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Original article
Impact of SARS-CoV-2 infection in patients with cardiac amyloidosis: Results of a multicentre registry
Impacto de la infección por SARS-CoV-2 en pacientes con amiloidosis cardiaca: resultados de un registro multicéntrico
José M. Larrañaga-Moreiraa,
Corresponding author
c.larranaga88@gmail.com

Corresponding author.
, Ana I. Rodriguez-Serranob,c, Fernando Domínguezc,d,e, Andrea Lalariof, Esther Zorioe,g,h, Roberto Barriales-Villaa,e, on behalf of the Dilemma International Cardiomyopathy, Heart Failure Registry Investigators Group
a Unidad de Cardiopatías Familiares, Instituto de Investigación Biomédica de A Coruña (INIBIC), Hospital Universitario de A Coruña (HUAC), Servizo Galego de Saúde (SERGAS), Universidade da Coruña (UDC), A Coruña, Spain
b Hospital Universitario Virgen de Arrixaca, Murcia. Spain
c European Reference Networks for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), Amsterdam, The Netherlands
d Unidad Cardiopatias Familiares, Hospital Universitario Puerta Hierro Majadahonda, IDIPHISA, Madrid, Spain
e Center for Biomedical Network Research on Cardiovascular Diseases (CIBERCV), Madrid, Spain
f Cardiovascular Department ‘Ospedali Riuniti’ and University of Trieste, Trieste, Italy
g Unidad Cardiopatías Familiares, Hospital Universitario y Politécnico La Fe, Valencia, Spain
h Instituto de Investigación Sanitaria La Fe, Valencia, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The severe acute respiratory syndrome coronavirus 2 &#40;SARS-CoV-2&#41; infection&#44; popularly known as the COVID-19&#44; has a great variability in clinical presentation and outcomes between individuals&#46; It has been described an adverse association between patient&#39;s pre-existing comorbidities such as cardiac disease &#40;including heart failure &#91;HF&#93;&#41;&#44; with SARS-CoV-2 related mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">1&#44;2</span></a> However&#44; different causes of HF could carry different SARS-CoV-2 infection prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Cardiac amyloidosis &#40;CA&#41; is a progressive infiltrative disease caused by the deposit of amyloid fibrils in the heart&#46; Most of CA cases are caused by the deposit of monoclonal immunoglobulin light chains &#40;AL&#41; or transthyretin &#40;ATTR&#41;&#44; that could be hereditary &#40;&#8220;variant&#8221;&#44; ATTRv&#41; or acquired &#40;&#8220;wild-type&#8221;&#44; ATTRwt&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">4</span></a> Nowadays&#44; it is acknowledged that CA is a more frequent disease than traditionally considered&#44; mostly due to an improved diagnosis of ATTRwt&#44; now the most common form of CA&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">5&#44;6</span></a> The prevalence of ATTRwt increases with age and it has been found in 10&#37;&#8211;16&#37; of patients with preserved HF or aortic stenosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">4&#44;7&#44;8</span></a> Amyloid deposition in the heart causes an increase in left ventricular mass&#44; diastolic dysfunction with evolution to restrictive filling and systolic dysfunction in an advanced phase&#46; Moreover&#44; amyloidosis is a systemic disease so deposits are not limited to the heart and could happen in other organs&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">CA patients with SARS-CoV-2 infection are likely to have worse outcomes<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">9</span></a> and an excess of mortality was described in amyloid patients in early pandemic years&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">10</span></a> The relative rarity of CA mandates a multicentre study on a large scale to adequately examine outcomes associated with COVID-19&#46; Thus&#44; the primary aim of the registry was to describe the short and intermediate term natural history of SARS-CoV-2 infection in patients with CA in early pandemic and to compare it to a control group&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Registry design and patients</span><p id="par0020" class="elsevierStylePara elsevierViewall">Inclusion criteria were prior diagnosis of CA and demonstration of SARS-CoV-2 infection by antigen or polymerase chain reaction tests&#46; Participating centres were selected based on an established cardiomyopathy clinic and&#47;or inherited cardiac disease unit&#46; There was a total of 11 centres from Spain &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;&#44; Italy &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41; and Russia &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41; reporting CA cases&#46; Patients were consecutively enrolled over a 14-month period&#44; from early in the SARS-CoV-2 pandemic in March 2020&#44; to the last patient included on 12th May 2021&#46; The full spectrum of SARS-CoV-2 cases&#44; from mild to severe&#44; including outpatient and hospitalized individuals&#44; was enrolled&#46; Last follow-up data was also collected&#46; Because of the retrospective design of the registry&#44; only unvaccinated patients against SARS-CoV-2 were included to maintain homogeneity into the cohort&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The study was approved by each local Ethics Committee and informed consent was obtained prior to data collection&#46; All diagnostic or therapeutic procedures were left to the discretion of the attending physician&#46; A dedicated on-line software was developed for the study &#40;Dilemma Solutions SL&#41; to capture data in the desired format&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Patient population</span><p id="par0030" class="elsevierStylePara elsevierViewall">The participating sites identified patients with CA and SARS-CoV-2 infection through regular query of the electronic medical records using available local cardiomyopathy registries&#46; This was supplemented by direct communication to and from providers at the time of SARS-CoV-2 infection diagnosis&#44; and review of SARS-CoV-2 history at the time of scheduled and unscheduled clinical encounters&#46; Contribution from participants centres is summarized in <a class="elsevierStyleCrossRef" href="#sec0090">supplementary online Table 1</a>&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">A control group consisting of all consecutive individuals with 40 years-old or older diagnosed with SARS-CoV-2 infection in the Region of Murcia&#44; Spain from 8th March 2020 till 12th of May 2021 was obtained from the Subdirecci&#243;n General de Tecnolog&#237;as de la Informaci&#243;n of the Servicio Murciano de Salud&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">11</span></a> Baseline demographics and vital status&#44; but not comorbidities and medications&#44; were available for all control patients&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Clinical variables and outcomes</span><p id="par0040" class="elsevierStylePara elsevierViewall">Recorded variables included the type of amyloidosis&#44; demographics&#44; cardiovascular risk factors &#40;hypertension&#44; diabetes&#44; obesity&#44; smoking&#41;&#44; comorbidities &#91;coronary artery disease&#44; chronic obstructive pulmonary disease &#40;COPD&#41;&#44; chronic kidney disease &#40;CKD&#41;&#44; stroke&#93;&#44; baseline cardiac related variables &#91;rhythm&#44; maximal left ventricular wall thickness &#40;LVWT&#41;&#44; left ventricular ejection fraction &#40;LVEF&#41; and type of HF&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">12</span></a> New York Heart Association &#40;NYHA&#41; Class&#44; pulmonary hypertension&#44; cardiac medications&#93;&#44; SARS-CoV-2 related characteristics &#40;care setting&#44; symptoms&#44; admission tests&#44; diagnosis of pneumonia&#44; medications&#41; and outcome&#46; The following endpoints were assessed in the study&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0045" class="elsevierStylePara elsevierViewall">SARS-CoV-2 related mortality&#58; death caused by or precipitated by SARS-CoV-2 infection &#40;occurring as direct consequence of the infection or death in less than 30 days since diagnosis&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0050" class="elsevierStylePara elsevierViewall">Severe clinical course&#58; defined as SARS-CoV-2 related mortality or need for intensive care unit &#40;ICU&#41; admission&#46;</p></li></ul></p><p id="par0055" class="elsevierStylePara elsevierViewall">Incident CA related outcomes&#44; including new onset of atrial fibrillation&#44; ventricular arrhythmias&#44; cardiogenic shock&#44; and stroke&#44; were collected&#46; Vital status at last follow-up was also recorded&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">Continuous variables were tested for normality using Shapiro&#8211;Walk test and were reported as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation &#40;SD&#41; if their distribution was normal and as median<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>interquartile range &#40;IQR&#41; if it was not normal&#46; Among-group comparisons were made using a t-student or non-parametric test where appropriate&#46; Categorical variables were reported as counts and percentages&#46; Among-group comparisons 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 were made using a chi-square test or Fisher&#39;s exact test if any expected cell count was less than five&#46; For comparison between CA and control group&#44; multivariable logistic regression was performed&#44; including age and sex as potential confounding variables&#46; A two-sided <span class="elsevierStyleItalic">p</span>-value of &#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 was considered as statistically significant&#46; All analyses were performed using Stata software version 14&#46;2 &#40;StataCorp LCC&#44; College Station&#44; TX&#44; USA&#41;&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Baseline characteristics of the CA cohort with SARS-CoV-2 infection</span><p id="par0065" class="elsevierStylePara elsevierViewall">A total of 41 patients &#91;aged 77&#46;4 &#40;IQR 70&#46;6&#8211;83&#46;2&#41; years old&#44; 34 &#40;82&#46;9&#37;&#41; males&#44; 7 &#40;17&#46;1&#37;&#41; females&#93; with prior CA experiencing SARS-CoV-2 infection were enrolled &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Twenty-five &#40;61&#37;&#41; had ATTRwt&#44; 8 &#40;19&#46;5&#37;&#41; had ATTRv and 8 &#40;19&#46;5&#37;&#41; had AL&#46; Patients with ATTRwt were older when compared to other CA patients &#40;80&#46;4 vs&#46; 68&#46;5 years-old&#44; <span class="elsevierStyleItalic">p</span> &#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Within the ATTRv cohort&#44; the most common variant found in the <span class="elsevierStyleItalic">TTR</span> gene was p&#46;Val142Ile &#40;3&#44; 37&#46;5&#37;&#41;&#59; the other variants in this cohort were p&#46;Ser43Asn&#44; p&#46;Val50Met&#44; p&#46;Ser97Tyr&#44; p&#46;Glu109Gln and p&#46;Glu112Lys&#46; Comorbidities and cardiovascular risk factors associated were common&#58; 56&#46;1&#37; had overweight or obesity&#44; 51&#46;2&#37; patients had prior arterial hypertension&#44; 36&#46;6&#37; were smokers and 26&#46;8&#37; were diabetic&#46; In total&#44; 70&#46;7&#37; patients had any cardiovascular risk factor&#44; and 56&#46;1&#37; had other comorbidities&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Key baseline cardiac characteristics included LVEF of 52&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;7&#37; and a maximal LVWT of 17&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;9<span class="elsevierStyleHsp" style=""></span>mm&#46; There was a high rate of patients with atrial fibrillation &#40;58&#46;5&#37;&#41; and pacemaker &#40;26&#46;8&#37;&#41;&#46; Prior to SARS-CoV-2 infection&#44; most patients &#40;53&#46;7&#37;&#41; exhibited NYHA class II functional status&#44; 31&#46;7&#37; were in class III&#47;IV and only 14&#46;6&#37; were in class I&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Cardiac medications prior to infection included 80&#46;5&#37; patients on a loop diuretic&#44; 53&#46;7&#37; on anticoagulation&#44; 34&#46;2&#37; patients on beta-blockers and 24&#46;4&#37; on angiotensin converting enzyme inhibitor&#47;angiotensin II receptor blocker&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Finally&#44; there were not significant differences in basal characteristics between men and women &#40;<a class="elsevierStyleCrossRef" href="#sec0090">supplementary online Table 2</a>&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Outcomes</span><p id="par0085" class="elsevierStylePara elsevierViewall">Most CA patients with SARS-CoV-2 were hospitalized &#40;73&#46;2&#37;&#41;&#44; the rest were outpatients with 2&#46;4&#37; of patients needing emergency department evaluation without requiring hospital admission &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Of those hospitalized&#44; 12 &#40;40&#37;&#41; developed a severe clinical course &#40;defined as requiring ICU care and&#47;or death&#41;&#46; Hospitalized patients had a median age of 78 years-old&#44; high prevalence of cardiovascular risk factors &#40;73&#46;3&#37;&#41; and other comorbidities &#40;63&#46;3&#37;&#41;&#44; and significantly more HF symptoms &#40;NYHA Class II or more in 93&#46;3&#37; hospitalized vs&#46; 63&#46;6&#37; outpatients&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41;&#46; They had significantly more SARS-CoV-2 related pneumonia &#40;70&#37; vs&#46; 0&#37;&#44; <span class="elsevierStyleItalic">p</span> &#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and acute heart failure &#40;56&#46;7&#37; vs&#46; 9&#46;1&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;011&#41; than patients managed on an outpatient basis&#46; There were not statistically significant differences in the remaining characteristics between hospitalized and non-hospitalized patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">There were ten CA patients with SARS-CoV-2 related mortality &#40;24&#46;4&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Five deaths were due to SARS-CoV-2 pneumonia&#44; two refractory HF&#44; one respiratory failure&#44; one sudden cardiac death and one died at home after palliative care was decided &#40;<a class="elsevierStyleCrossRef" href="#sec0090">supplementary online Table 3</a>&#41;&#46; Median age of the deceased patients was 80&#46;9 years old&#44; and they had high rate of cardiovascular risk factors &#40;90&#37;&#41; and comorbidities &#40;70&#37;&#41;&#46; Atrial fibrillation &#40;80&#37;&#41; and preserved LVEF &#40;70&#37;&#41; were common&#44; and all of them were in NYHA Class II or higher&#46; Those who died were commonly hospitalized &#40;90&#37;&#41; and most of them developed pneumonia &#40;70&#37;&#41; and acute heart failure &#40;70&#37;&#41;&#46; Among those patients&#44; 70&#37; received any SARS-CoV-2 treatment and they had significantly less lymphocytes than survivors &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;039&#41;&#46; There were not significant differences regarding other basal characteristics or laboratory parameters &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">A total of thirteen patients had a severe clinical course &#40;31&#46;7&#37;&#41; <span class="elsevierStyleBold">&#40;</span><a class="elsevierStyleCrossRef" href="#sec0090">supplementary online Table 4</a>&#41;&#46; Of three ICU admissions&#44; two were AL patients with 62&#46;1 and 69&#46;5 years-old&#44; and one 76 years-old ATTRwt patient&#46; Patients with a severe clinical course had high rates of CKD &#40;53&#46;9&#37;&#41; and overweight&#47;obesity &#40;76&#46;9&#37;&#41;&#46; Acute heart failure was significantly more common in those &#40;69&#46;2&#37; vs&#46; 32&#46;1&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;043&#41;&#46; Finally&#44; ferritin values were significantly higher in this group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41;&#46; No significant differences were found regarding other basal characteristics&#44; prior medications&#44; or laboratory parameters&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Non-fatal CA related complications coincident with SARS-CoV-2 infection included atrial fibrillation in 2 patients &#40;7&#46;4&#37;&#41; and stroke in 1 patient &#40;4&#46;6&#37;&#41; of the cohort&#46; There were not ventricular arrythmias in CA patients&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Mean follow-up time of discharged patients was 311 days &#40;range 42&#8211;588 days&#41;&#46; At the end of follow-up&#44; there were 7 additional deaths apparently not related to SARS-CoV-2 infection &#40;<a class="elsevierStyleCrossRef" href="#sec0090">supplementary online Table 3</a>&#41;&#46; Of those&#44; 6 patients were males&#44; 4 of them with ATTRwt&#44; &#62;<span class="elsevierStyleHsp" style=""></span>80 years old and LVEF &#60;<span class="elsevierStyleHsp" style=""></span>50&#37;&#59; one of which was followed in an outpatient basis and suffered sudden cardiac death at home 42 days after the infection&#46; Other three patients died of sepsis&#44; refractory HF&#44; and subdural haematoma&#44; respectively&#44; which happened several months after the SARS-CoV-2 infection&#46; Other 2 male patients had AL and died of cancer related complications&#46; Finally&#44; the remaining death was an elderly female patient with ATTRwt who died of severe acute anaemia months later&#46; Overall&#44; 41&#46;5&#37; of our cohort had died at the end of follow-up&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Comparison of SARS-CoV-2 infection in CA vs&#46; control population</span><p id="par0110" class="elsevierStylePara elsevierViewall">We compared mortality among CA patients to a contemporary cohort of 49&#44;773 consecutive patients of the same age intervals diagnosed with SARS-CoV-2 infection in the general population&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">CA patients had a higher frequency of men &#40;82&#46;9&#37; vs&#46; 46&#46;9&#37;&#44; <span class="elsevierStyleItalic">p</span> &#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and were older &#40;mean age 75&#46;7 vs&#46; 57&#46;7 years-old&#44; <span class="elsevierStyleItalic">p</span> &#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; compared to the control cohort&#46; Age and male sex were associated in univariable analysis with SARS-CoV-2 hospitalization and mortality <span class="elsevierStyleBold">&#40;</span><a class="elsevierStyleCrossRefs" href="#tbl0015">Tables 3 and 4</a><span class="elsevierStyleBold">&#41;&#46;</span> In a multivariable model adjusted by sex and age&#44; hospital admissions were significantly more common in the CA group than the control cohort &#91;OR 6&#46;23 &#40;3&#46;05&#8211;12&#46;74&#41;&#44; <span class="elsevierStyleItalic">p</span> &#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#93;&#46; CA patients also had significantly higher SARS-CoV-2 related adjusted mortality than control cohort &#91;OR 2&#46;18 &#40;1&#46;01&#8211;4&#46;68&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;047&#93; &#40;<a class="elsevierStyleCrossRefs" href="#tbl0015">Tables 3 and 4</a>&#41;&#46; However&#44; when considering only hospitalized patients&#44; age &#91;OR 1&#46;096 &#40;1&#46;09&#8211;1&#46;102&#41; per year&#44; <span class="elsevierStyleItalic">p</span> &#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#93; and male sex &#91;OR 1&#46;55 &#40;1&#46;36&#8211;1&#46;78&#41;&#44; <span class="elsevierStyleItalic">p</span> &#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#93; were independent predictors of mortality&#44; but not CA diagnosis &#91;OR 0&#46;98 &#40;0&#46;43-2&#46;21&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;959&#93;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">In this multicentre study&#44; we have examined the impact of SARS-CoV-2 infection in early pandemic on patients with CA&#46; A vast majority of patients were hospitalized and there were high rates of severe clinical course&#44; with almost one quarter of CA patients dying because of COVID-19 in the first month after diagnosis&#46; This finding could reflect an older population&#44; which was expected due to the epidemiology of CA&#44; specially ATTRwt&#44; which was the most common CA in our cohort&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">4&#44;5&#44;13</span></a> However&#44; when compared to a control cohort&#44; risks of hospitalization and mortality were 6&#46;2 and 2&#46;2 respectively higher in CA patients after adjustment by age and sex &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; Although there were not differences in mortality when considering only hospitalized patients&#44; it is known that hospitalized patients from general population had high rates of comorbidities that put them at high risk of mortality like CA group&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">1&#44;2</span></a> CA patients were anticipated to be at high risk of complications and death from SARS-CoV-2 infection<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">9</span></a> and a recently published study showed that in early pandemic years there were an excess of mortality in amyloidosis patients&#44; likely reflecting high COVID-19 related mortality in this group&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">10</span></a> These patients have limited cardiac reserve and elevated pulmonary vascular resistances&#44; so SARS-CoV-2 infection would be poorly tolerated&#44; with an increased risk for lower cardiac output and pulmonary oedema which can further worsen respiratory failure&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">9</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">It is worth to comment that&#44; despite high hospitalization and mortality rates&#44; only 7&#46;3&#37; patients were admitted to ICU&#46; This is likely to reflect a conservative approach in early pandemic when managing elderly patients with ATTRwt due to the perception that poor outcomes were inevitable for those specially in a time of shortage of resources&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">9</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">In our cohort&#44; 50&#37; of AL patients had the combined endpoint of ICU or death and 25&#37; died as consequence of COVID-19&#46; In this sense&#44; it is known that AL patients have poorer prognosis than other CA patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">6&#44;14</span></a> Despite the anticipated worse clinical evolution&#44; AL patients are younger and therefore it is more likely that those are considered for ICU admission in the case of severe clinical course&#46; There was prior concern regarding the vulnerability of AL patients with SARS-CoV-2 infection&#44; which commonly have multisystemic involvement and usually need to receive chemotherapeutic agents with or without autologous stem cell transplant&#44; whose immunosuppression probably increases infection risk&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">15</span></a> A recent small observational study that included 13 AL patients with COVID-19&#44; also showed that those patients have high mortality &#40;23&#37;&#41;&#44; all of them with cardiac involvement&#44; which was an independent predictor of mortality in this study&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">14</span></a> Of note&#44; this study also included vaccinated patients and there were no deceased patients in this group&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">14</span></a> Our data supports that AL patients are at high risk and strict monitorization of those should be carried out&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">We have also found that higher NYHA Classes are associated with hospitalization&#44; and that presence of acute heart failure predicts severe clinical course&#46; Patients with CA usually have preserved or mildly depressed LVEF and they could have advanced HF because of severe diastolic dysfunction&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">5&#44;6</span></a> Thus&#44; ICU or death only happened in symptomatic patients before SARS-CoV-2 infection &#40;NYHA Class II or higher&#41;&#44; likely reflecting advanced disease&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">CA patients with lymphopenia are at high risk of SARS-CoV-2 infection related death&#46; Presence of lymphopenia was independent of the type of amyloidosis&#46; Those findings are in accordance with prior literature that found that lymphopenia on admission was associated with poorer outcome in those patients&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">16</span></a> Although its mechanism is still unclear&#44; it has been hypothesized that either the expression of ACE2 receptor in lymphocytes or the increase in proinflammatory cytokines could lead to lymphopenia in the context of SARS-CoV-2 infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">16&#44;17</span></a> Finally&#44; higher levels of ferritin were also associated with ICU admission or death&#44; which is in accordance prior literature reflecting a more severe inflammatory syndrome and that is also associated with lymphopenia&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">17&#44;18</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">In our CA cohort&#44; we did not find significant differences regarding to cardiovascular risk factors or comorbidities&#46; This is likely related to limitations on sample size&#46; In fact&#44; like studies conducted in general population&#44;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">1&#44;2</span></a> there was a trend showing that advanced age &#40;&#8805;80 years-old&#41; and BMI could be related to SARS-CoV-2 mortality&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Finally&#44; there was a high rate of mortality not-related to SARS-CoV-2 infection over a median follow-up of over 10 months&#44; which is in accordance with the poor prognosis of CA patients&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">6</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The present study is in keeping with the published literature which has suggested that patients with cardiovascular comorbidities and heart conditions are more likely to develop an adverse course SARS-CoV-2 infection&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> We have expanded upon prior findings by describing that CA patients had significant worse prognosis than other patients&#46; It has been described that vaccinated amyloidosis patients are still at risk of complications but with low death rates in this group&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">10&#44;14</span></a> Thus&#44; careful preventive measures should be carried in CA patients to prevent infection&#44; including use of vaccination&#44; booster vaccine doses&#44; masks&#44; and avoiding exposure to other infected patients&#46; Unvaccinated CA patients with COVID-19 disease are at high risk of death &#40;&#8776;25&#37;&#41; so careful monitoring in a dedicated setting and specific treatment should be initiated at the minimum sign of respiratory or haemodynamic decompensation&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">There are inherent limitations to this type of studies based on multicentre registries&#46; The magnitude of the pandemic and the isolation and lockdown measurements to avoid spreading of the SARS-CoV-2&#44; had led to heterogenicity of clinical data&#44; without a unified protocol of examinations&#46; Access to blood tests for outpatients and clinical evaluations of very severe cases were difficult to obtain&#46; Completeness of the data collection was based on the interview of patients&#47;relatives and the review of available medical records&#46; Importantly&#44; because of the rarity of the CA&#44; there are obvious limitations on sample size that reduced the power of our analysis&#46; Besides&#44; there might be a selection bias towards the most severe cases &#40;those were more likely to be identified by their doctors&#47;investigators&#44; while mildly symptomatic patients could be underdiagnosed&#41;&#44; although this limitation also applies for the control group&#46; We did not have information on comorbidities of the control cohort so we could not adjust for those in the comparison analysis&#44; which could limit interpretation of our results&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Finally&#44; we cannot rule out that new SARS-CoV-2 strains or infection in vaccinated CA patients could have different prognosis&#44; so our results should not be extrapolated to those cohorts&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conclusions</span><p id="par0170" class="elsevierStylePara elsevierViewall">CA patients with SARS-CoV-2 infection are at high risk of hospitalization and mortality&#44; which exceed that expected by their sex and advanced age&#46; Preventive measures should be implemented to reduce their risk of infection and close monitoring of those infected must be undertaken to reduce the risk of death&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Ethical considerations</span><p id="par0175" class="elsevierStylePara elsevierViewall">The study was approved by each local Ethics Committee and informed consent was obtained prior to data collection&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Author&#39;s contributions</span><p id="par0180" class="elsevierStylePara elsevierViewall">J&#46;M&#46; Larra&#241;aga-Moreira&#44; A&#46;I&#46; Rodriguez-Serrano&#44; J&#46;R&#46; Gimeno-Blanes and R&#46; Barriales-Villa conceived and designed the study&#46; C&#46; Pe&#241;a-Gil&#46; and L&#46; Monserrat participated in the design of the study&#44; built&#44; and maintained the database&#46; J&#46;M&#46; Larra&#241;aga-Moreira collected clinical data&#44; performed the statistical analysis&#44; and drafted the manuscript&#46; A&#46;I&#46; Rodriguez-Serrano&#44; F&#46; Hern&#225;ndez-Terciado&#44; A&#46; Lalario&#44; C&#46; G&#243;mez-Gonz&#225;lez&#44; L&#46; Tojal-Sierra&#44; T&#46; Ripoll-Vera&#44; E&#46; Zorio&#44; E&#46; Villacorta&#44; O&#46; Chumakova&#44; D&#46; Vaqueriza-Cubillo&#44; M&#46; Gallego-Delgado&#44; J&#46;C&#46; S&#225;nchez-Mart&#237;nez&#44; F&#46; Dom&#237;nguez&#44; M&#46; Merlo&#44; M&#46;A&#46; Espinosa-Castro&#44; G&#46; Sinagra and P&#46; Garc&#237;a-Pavia collected clinical data&#46; A&#46;I&#46; Rodriguez-Serrano&#44; E&#46; Zorio&#44; E&#46; Villacorta&#44; F&#46; Dominguez&#44; M&#46; Merlo&#44; J&#46;R&#46; Gimeno-Blanes and R&#46; Barriales-Villa revised the manuscript critically&#46; All authors approved the final version to be published&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Funding</span><p id="par0185" class="elsevierStylePara elsevierViewall">The project was funded by a grand of the <span class="elsevierStyleGrantSponsor" id="gs1">Instituto de Salud Carlos III</span> &#40;ISCIII&#41; through grants COV20 00420 and <span class="elsevierStyleGrantNumber" refid="gs1">PI20&#47;1379</span>&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflict of interest</span><p id="par0190" class="elsevierStylePara elsevierViewall">Carlos Pe&#241;a&#44; and Lorenzo Monserrat work for Dilemma Solutions SL company and made substantial contributions to the study&#46; They participated in development of the eCRF&#44; in the revision&#44; and in the approval of the manuscript&#46; The rest of the authors declared no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Materials and methods"
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            0 => array:2 [
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              "titulo" => "Registry design and patients"
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              "titulo" => "Patient population"
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              "titulo" => "Clinical variables and outcomes"
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              "titulo" => "Statistical analysis"
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          "titulo" => "Results"
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            0 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Baseline characteristics of the CA cohort with SARS-CoV-2 infection"
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              "identificador" => "sec0045"
              "titulo" => "Outcomes"
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              "identificador" => "sec0050"
              "titulo" => "Comparison of SARS-CoV-2 infection in CA vs&#46; control population"
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          "titulo" => "Discussion"
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          "titulo" => "Ethical considerations"
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          "identificador" => "sec0070"
          "titulo" => "Author&#39;s contributions"
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          "identificador" => "sec0075"
          "titulo" => "Funding"
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          "titulo" => "References"
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    "fechaRecibido" => "2023-03-07"
    "fechaAceptado" => "2023-06-24"
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1731705"
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            0 => "Cardiac amyloidosis"
            1 => "COVID-19"
            2 => "Heart failure"
            3 => "Prognosis"
            4 => "Registries"
            5 => "SARS-CoV-2 infection"
          ]
        ]
        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec1731706"
          "palabras" => array:19 [
            0 => "AL"
            1 => "ATTR"
            2 => "ATTRv"
            3 => "ATTRwt"
            4 => "BMI"
            5 => "CA"
            6 => "COPD"
            7 => "ED"
            8 => "HF"
            9 => "HFpEF"
            10 => "HFmEF"
            11 => "HFrEF"
            12 => "ICU"
            13 => "IQR"
            14 => "LVEF"
            15 => "LVWT"
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          "palabras" => array:6 [
            0 => "Amiloidosis card&#237;aca"
            1 => "COVID-19"
            2 => "Insuficiencia card&#237;aca"
            3 => "Pron&#243;stico"
            4 => "Registro"
            5 => "Infecci&#243;n por SARS-CoV-2"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Descriptions on impact of SARS-CoV-2 infection in patients with cardiac amyloidosis &#40;CA&#41; are lacking&#46; Our aim was to describe the prognosis of those patients&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Retrospective observational study of unvaccinated patients with CA who developed SARS-CoV-2 infection enrolled in eleven centres &#40;March 2020 to May 2021&#41;&#46; Descriptive analysis of basal characteristics&#44; hospitalization&#44; mortality&#44; and severe clinical course was performed&#46; Comparisons to a population-based control group were made&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Forty-one patients were identified&#46; Most patients had wild-type transthyretin CA &#40;61&#37;&#41; and were on NYHA Class II&#8211;III &#40;80&#46;5&#37;&#41;&#46; CA patients were commonly hospitalized &#40;73&#46;2&#37;&#41; and those were more symptomatic than outpatients &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41;&#46; The 24&#46;4&#37; of CA patients died as consequence of SARS-CoV-2 infection&#46; Patients with CA had an increased risk of hospitalization &#91;OR 6&#46;23 &#40;3&#46;05&#8211;12&#46;74&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#93; and mortality &#91;OR 2&#46;18 &#40;1&#46;01&#8211;4&#46;68&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;047&#93; when compared to control population after adjustment by age and sex&#46; After a medium follow-time of 311 days&#44; 41&#46;5&#37; of the CA cohort died&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">SARS-CoV-2 infection is associated with high mortality and hospitalization rates in patients with CA&#44; which exceed that expected by their sex and advanced age&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0005"
            "titulo" => "Background"
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            "identificador" => "abst0010"
            "titulo" => "Methods"
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            "identificador" => "abst0015"
            "titulo" => "Results"
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            "identificador" => "abst0020"
            "titulo" => "Conclusions"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El impacto de la infecci&#243;n por SARS-CoV-2 en pacientes con amiloidosis card&#237;aca &#40;AC&#41; es desconocido&#46; El principal objetivo de este estudio es describir el pron&#243;stico de estos pacientes&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional retrospectivo de pacientes con AC no vacunados que desarrollaron infecci&#243;n por SARS-CoV-2 identificados en 11 centros &#40;marzo 2020&#47;mayo 2021&#41;&#46; Se realiza un an&#225;lisis descriptivo de caracter&#237;sticas basales&#44; hospitalizaci&#243;n&#44; mortalidad y curso cl&#237;nico grave&#44; y se comparan los resultados con una cohorte poblacional&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Cuarenta y un pacientes fueron identificados&#46; La mayor&#237;a eran AC por transtirretina <span class="elsevierStyleItalic">wild-type</span> &#40;61&#37;&#41; y estaban en clase NYHA II-III &#40;80&#44;5&#37;&#41;&#46; La mayor&#237;a de los pacientes fueron hospitalizados &#40;73&#44;2&#37;&#41;&#44; los cuales ten&#237;an peor clase funcional que los ambulatorios &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;035&#41;&#46; El 24&#44;4&#37; de los pacientes fallecieron como consecuencia de la infecci&#243;n&#46; Los pacientes con AC ten&#237;an un mayor riesgo de hospitalizaci&#243;n &#40;OR&#58; 6&#44;23&#59; 3&#46;05-12&#46;74&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; y fallecimiento &#40;OR&#58; 2&#44;18&#59; 1&#44;01-4&#44;68&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;047&#41; que la cohorte poblacional tras ajuste por sexo y edad&#46; Tras un seguimiento medio de 311 d&#237;as&#44; el 41&#44;5&#37; de los pacientes fallecieron&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La infecci&#243;n por SARS-CoV-2 presenta alto riesgo de mortalidad y hospitalizaci&#243;n en pacientes con AC&#44; mayor que la esperada por su sexo y edad&#46;</p></span>"
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            "apendice" => "<p id="par0195" class="elsevierStylePara elsevierViewall">Jos&#233; M&#46; Larra&#241;aga-Moreira<span class="elsevierStyleSup">a</span>&#42;&#44; Ana I&#46; Rodriguez-Serrano<span class="elsevierStyleSup">b&#44;c</span>&#44; Fernando Dom&#237;nguez<span class="elsevierStyleSup">c&#44;d&#44;e</span>&#44; Andrea Lalario<span class="elsevierStyleSup">f</span>&#44; Esther Zorio<span class="elsevierStyleSup">e&#44;g</span>&#44; Roberto Barriales-Villa<span class="elsevierStyleSup">a&#44;e</span>&#44; Fernando Hern&#225;ndez-Terciado<span class="elsevierStyleSup">d</span>&#44; Marco Merlo<span class="elsevierStyleSup">f</span>&#44; Cristina G&#243;mez-Gonz&#225;lez<span class="elsevierStyleSup">h</span>&#44; Lucas Tojal-Sierra<span class="elsevierStyleSup">i</span>&#44; Tom&#225;s Ripoll-Vera<span class="elsevierStyleSup">j</span>&#44; Eduardo Villacorta<span class="elsevierStyleSup">e&#44;k</span>&#44; Olga Chumakova<span class="elsevierStyleSup">l</span>&#44; David Vaqueriza-Cubillo<span class="elsevierStyleSup">m</span>&#44; Mar&#237;a A&#46; Espinosa-Castro<span class="elsevierStyleSup">e&#44;h</span>&#44; Mar&#237;a Gallego-Delgado<span class="elsevierStyleSup">e&#44;k</span>&#44; Jos&#233; Carlos S&#225;nchez-Mart&#237;nez<span class="elsevierStyleSup">g</span>&#44; Gianfranco Sinagra<span class="elsevierStyleSup">f</span>&#44; Pablo Garc&#237;a-Pavia<span class="elsevierStyleSup">c&#44;d&#44;e&#44;n</span>&#44; Carlos Pe&#241;a-Gil<span class="elsevierStyleSup">o</span>&#44; Lorenzo Monserrat<span class="elsevierStyleSup">o</span>&#44; Juan R&#46; Gimeno-Blanes<span class="elsevierStyleSup">b&#44;c&#44;e</span></p> <p id="par0200" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleSup">a</span>Unidad de Cardiopat&#237;as Familiares&#46; Instituto de Investigaci&#243;n Biom&#233;dica de A Coru&#241;a &#40;INIBIC&#41;&#44; Hospital Universitario de A Coru&#241;a &#40;HUAC&#41;&#44; Servizo Galego de Sa&#250;de &#40;SERGAS&#41;&#44; Universidade da Coru&#241;a &#40;UDC&#41;&#44; A Coru&#241;a&#44; Espa&#241;a&#59; <span class="elsevierStyleSup">b</span>Hospital Universitario Virgen de Arrixaca&#44; Murcia&#46; Spain&#59; <span class="elsevierStyleSup">c</span>European Reference Networks for rare&#44; low prevalence and complex diseases of the heart &#40;ERN GUARD-Heart&#41;&#44; Amsterdam&#44; The Netherlands&#59; <span class="elsevierStyleSup">d</span>Unidad Cardiopatias Familiares&#44; Hospital Universitario Puerta Hierro Majadahonda&#44; IDIPHISA&#44; Madrid&#44; Spain&#59; <span class="elsevierStyleSup">e</span>Center for Biomedical Network Research on Cardiovascular Diseases &#40;CIBERCV&#41;&#44; Madrid&#44; Spain&#59; <span class="elsevierStyleSup">f</span>Cardiovascular Department &#8216;Ospedali Riuniti&#8217; and University of Trieste&#44; Trieste&#44; Italy&#59; <span class="elsevierStyleSup">g</span>Unidad Cardiopat&#237;as Familiares&#44; Hospital Universitario y Polit&#233;cnico La Fe&#44; Valencia&#44; Spain&#46; Instituto de Investigaci&#243;n Sanitaria La Fe&#44; Valencia&#44; Spain&#59; <span class="elsevierStyleSup">h</span>Unidad de Cardiopat&#237;as Familiares&#44; Hospital General Universitario Gregorio Mara&#241;&#243;n&#44; Madrid&#44; Spain&#59; <span class="elsevierStyleSup">i</span>Hospital Universitario de Araba &#40;Txagorritxu&#41;&#44; Vitoria&#44; Spain&#59; <span class="elsevierStyleSup">j</span>Unidad Cardiopatias Familiares&#44; Hospital Universitario Son Ll&#224;tzer&#44; Mallorca&#44; Spain&#59; <span class="elsevierStyleSup">k</span>Inherited Cardiovascular Disease Unit&#46; Cardiology Department&#46; Complejo Asistencial Universitario de Salamanca&#59; Biomedical Research Institute of Salamanca &#40;IBSAL&#41;&#59; Gerencia Regional de Salud de Castilla y Le&#243;n &#40;SACYL&#41;&#46; Medicine department&#46; University of Salamanca&#44; Salamanca&#44; Spain&#59; <span class="elsevierStyleSup">l</span>Municipal Clinical Hospital &#35;17&#44; Moscow&#44; Russia&#59; <span class="elsevierStyleSup">m</span>Hospital Universitario Infanta Leonor&#44; Madrid&#44; Spain&#59; <span class="elsevierStyleSup">n</span>Centro Nacional de Investigaciones Cardiovasculares &#40;CNIC&#41;&#44; Madrid&#44; Spain&#59; <span class="elsevierStyleSup">o</span>Dilemma Solutions SL&#44; A Coru&#241;a&#44; Spain&#46;</p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Dilemma International Cardiomyopathy and Heart Failure Registry Investigators Group"
            "identificador" => "sec0085"
          ]
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            "etiqueta" => "Appendix C"
            "titulo" => "Supplementary data"
            "identificador" => "sec0095"
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                  \t\t\t\t"><span class="elsevierStyleBold">BMI category</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Normal</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Overweight</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">SARS-CoV-2 episode</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Care setting</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Outpatient&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>ED visit&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Hospitalized&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>ICU level care&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Any SARS-CoV-2 treatment</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Haemoglobin &#40;g&#47;dl&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">12&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                      "titulo" => "Comorbidity and its impact on 1590 patients with COVID-19 in China&#58; a nationwide analysis"
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