM structural characteristics including distribution of left ventricular hypertrophy (LVH), systolic anterior motion (SAM), left ventricular outflow tract (LVOT) obstruction, mid-ventricular obstruction, apical aneurysm, and mitral annular calcification (MAC). Clinical information was recorded, including medical therapy, history of septal myectomy or alcohol septal ablation, comorbid conditions, COVID-19 presenting symptoms, treatment, hospitalizations, and outcomes. Statistical analysis was performed using STATA 16 (StataCorp LLC, College Station, TX) (8). Data were expressed as means and standard deviation (SD) or medians (interquartile range) for
The majority of patients, 45 (64%), in this sample had obstructive HCM, defined as ≥30 mmHg LVOT or midventricular gradient at rest or with provocation. Apical aneurysm was present in five (7.1%) patients, all of whom had a midsystolic Doppler signal void (9). Asymmetric septal hypertrophy (ASH) was present in 60 (85.7%) individuals, Mean (SD) left ventricular ejection fraction was 69.6 (5.6) % and mean maximal LV wall thickness was 17.6 (4.2) mm. Fifteen patients (21.7%) had an implantable cardioverter defibrillator and one patient had a permanent pacemaker. Most patients were on standard HCM specific medical therapy including beta blockers and calcium channel blockers ( Table 1). Disopyramide was used in 11 (15.9%)

COVID-19 Course and Outcomes
Fifteen individuals (24.3%) in this cohort were asymptomatic. The most common symptoms included fever in 33 (47.1%), cough in 33 (47.1%), shortness of breath in 28 (40.0%) and fatigue in 28 (40.0%) patients ( Table 3). The majority of patients, 45 (64.3%), did not seek or require medical interventions. Medical therapy included the use of antibiotics and steroids. Azithromycin was given to five (7.1%) patients and hydroxychloroquine to six (8.6%). Fourteen (20.0%) patients were hospitalized. There were no significant differences in demographics, HCM characteristics, or co-morbidity profile between the hospitalized and the non-hospitalized group. However, there were differences in presenting symptoms between the groups, as expected. The majority of hospitalized patients presented with shortness of breath, cough and fever than the non-hospitalized patients, 13    atrial fibrillation, chronic renal disease, and an implantable cardiac defibrillator for primary prevention of sudden cardiac death. The male patient had obstructive HCM with SAM, LVOT obstruction with a peak LVOT gradient at rest of 108 mmHg, moderate aortic valve stenosis and obstructive sleep apnea. In addition, two (2.9%) patients presented with nonfatal pulmonary embolisms, one of whom was also found to have a tibial deep vein thrombosis and presented with atrial fibrillation requiring electrical cardioversion. One patient (1.4%) presented with acute decompensated heart failure requiring intravenous diuretics.

DISCUSSION
This study is the first to examine the clinical course and outcomes of COVID-19 in patients with HCM, a significant proportion of whom had prior septal myectomy surgery and implantable cardioverter defibrillators. The hospital admission rate was high at 20%.The case fatality rate in this sample was similar to the general population (1). Both individuals who died had multiple co-morbid conditions associated with higher morbidity and mortality [2, 3.] Among hospitalized patients, the distribution of non-obstructive and obstructive HCM patients mirrors the distribution in unselected HCM cohorts (10). There were no significant differences in demographics, HCM characteristics, or COVID-19 risk factors between the hospitalized and not hospitalized group. One reason for this may be that only four patients required an ICU level of care. Moreover, a majority of the non-ICU hospitalized patients were treated with supportive care. It is likely that most were admitted for observation and monitoring of possible COVID-19 related deterioration, given that the presenting COVID-19 related symptom of the vast majority of hospitalized patients was shortness of breath. The overall low numbers of seriously ill HCM patients with COVID-19 in the sample preclude an adequate statistical analysis on risk profiles. Two patients presented with non-fatal pulmonary embolisms, a known complication of COVID-19 (11). Furthermore, even though one patient presented with acute decompensated heart failure, this is not uncommon in the setting of acute illness (12).
Prior reports have noted that there is ACE2 receptor upregulation in HCM tissue specimens (7), and ACE2 is the entry point of SARS-Cov-2. One small study examined cardiac samples from individuals with dilated cardiomyopathy, hypertrophic cardiomyopathy and healthy controls, which also supported upregulation of ACE2 in HCM tissue, but did not observe a difference in ACE2 expression between HCM patients taking ACE inhibitor medicines and those who did not (13). However, the clinical impact of this upregulation in HCM is unclear. Our study is the first to examine the clinical impact of COVID-19 on HCM patients in real world conditions. Our data suggest that HCM may not in itself contribute to worse clinical outcomes from COVID-19, above other established risk factors, such as age and obesity. Further studies in larger cohorts of patients with HCM and COVID-19 are needed.
Limitations of this study include the possibility of selection bias, underreporting and asymptomatic infections leading to a high admission rate. Furthermore, the relatively small sample size may limit the generalization of results. However, our cohort is representative of a diverse population. Last, as patients with HCM were deemed high risk for COVID-19 complications along with other types of cardiovascular disease, this awareness may have led to strict adherence with social distancing recommendations, which may have been the cause of a lower infection rate.
In conclusion, our data suggest that HCM in itself does not carry a higher risk of COVID-19 disease severity and complications. Established risk factors for severe COVID-19, such as age and obesity may be more influential.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors upon reasonable request.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by NYU Langone Health Institutional Review Board. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

AUTHOR CONTRIBUTIONS
MA: conceptualization, methodology, formal analysis, investigation, data curation, and writing-original draft. MR: investigation, writing-review, and editing. AS: investigation.
MS: writing-review and editing. DM: conceptualization, methodology, data curation, supervision, and writing-original draft. All authors on this manuscript have fulfilled the criteria for authorship as set forth by the ICMJE guidelines.