ESC HEART FAILURE ORIGINAL ARTICLE ESC Heart Failure 2022; 9: 2189–2198 Published online 3 June 2022 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.13964 Impact of SARS-Cov-2 infection in patients with hypertrophic cardiomyopathy: results of an international multicentre registry Juan R. Gimeno1,2,3* , Iacopo Olivotto4 , Ana Isabel Rodríguez1,2, Carolyn Y. Ho5, Adrián Fernández6, Alejandro Quiroga6, Mari Angeles Espinosa3,7, Cristina Gómez-González3,7, María Robledo8, Lucas Tojal-Sierra8, Sharlene M. Day9, Anjali Owens9, Roberto Barriales-Villa3,10 , Jose María Larrañaga3,10, Jose Rodríguez-Palomares3,11,12 , Maribel González-del-Hoyo3,11,12, Jesús Piqueras-Flores13, Nosheen Reza9, Olga Chumakova14, Euan A. Ashley15, Victoria Parikh15, Matthew Wheeler15, Daniel Jacoby16, Alexandre C. Pereira17, Sara Saberi18, Adam S. Helms18, Eduardo Villacorta3,19,20,21 , María Gallego-Delgado3,19,20,21 , Daniel de Castro2,3,22, Fernando Domínguez2,3,22, Tomás Ripoll-Vera23 , Esther Zorio-Grima3,24 , José Carlos Sánchez-Martínez3,24, Ana García-Álvarez3,25,26, Elena Arbelo3,25,26 , María Victoria Mogollón27, María Eugenia Fuentes-Cañamero28, Elias Grande29, Carlos Peña29, Lorenzo Monserrat29 , Neal K. Lakdawala5 and Dilema International Cardiomyopathy and Heart Failure Registry and international SHaRe (Sarcomeric Human Cardiomyopathy Registry) Investigators group 1 Departamento de Medicina Interna, Universidad de Murcia, Ctra. Finca Buenavista s/n, Campus Ciencias de la Salud, El Palmar, Murcia, 30120, Spain; 2European Reference Networks for rare, low prevalence and complex diseases of the heart (ERN GUARD-Heart), Amsterdam, The Netherlands; 3Center for Biomedical Network Research on Cardiovascular Diseases (CIBERCV), Madrid, Spain; 4Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy; 5Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA; 6Unidad de Cardiopatías Familiares, Favaloro Foundation University Hospital, Buenos Aires, Argentina; 7Unidad de Cardiopatías Familiares, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 8Hospital Universitario Araba (Txagorritxu), Alava, Spain; 9Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; 10Unidad CSUR Cardiopatías Familiares, Complexo Hospitalario Universitario de A Coruña, A Coruña, Spain; 11Department of Cardiology, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 12Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; 13 Cardiac Department, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain; 14Municipal Clinical Hospital #17, Moscow, Russia; 15Center for Inherited Heart Disease, Stanford University Medical Center, Stanford, CA, USA; 16Yale New Haven Hospital, New Haven, CT, USA; 17Hospital das Clinicas da Univerisidade de Sao Paulo, Sao Paulo, Brazil; 18Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, MI, USA; 19Unidad de Cardiopatías Familiares, Servicio de Cardiología, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain; 20Gerencia Regional de Salud de Castilla y León (SACYL), Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; 21Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain; 22Unidad CSUR/ERN Cardiopatias Familiares, Hospital Universitario Puerta Hierro Majadahonda, Madrid, Spain; 23Unidad Cardiopatias Familiares, Hospital Universitario Son Llàtzer, Mallorca, Spain; 24Unidad Cardiopatias Familiares, Hospital Universitario y Politécnico La Fe, Valencia, Spain; 25Arrhythmia Section, Cardiology Department, Hospital Clínic, University of Barcelona, Barcelona, Spain; 26Institut d’Investigació August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 27Cardiac Department, Hospital San Pedro de Alcantara, Cáceres, Spain; 28Cardiac Department, Badajoz University Hospital, Badajoz, Spain; 29Dilemma Solution S.L, A Coruña, Spain; 30Unidad de Insuficiencia Cardiaca y Cardiopatías Familiares. Servicio de Cardiología, Hospital Universitario Virgen de la Victoria, IBIMA, Málaga, Spain; 31Cardiac Department, Hospital Vega Baja, Alicante, Spain; 32Unidad Cardiopatías Familiares, Hospital Universitario Virgen del Rocío, Sevilla, Spain; 33Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliana Isontina (ASUGI), University of Trieste, Trieste, Italy; 34Cardiac Department, Hospital Universitario Infanta Leonor, Madrid, Spain; 35Unidad Cardiopatías Familiares, Hospital General Universitario de Alicante, Alicante, Spain; 36City Hospital #51, Moscow, Russia; and 37Cardiac Department, Hospital Arquitecto Marcide, Ferrol, Spain Abstract Aims To describe the natural history of SARS-CoV-2 infection in patients with hypertrophic cardiomyopathy (HCM) com- pared with a control group and to identify predictors of adverse events. Methods and results Three hundred and five patients [age 56.6 ± 16.9 years old, 191 (62.6%) male patients] with HCM and SARS-Cov-2 infection were enrolled. The control group consisted of 91 131 infected individuals. Endpoints were (i) SARS-CoV-2 related mortality and (ii) severe clinical course [death or intensive care unit (ICU) admission]. New onset of atrial fibrillation, ventricular arrhythmias, shock, stroke, and cardiac arrest were also recorded. Sixty-nine (22.9%) HCM patients were hospital- ized for non-ICU level care, and 21 (7.0%) required ICU care. Seventeen (5.6%) died: eight (2.6%) of respiratory failure, four (1.3%) of heart failure, two (0.7%) suddenly, and three (1.0%) due to other SARS-CoV-2-related complications. Covariates as- sociated with mortality in the multivariable were age {odds ratio (OR) per 10 year increase 2.25 [95% confidence interval (CI): 1.12–4.51], P = 0.0229}, baseline New York Heart Association class [OR per one-unit increase 4.01 (95%CI: 1.75–9.20), © 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any me- dium, provided the original work is properly cited and is not used for commercial purposes. 2190 J.R. Gimeno et al. P = 0.0011], presence of left ventricular outflow tract obstruction [OR 5.59 (95%CI: 1.16–26.92), P = 0.0317], and left ventric- ular systolic impairment [OR 7.72 (95%CI: 1.20–49.79), P = 0.0316]. Controlling for age and sex and comparing HCM patients with a community-based SARS-CoV-2 cohort, the presence of HCM was associated with a borderline significant increased risk of mortality OR 1.70 (95%CI: 0.98–2.91, P = 0.0600). Conclusions Over one-fourth of HCM patients infected with SARS-Cov-2 required hospitalization, including 6% in an ICU set- ting. Age and cardiac features related to HCM, including baseline functional class, left ventricular outflow tract obstruction, and systolic impairment, conveyed increased risk of mortality. Keywords Hypertrophic cardiomyopathy; COVID-19; SARS-CoV-2 infection; Heart failure; Registry; Prognosis Received: 19 January 2022; Revised: 22 April 2022; Accepted: 27 April 2022 *Correspondence to: Juan R. Gimeno, Universidad de Murcia, Campus Ciencias de la Salud, Ctra Finca Buenavista s/n, El Palmar, Murcia 30120, Spain. Tel: +34 619068153; Fax: +34 968369558. Email: jgimeno@um.es Juan R. Gimeno and Iacopo Olivotto (as first authors) and Lorenzo Monserrat and Neal K. Lakdawala (as last authors) contributed equally. A complete list of the Investigators [on behalf of the Dilema International Cardiomyopathy and Heart Failure Registry and international SHaRe (Sarcomeric Human Cardiomyopathy Registry) Investigators group] is provided in Appendix S1. Introduction North America (n = 75), and South America (n = 48) were included. Centres were requested to report the full One of the characteristics of SARS-CoV-2 infection is the high spectrum of consecutive SARS-CoV-2 cases, from mild to variability of clinical presentation and outcome. Underlying severe, including outpatient and hospitalized individuals. cardiac disease, including heart failure (HF), is associated with Patients were enrolled over a 12 month period, from increased SARS-CoV-2-related mortality.1,2 To date, however, early in the SARS-CoV-2 pandemic, in February 2020 to 2 assessment of SARS-CoV-2 outcomes in specific causes of HF, February 2021. such as cardiomyopathies, is limited. The study was approved by each local Ethics Committee, Hypertrophic cardiomyopathy (HCM) is the most common and where required (in view of the anonymized, retrospec- inherited cardiac disease, with an estimated prevalence of 1 tive nature of the study), informed consent was obtained in 500 in the adult population.3,4 HF in HCM may be associ- prior to data collection. All diagnostic or therapeutic proce- ated with left ventricular outflow tract obstruction, diastolic dures were left to the discretion of the treating physician. A dysfunction, and less frequently, systolic dysfunction.5 More- dedicated online software was developed for the study over, atrial fibrillation and ventricular tachyarrhythmias are (Dilemma SL Solutions) in order to capture data in the desired an important source of morbidity and mortality.5,6 format and utilized at 79% of the sites. The prognosis of SARS-CoV-2 infection in HCM patients, who are often young and otherwise do not fulfil high-risk criteria for SARS-CoV-2-related outcomes, is unknown. This Patient population potentially includes predisposition to SARS-CoV-2-related complications as well as exacerbation of underlying cardiac The participating sites identified patients through regular disease. The relative rarity of HCM mandates multicentre query of the electronic medical records for the results of studies on a large scale to address this issue. Thus, in the SARS-CoV-2 infection and cross reference with active HCM present, dedicated registry, we aimed (i) to describe the nat- registries. This was supplemented by direct communication ural history of SARS-CoV-2 infection in patients with HCM to and from providers at the time of SARS-CoV-2 infection di- compared with a control group of SARS-CoV-2 individuals agnosis, and review of SARS-CoV-2 history at the time of over a 12 month period and (ii) to identify predictors of ad- scheduled and unscheduled clinical encounters. Contribution verse events in patients with HCM and SARS-CoV-2 infection. from participant centres is summarized in Supporting Infor- mation, Table S1. For the mortality analysis, a control group consisting of all Methods consecutive individuals diagnosed with SARS-CoV-2 infection in the Region of Murcia, Spain, from 8 March 2020 till 2 Registry design and patients February 2021 was obtained from the Subdirección General de Tecnologías de la Información of the Servicio Murciano We solicited participating centres to report all patients with de Salud.7 A total of 91 131 from a cohort of 96 394 SARS- a diagnosis of HCM3,4 and demonstration SARS-CoV-2 infec- CoV-2-infected individuals with available follow-up informa- tion by antigen or PCR tests. Selected centres were either tion up to 31 August 2021 were included in the registry. In established cardiomyopathy clinics or inherited cardiac dis- the control group, 1687 deaths were attributed or related ease units. A total of 29 centres from Europe (n = 182), to SARS-CoV-2 infection (1259 died during hospital ESC Heart Failure 2022; 9: 2189–2198 DOI: 10.1002/ehf2.13964 Impact of SARS-Cov-2 infection in patients with HCM 2191 admission), and 214 deaths were not attributed to SARS- Results Cov-2 infection. Baseline demographics and vital status, but not comorbidities and medications, were available for all Baseline characteristics of patients with HCM and control patients. SARS-CoV-2 infection A total of 305 patients (aged 56.6 ± 16.9 years old, 191 Clinical variables and outcomes [62.6%] male patients, 114 [37.4%] female patients) with prior HCM diagnosis developed SARS-Cov-2 infection. The Recorded variables included the care setting [outpatient, hos- majority of patients were White (274; 90.3%). Comorbidities pitalization, intensive care unit (ICU) admission], demo- were common: 120 (39.3%) had hypertension, 43 (14.1%) graphics, comorbidities (hypertension, diabetes, obesity, were diabetic, 42 (13.8%) were smokers, and 95 (31.1%) were smoking, coronary artery disease, chronic obstructive pulmo- obese. Of these 305, 90 (29.9%) were hospitalized, including nary disease), baseline HCM-related variables [rhythm, 69 (22.9%) receiving non-ICU level care and 21 (7.0%) treated presence of left ventricular outflow tract obstruction in an ICU (Table 1, Figure 1). (LVOTO) ≥ 30 mmHg, maximal left ventricular wall thickness Key baseline HCM characteristics included max LVWT (max LVWT), left ventricular ejection fraction (LVEF), arrhyth- 19.2 ± 4.9 mm, LVOTO in (23.3%) and prior history of parox- mias, and cardiac medications], and SARS-CoV-2-related char- ysmal, persistent, or permanent atrial fibrillation in 92 acteristics (symptoms, admission tests, diagnosis of pneumo- (33.1%). At baseline, most patients exhibited New York Heart nia, respiratory failure, medications, and outcome). Left Association (NYHA) class I functional status (n = 158, 57%) ventricular systolic dysfunction (LVSD) was defined by the prior to SARS-CoV-2 infection with 90 and 29 patients presence of LVEF < 55%. (32.5%, 10.4%) with NYHA II and III/IV effort intolerance, The following endpoints were assessed in the study: respectively. Cardiac medications prior to infection included 189 pa- 1 SARS-CoV-2-related mortality: death caused by or precipi- tients (62.0%) on beta-blockers, 71 (23.3%) on angiotensin II tated by SARS-CoV-2 infection. receptor blockers, 40 (13.1%) on angiotensin-converting en- 2 Severe clinical course: defined as SARS-CoV-2-related mor- zyme inhibitors, 76 (24.9%) on anticoagulation, and 82 tality or need for ICU admission. (26.9%) on loop diuretics. Incident HCM-related outcomes, including new onset of atrial In comparison with women, men with SARS-CoV-2 infec- fibrillation, ventricular arrhythmias, shock, stroke, and cardiac tion were younger (54.8 ± 15.0 vs. 58.6 ± 19.3 years old, arrest, were also recorded. P = 0.076), with less hypertension (65, 34.8% vs. 55, 49.1%, P = 0.014) and lower utilization of medications including beta-blockers (109, 58.3% vs. 77, 68.8%, P = 0.07), angioten- sin II receptor blockers (36, 19.3% vs. 34, 30.4%, P = 0.028) Statistical analysis and loop diuretics (39, 20.9% vs. 40, 35.7%, P = 0.0005) de- spite similar mean max LVWT, proportion of LVOTO, and Continuous variables were reported as mean ± SD. NYHA functional class at baseline. Among-group comparisons were made using a Student’s t- test or non-parametric test where appropriate. Categorical variables were reported as counts and percentages. Among-group comparisons 2 × 2 were made using a χ 2 test Outcomes or Fisher’s exact test if any expected cell count was less than five. Of the 90 HCM patients hospitalized with SARS-CoV-2 (Table A stepwise multivariable logistic regression analysis was 1), 29 (32.6%) developed a severe clinical course (defined as performed to analyse the relationship between patient char- death or ICU requirement) (Table S2). HCM patients with se- acteristics and mortality. We included all candidate covariates vere course more often developed pneumonia (22, 75.9% vs. and those with P < 0.10 in a univariate analysis. A signifi- 33, 54.1%, P = 0.048), acute respiratory distress (9, 31.0% vs. cance level of 0.1 was required to allow a variable into the 2, 3.3%, P = 0.0005), and shock (7, 24.1% vs. 0, 0.0%, model, and a significance level of 0.05 was required to stay P < 0.0001), compared with those without severe SARS- in the model. Annual rates together with their 95%CIs were CoV-2 infection. estimated. There were 17 (5.6%) HCM patients who died during or as A two-sided P value of <0.05 was considered as statisti- a consequence of SARS-Cov-2 infection. These were signifi- cally significant. All analyses were performed using SPSS cantly older compared with survivors (70.2 ± 10.9 vs. statistical software Version 24.0 (SPSS, Inc., Chicago, 55.4 ± 16.6 years old, P = 0.0003), had higher percentage of IL, USA). comorbidities including hypertension (11, 64.7% vs. 108, ESC Heart Failure 2022; 9: 2189–2198 DOI: 10.1002/ehf2.13964 2192 J.R. Gimeno et al. Table 1 Baseline characteristics of patients requiring hospitalization Outpatient Admission Total sig (P) n 211 (70.1) 90 (29.9) 301 (100) - Age 52.7 (16.9) 64.2 (13.1) 56.1 (16.7) <0.0001 Sex Female 80 (37.9) 31 (36.9) 111 (37.6) 0.9 Male 131 (62) 53 (63.1) 184 (62.4) 0.9 Registry Dilema 156 (73.9) 67 (74.4) 223 (74.1) 0.9 Share 55 (26.0) 23 (25.6) 78 (25.8) 0.9 Race Other or not reported 7 (3.3) 11 (12.2) 18 (6.0) - White 199 (94.3) 73 (81.1) 272 (90.3) 0.1 Black 3 (1.4) 6 (6.7) 9 (3.0) - Asian 2 (0.9) 0 (0) 2 (0.7) - a Care setting ICU level care 0 (0) 21 (23.3) 21 (7.0) <0.0001 HTN 70 (33.1) 48 (53.3) 118 (60.8) 0.001 Diabetes 24 (11.3) 19 (21.1) 43 (14.3) 0.027 CAD 2 (0.9) 3 (3.3) 5 (1.7) 0.16 Tobacco 31 (14.6) 11 (12.2) 42 (14.0) 0.6 COPD 15 (7.1) 9 (10.1) 24 (8.0) 0.4 BMI category Normal 69 (34.3) 15 (17.4) 84 (29.3) 0.004 Overweight 70 (34.8) 41 (47.7) 111 (38.7) 0.04 Obesity 62 (30.8) 30 (34.9) 92 (32.1) 0.5 NYHA class I 128 (64.6) 29 (37.2) 157 (56.9) - II 64 (32.3) 26 (33.3) 90 (32.6) - III 6 (3.1) 16 (20.5) 22 (8.0) - IV 0 (0) 7 (9.0) 7 (2.5) <0.0001 Beta-blocker 131 (62.1) 56 (62.2) 187 (62.1) 0.9 Loop diuretic 47 (22.2) 35 (38.9) 82 (27.2) 0.003 Anticoagulant 48 (22.7) 28 (31.1) 76 (25.2) 0.1 ACEi 24 (11.3) 14 (15.6) 38 (12.6) 0.3 ARB 47 (22.2) 24 (26.7) 71 (23.6) 0.4 ARNi 3 (1.4) 4 (4.4) 7 (2.3) 0.2 max LVWT 19.2 (5.1) 19.1 (4.4) 19.1 (4.8) 0.9 LVOT obstruction 60 (30.1) 31 (40.8) 91 (33.1) 0.09 LVEF % 65.4 (7.2) 62 (11.9) 64.4 (9.1) 0.016 LVEF interval <35% 0 (0) 6 (7.2) 6 (2.2) - 35–54% 4 (2.1) 7 (8.4) 11 (4.0) - ≥55% 186 (97.9) 70 (84.3) 256 (93.8) <0.0001 LVSD 4 (2.1) 13 (15.7) 17 (6.2) <0.0001 LVEDd 44.5 (7.7) 45.1 (8.3) 44.7 (7.8) 0.6 Rhythm Atrial fibrillation 43 (20.3) 28 (31.1) 71 (23.6) 0.045 Ventricular pacing 1 (0.4) 3 (3.3) 4 (1.3) 0.08 ACEi, angiotensin converter enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor/neprilysin inhibitor; BMI, body mass index; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; HTN, hypertension; ICU, intensive care unit; LVEDd, left ventricular end diastolic diameter (mm); LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; LVSD, left 2 ventricular systolic dysfunction (LVEF < 55%); obesity ≤ 30 kg/m ; overweight ≥ 25 and <30; max LWT: maximal left ventricular wall thick- ness (mm); NYHA class, New York Heart Association dyspnoea class. a Information on care setting (outpatient/hospitalization) was missing in four individuals. 37.6%, P = 0.026) and diabetes (6, 35.3% vs. 37, 12.9%, (two ICU patients and one outpatient), all in the context of P = 0.021) and were more frequently hospitalized (n = 17, new onset atrial fibrillation. None of the 34 patients with 100.0% vs. n = 71, 24.7%, P < 0.0001) (Table S3). They also an ICD (11.1%) had appropriate discharges. were symptomatically more limited at baseline (NYHA III–IV 9, 52.9% vs. 20, 6.9%, P < 0.0001) and with a higher fre- quency of prior atrial fibrillation (8, 47.1% vs. 62, 21.6%, Characteristics of HCM patients experiencing P = 0.032). Figure 2 presents the age and sex distribution of adverse outcomes patients with HCM who died of SARS-Cov-2. Out of the total 17 (5.6%) deaths, there were 4 (1.3%) due to HF, 2 (0.7%) Hospitalized patients were older (64.3 ± 13.2 vs. sudden deaths, and 1 (0.3%) other cardiac-related death. 52.7 ± 16.9 years, P < 0.0001) and had a higher burden of Eight (2.6%) died of respiratory failure and two (0.7%) from hypertension (47, 52.8% vs. 70, 33.2%, P = 0.001), diabetes other SARS-CoV-2-related complications. (19, 21.3% vs. 24, 11.4%, P = 0.02), and overweight or obesity Non-fatal HCM-related complications coincident with (70, 82.3% vs. 132, 65.6%, P = 0.005), compared with outpa- SARS-Cov-2 infection included atrial fibrillation and stroke, tients. Hospitalized patients were also more likely to have in nine patients (2.9%; including five outpatients, three ICU, NYHA III–IV effort intolerance (23, 29.9% vs. 6, 3.0%, and one non-ICU inpatient). There were three (1.0%) strokes P < 0.0001), treatment with loop diuretics (35, 39.3% vs. ESC Heart Failure 2022; 9: 2189–2198 DOI: 10.1002/ehf2.13964 Impact of SARS-Cov-2 infection in patients with HCM 2193 Figure 1 Distribution of the percentage of hypertrophic cardiomyopathy patients with SARS-Cov-2 regarding care setting (upper chart) and proportion of sex by care setting (lower chart). ICU, intensive care unit. Figure 2 Distribution of the number of patients with hypertrophic cardiomyopathy-related and SARS-CoV-2-related death by age interval and sex. 47, 22.3%, P = 0.002), or prior atrial fibrillation (28, 31.5% vs. Patients who required ICU stay or died had a higher per- 43, 20.4%, P = 0.039). Compared with HCM patients not re- centage of LVOTO (13, 59.1% vs. 19, 34.5%, P = 0.048) and quiring hospitalization, admitted patients had significantly baseline NYHA III–IV effort intolerance (14, 63.6% vs. 9, lower LVEF (62.0% ± 12.0% vs. 65.4% ± 7.3%, P = 0.018), al- 16.3%, P = 0.0002). The odds associated with risk factors though with similar max LVWT and proportion of LVOTO. for severe clinical course (ICU or hospital death) were ESC Heart Failure 2022; 9: 2189–2198 DOI: 10.1002/ehf2.13964 2194 J.R. Gimeno et al. Table 2 Multivariable analysis of the predictors of ICU admission and death Univariable Mutivariable ICU/Death OR sig. (P) OR sig. (P) Age (10) 1.65 (1.25–2.17) 0.0004 1.67 (1.00–2.78) 0.0483 Sex Male 1.1 (0.47–2.58) 0.8283 HTN 2.08 (0.96–4.50) 0.0631 Diabetes 3.22 (1.35–7.66) 0.0082 Tobacco 1 (0.33–3.05) 0.9954 COPD 0.83 (0.19–3.73) 0.8098 BMI category Overweight/Obese 6.29 (1.46–27.08) 0.0136 Obese 1.36 (0.61–3.01) 0.4503 NYHA class 5.53 (3.06–9.98) <0.0001 4.9 (2.40–10.02) <0.0001 Beta-blocker 1.38 (0.61–3.14) 0.4449 Loop diuretic 2.4 (1.10–5.25) 0.0281 Anticoagulant 1.17 (0.50–2.77) 0.7181 ACEi 1.17 (0.50–2.77) 0.4481 ARB 1.04 (0.43–2.55) 0.9310 ARNi 3.91 (0.72–21.13) 0.1131 max LVWT 1.04 (0.96–1.13) 0.3407 LVOT Obstruction 3.24 (1.33–7.9) 0.0097 3.18 (0.98–10.38) 0.0552 LVEF 0.93 (0.90–0.97) 0.0001 LVEF interval 0.22 (0.10–0.47) 0.0001 LVSD 7.8 (2.69–22.61) 0.0002 6.43 (0.96–43.06) 0.0551 LVEDd 1 (0.95–1.06) 0.9325 Rhythm Atrial fibrillation 1.57 (0.68–3.62) 0.2928 Univariable Mutivariable Death OR sig. (P) OR sig. (P) Age (10) 1.95 (1.33–2.87) 0.0007 2.25 (1.12–4.51) 0.0229 Sex Male 1.07 (1.03–1.11) 0.9943 HTN 3.04 (1.09–8.45) 0.0332 Diabetes 3.69 (1.29–10.56) 0.0152 Tobacco 1.36 (0.37–4.96) 0.6387 COPD 1.61 (0.35–7.48) 0.5460 BMI category Overweight/Obese 3.26 (0.73–14.57) 0.1221 Obese 1.15 (0.41–3.22) 0.7867 NYHA class 5.6 (2.82–11.13) <0.0001 4.01 (1.75–9.2) 0.0011 Beta-blocker 0.81 (0.30–2.19) 0.6785 Loop diuretic 3.36 (1.25–9.03) 0.0163 Anticoagulant 2.25 (0.83–6.15) 0.1123 ACEi 0.87 (0.19–3.97) 0.8613 ARB 1.01 (0.32–3.20) 0.9861 ARNi 7.52 (1.35–42.00) 0.0215 max LVWT 1.04 (0.94–1.15) 0.4568 LVOT obstruction 3.93 (1.28–12.08) 0.0171 5.59 (1.16–26.92) 0.0317 LVEF 0.94 (0.90–0.98) 0.0020 LVEF interval 0.25 (0.11–0.56) 0.0007 LVSD 8.57 (2.59–28.31) 0.0004 7.72 (1.20–49.79) 0.0316 LVEDd 1.02 (0.95–1.09) 0.6251 Rhythm Atrial fibrillation 3.23 (1.20–8.71) 0.0208 ACEi, angiotensin converter enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor/neprilysin inhibitor; BMI, body mass index; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; HTN, hypertension; ICU, intensive care unit; LVEDd, left ventricular end diastolic diameter (mm); LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; LVSD, left 2 ventricular systolic dysfunction (LVEF < 55%); obesity ≤ 30 kg/m ; overweight ≥ 25 and <30; max LWT: maximal left ventricular wall thick- ness (mm); NYHA class, New York Heart Association dyspnoea class. examined in univariate and multivariate models and are pre- [OR 6.43 (95%CI: 0.96–43.06), P = 0.0551] with severe clini- sented in Table 2. The only covariates associated with a se- cal course. vere COVID-19 course in the multivariable model were age Also presented in Table 2 were covariates associated with [OR per 10 year increase 1.67 (95%CI: 1.00–2.78), mortality. In the multivariable analysis, age [OR per 10 year P = 0.0483] and baseline NYHA class [OR per one-unit in- increase 2.25 (95%CI: 1.12–4.51), P = 0.0229], baseline NYHA crease 4.90 (95%CI: 2.40–10.02), P < 0.0001]. There was a class [OR per one-unit increase 4.01 (95%CI: 1.75–9.20), borderline significant relationship of both LVOTO [OR 3.18 P = 0.0011], LVOTO [OR 5.59 (95%CI: 1.16–26.92), (95%CI: 0.98–10.38), P = 0.0552] and systolic impairment P = 0.0317], and systolic impairment [OR 7.72 (95%CI: ESC Heart Failure 2022; 9: 2189–2198 DOI: 10.1002/ehf2.13964 Impact of SARS-Cov-2 infection in patients with HCM 2195 1.20–49.79), P = 0.0316] were all associated with increased pared with the control cohort. Mortality was 3.0-fold higher mortality. in the HCM cohort (n = 17 or 5.6% [95%CI: 4.97–6.22] vs. n = 1687 or 1.9% [95%CI: 1.87–1.90], P < 0.001) (Figure 3). In a multivariable model comparing death rates among Analysis of SARS-CoV-2-related mortality in HCM HCM and control patients, age [OR per 10 year increase vs. control population 3.46 (95%CI: 3.31–3.61), P < 0.0001] and male sex [OR 2.03 (95%CI: 1.82–2.27), P < 0.0001] were significantly associated We compared mortality among HCM patients to a contempo- with mortality (Table 3). The presence of HCM was associated rary cohort of 91 131 consecutive patients diagnosed with with borderline increase in mortality [OR 1.70 (95%CI: SARS-CoV-2 infection in the general population (mean age 0.98–2.91), P = 0.0600]. However, when the analysis was lim- 39.6 ± 21.8 years old, 47.5% male patients). There were ited to patients younger than 80 years, risk associated with a 7502 (8.2%) who required hospital admission and 1687 diagnosis of HCM became significant [OR 2.24 (95%CI: (1.9%) deaths. The time from SARS-CoV-2 diagnosis to death 1.21–4.12), P = 0.0099]. was 2.0 ± 2.6 months (median 0.80 months, [0.51, 2.29]). Although ascertainment methods differed, hospital admis- sions were almost four times more common in the HCM than control cohort (n = 91 or 29.8% vs. n = 7502 or 8.2%, Discussion P < 0.0001). HCM patients were older (56.6 ± 16.9 vs. 39.6 ± 21.8 years, P < 0.0001), more often male patients In this international study representing 29 centres, we have (n = 191 or 62.6% vs. n = 43 317 or 47.5%, P < 0.0001) com- prospectively examined the impact of SARS-CoV-2 infection Figure 3 Percentage of SARS-CoV-2-related death by age interval for patients with HCM and controls. HCM, hypertrophic cardiomyopathy. ESC Heart Failure 2022; 9: 2189–2198 DOI: 10.1002/ehf2.13964 2196 J.R. Gimeno et al. Table 3 HCM vs. control, age, and gender adjusted analysis of LVOTO may be crucial in HCM patients with clinical worsen- mortality ing in the context of SARS-CoV-2 infection. In obstructive pa- Death OR sig. (P) tients, management should include continuation of baseline Whole cohort medical therapy, if appropriate, associated with judicious Age (10) 3.46 (3.31–3.61) <0.0001 use of crystalloid infusion and vasopressors to prevent hemo- Sex (male) 2.03 (1.82–2.27) <0.0001 HCM vs. controls 1.70 (0.98–2.91) 0.0600 dynamic deterioration. Age ≤ 80 years old only Left ventricular systolic dysfunction is an adverse complica- Age (10) 3.59 (3.33–3.88) <0.0001 tion presenting in ~8% of HCM patients,5,8 associated with a Sex (male) 2.12 (1.80–2.50) <0.0001 HCM vs. controls 2.24 (1.21–4.12) 0.0099 substantial increase in risk of virtually all HCM-related com- plications (e.g. death, advanced HF, sudden death, and atrial HCM, hypertrophic cardiomyopathy; OR, odds ratio. fibrillation). In this context, it is not surprising that HCM patients with LVSD may incur increased risk of SARS-CoV-2- related death. In contrast to LVOTO, however, HF in these on patients with HCM. Advanced age and key markers of patients may be exacerbated by expansion of intravascular HCM disease severity—as can be obtained with by clinical volume. Moreover, in the event of septic shock, patients with history and echocardiogram—were associated with hospitali- systolic dysfunction may not be able to mount a compensa- zation, ICU admission, or death.2 In particular, for every class tory increase in cardiac output necessary to maintain tissue increase in NYHA functional state risk of death increased perfusion. Thus, the required strategy in these patients is nearly five-fold. LVSD and LVOTO were associated with 7.7- based on judicious diuresis and use of beta agonists in case fold and 5.6-fold increases in mortality, respectively. When of haemodynamic deterioration or shock. compared with a control cohort of individuals in the general Overall, the present findings are in keeping with recent re- population, the presence of HCM conferred a four-fold (2.4 ports that patients with cardiovascular comorbidities are adjusted by age and gender) higher likelihood of hospital ad- more likely to develop an adverse course due to SARS-Cov-2 mission and a three-fold (1.7 adjusted by age and gender) in- infection8–12 and support aggressive and systematic imple- crease in mortality, which was evident in all but the oldest pa- mentation of SARS-Cov-2 prophylaxis and management op- tients (>80 years). Overall, 5% of HCM patients in this series tions in HCM patients, particularly in the presence of died, which may have reflected an older cohort enriched with high-risk features. classes III–IV symptoms and relevant comorbidities. The ma- jority of the deaths were SARS-Cov-2 respiratory related, which may have been aggravated by underlying heart disease including, two patients who died suddenly. Incident atrial fi- Limitations brillation was the most common non-fatal HCM complication There are inherent limitations to retrospective studies based related to SARS-CoV-2 infection, affecting 3% of infected pa- on multicentre registries. The magnitude of the pandemic tients whereas ICD discharges were not observed. and subsequent lockdown led to heterogeneity of clinical data, due to differential access of patients to medical care de- pending on local policies. Data collection was based on the Characteristics of HCM patients experiencing interview of patients/relatives and the review of available adverse SARS-CoV-2 outcomes medical records. Although data collection was implemented homogeneously over a short time-course, there was not a Similar to studies conducted in the broader population, we standardized protocol of examinations at each participating identified that advanced age was a strong risk factor for ad- site. Standard COVID-19 outcomes scores could therefore verse SARS-CoV-2 outcomes. Specific to the HCM population, not be evaluated. we observed that traditional markers of disease severity, Similar to other published HCM studies, this cohort is pre- LVOTO, LVSD, and NYHA functional class, have poor prognos- dominantly middle age, White, and male with characteristic tic values.5 In the specific case of outflow tract obstruction, morphology and associated comorbidities. In addition, we adverse outcomes may be related to the dynamic changes cannot exclude a selection bias towards the most severe in loading conditions that accompany critical illness. A de- cases (admitted patients were more likely to be identified crease in preload related to diminished appetite, fever, or by their doctors/investigators). In this regard, the proportion other gastrointestinal symptoms, coupled with a decrease in of hospitalized patients in the centres with higher enrolment afterload due to the vasoplegia of sepsis could worsen the rate was 25.9%, while intermediate enrolment centres had a hemodynamic severity of LVOTO. In the setting of associated 42.9% and lower enrollers a 33.3%. Alternatively, HCM pa- pneumonia and critical illness, worsening LVOTO may precip- tients followed in specialty centres may have been more itate pulmonary oedema and further complicate acute respi- likely to be offered earlier admission through established ac- ratory failure. Thus, baseline assessment and monitoring of cess to specialty care. ESC Heart Failure 2022; 9: 2189–2198 DOI: 10.1002/ehf2.13964 Impact of SARS-Cov-2 infection in patients with HCM 2197 In contrast to general population series of SARS-CoV-2, Conflict of interest male sex and comorbidities were not predictors of adverse course or mortality in our study.13 However, our sample size Elias Grande, Carlos Peña, and Lorenzo Monserrat work for a is limited and there is no a priori reason to suspect these co- Dilemma SL company and made substantial contributions to variates are unimportant for patients with HCM. The control the study. They participated in development of the eCRF, in group might not be representative of the general population the revision, and in the approval of the manuscript. The rest SARS-CoV-2 mortality in other geographical areas. Impor- of the authors declared no conflict of interest. tantly, SARS-Cov-2 vaccination was not recorded. However, the impact of vaccination on our results is very low as enrol- ment finished just as vaccines became available, with less than 2% of the population fully vaccinated by the end of Funding study period. The project was funded by a grant from the Instituto de Salud Carlos III (ICSIII, COV20 00420). We should state that the SHaRe registry has been supported by an unrestricted grant Conclusions from MyoKardia/Bristol Myers Squibb. Patients with HCM and SARS-Cov-2 patients are more likely to require hospitalization and die, compared with the general Supporting information population, particularly in presence of older age, worse func- tional class, LVOTO, and systolic impairment. These data sug- Additional supporting information may be found online in the gest the need for aggressive and systematic implementation Supporting Information section at the end of the article. of prophylactic measures for SARS-Cov-2 in patients with inherited cardiac disease. Table S1. List of participating centres. Table S2. Characteristics of hospitalized patients with adverse clinical course (ICU admission or hospital death). Acknowledgements Table S3. Comparison of patients who survived to those who died. We want to thank all patients and their relatives for their col- Appendix S1. Full list of authors. laboration. A full list of the investigators of the SHaRe and Dilema registries is provided in Appendix S1. References 1. Guan WJ, Liang WH, Zhao Y, Liang HR, COVID-19. Clinical characteristics of tion. Contemporary definitions and clas- Chen ZS, Li YM, Liu XQ, Chen RC, Tang coronavirus disease 2019 in sification of the cardiomyopathies: an CL, Wang T, Ou CQ, Li L, Chen PY, Sang China. N Engl J Med. 2020; 382: American Heart Association scientific L, Wang W, Li JF, Li CC, Ou LM, Cheng 1708–1720. statement from the council on clinical B, Xiong S, Ni ZY, Xiang J, Hu Y, Liu L, 3. 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