Age is the main determinant of COVID-19 related in-hospital mortality with minimal impact of pre-existing comorbidities, a retrospective cohort study

BACKGROUND: Age and comorbidities increase COVID-19 related in-hospital mortality risk, but the extent by which comorbidities mediate the impact of age remains unknown. METHODS: In this multicenter retrospective cohort study with data from 45 Dutch hospitals, 4806 proven COVID-19 patients hospitalized in Dutch hospitals (between February and July 2020) from the CAPACITY-COVID registry were included (age 69[58–77]years, 64% men). The primary outcome was defined as a combination of in-hospital mortality or discharge with palliative care. Logistic regression analysis was performed to analyze the associations between sex, age, and comorbidities with the primary outcome. The effect of comorbidities on the relation of age with the primary outcome was evaluated using mediation analysis. RESULTS: In-hospital COVID-19 related mortality occurred in 1108 (23%) patients, 836 (76%) were aged ≥70 years (70+). Both age 70+ and female sex were univariably associated with outcome (odds ratio [OR]4.68, 95%confidence interval [4.02–5.45], OR0.68[0.59–0.79], respectively;both p<  0.001). All comorbidities were univariably associated with outcome (p<0.001), and all but dyslipidemia remained significant after adjustment for age70+ and sex. The impact of comorbidities was attenuated after age-spline adjustment, only leaving female sex, diabetes mellitus (DM), chronic kidney disease (CKD), and chronic pulmonary obstructive disease (COPD) significantly associated (female OR0.65[0.55–0.75], DM OR1.47[1.26–1.72], CKD OR1.61[1.32–1.97], COPD OR1.30[1.07–1.59]). Pre-existing comorbidities in older patients negligibly (<6% in all comorbidities) mediated the association between higher age and outcome. CONCLUSIONS: Age is the main determinant of COVID-19 related in-hospital mortality, with negligible mediation effect of pre-existing comorbidities

Clinical care of family members of patients with dilated cardiomyopathy

Genetic family screening following the detection of a pathogenic or likely pathogenic variant in a proband with dilated cardiomyopathy (DCM) remains one of the main applications of genetic testing. While cardiac screening is recommended for all first-degree relatives, the a priori risk among family members varies. Consequently, screening regimens should be tailored according to both genetic and clinical information at the individual and familial level. This clinical consensus statement provides tools to help with the risk assessment and follow-up of screening for family members and discusses the utility for integration of genotype-specific information, cardiac imaging, and electrocardiogram findings to personalize cardiac screening regimens, which in conjunction will likely improve individualized risk prediction. Early phenotypic detection of DCM in family members remains an active area of research and innovation. In addition, data are starting to accrue on the utility of early therapeutic intervention in family members with very mild phenotypes that may inform future management in addition to screening. A systematic strategy is proposed to determine the a priori risk of developing DCM for a family member, and the potential of integrating genotype–phenotype knowledge towards family management. Lastly, there is a focus on the current knowledge gaps and ongoing and future opportunities to improve risk prediction, early disease detection, and treatment of family members of patients with DCM

Natural History of MYH7-Related Dilated Cardiomyopathy

BACKGROUND: Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVE: We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS: We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 ± 19.2 years) recruited from 29 international centers. RESULTS: At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% ± 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of ≤35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS: MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare

Sex differences in cardiovascular complications and mortality in hospital patients with covid-19: registry based observational study

Objective To assess whether the risk of cardiovascular complications of covid-19 differ between the sexes and to determine whether any sex differences in risk are reduced in individuals with pre-existing cardiovascular disease. Design Registry based observational study. Setting 74 hospitals across 13 countries (eight European) participating in CAPACITY-COVID (Cardiac complicAtions in Patients With SARS Corona vIrus 2 regisTrY), from March 2020 to May 2021 Participants All adults (aged ≥18 years), predominantly European, admitted to hospital with highly suspected covid-19 disease or covid-19 disease confirmed by positive laboratory test results (n=11 167 patients). Main outcome measures Any cardiovascular complication during admission to hospital. Secondary outcomes were in-hospital mortality and individual cardiovascular complications with ≥20 events for each sex. Logistic regression was used to examine sex differences in the risk of cardiovascular outcomes, overall and grouped by pre-existing cardiovascular disease. Results Of 11 167 adults (median age 68 years, 40% female participants) included, 3423 (36% of whom were female participants) had pre-existing cardiovascular disease. In both sexes, the most common cardiovascular complications were supraventricular tachycardias (4% of female participants, 6% of male participants), pulmonary embolism (3% and 5%), and heart failure (decompensated or de novo) (2% in both sexes). After adjusting for age, ethnic group, pre-existing cardiovascular disease, and risk factors for cardiovascular disease, female individuals were less likely than male individuals to have a cardiovascular complication (odds ratio 0.72, 95% confidence interval 0.64 to 0.80) or die (0.65, 0.59 to 0.72). Differences between the sexes were not modified by pre-existing cardiovascular disease; for the primary outcome, the female-to-male ratio of the odds ratio in those without, compared with those with, pre-existing cardiovascular disease was 0.84 (0.67 to 1.07). Conclusions In patients admitted to hospital for covid-19, female participants were less likely than male participants to have a cardiovascular complication. The differences between the sexes could not be attributed to the lower prevalence of pre-existing cardiovascular disease in female individuals. The reasons for this advantage in female individuals requires further research

Role of targeted therapy in dilated cardiomyopathy: the challenging road toward a personalized approach

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Immunomodulation of Myocardial Fibrosis.

Immunotherapy is a potential cornerstone in the treatment of myocardial fibrosis. During a myocardial insult or heart failure, danger signals stimulate innate immune cells to produce chemokines and profibrotic cytokines, which initiate self-escalating inflammatory processes by attracting and stimulating adaptive immune cells. Stimulation of fibroblasts by inflammatory processes and the need to replace damaged cardiomyocytes fosters reshaping of the cardiac fibroblast landscape. In this review, we discuss new immunomodulatory strategies that manipulate and direct cardiac fibroblast activation and differentiation. In particular, we highlight immunomodulatory strategies that target fibroblasts such as chimeric antigen receptor T cells, interleukin-11, and invariant natural killer T-cells. Moreover, we discuss the potential of manipulating both innate and adaptive immune system components for the translation into clinical validation. Clearly, multiple pathways should be considered to develop innovative approaches to ameliorate myocardial fibrosis and hence to reduce the risk of heart failure

Myocardial strain overrules left ventricular ejection fraction and late gadolinium enhancement extent in predicting MACE in CMR-proven acute myocarditis

Abstract Funding Acknowledgements Type of funding sources: None. Background Cardiac magnetic resonance (CMR) plays a major role in both the diagnostic process and prognostic stratification in acute myocarditis. Presence of late gadolinium enhancement (LGE) and left ventricular (LV) ejection fraction (EF) are known predictors of major adverse cardiovascular events (MACE). However, in daily clinical practice it remains challenging to distinguish ‘the good from the bad’. The prognostic value of CMR feature tracking (FT) derived strain, with respect to LGE and LVEF, remains unclear. Purpose To evaluate the incremental prognostic value of left atrial (LA) phasic function, LV and right ventricular (RV) strain using CMR-FT in patients with CMR-proven acute myocarditis. Methods In this multicenter observational study, patients with CMR-proven acute myocarditis were included and followed with regard to MACE including all-cause mortality (ACM), heart-failure hospitalizations (HFH), and life-threatening arrhythmias (LTA). Using FT-derived strain, LV global longitudinal strain (GLS), circumferential strain (GCS), and radial strain (GRS), RV GLS and LA phasic function were measured. Uni- and multivariable analysis including clinical and CMR parameters were performed to assess the association with MACE. Results A total of 162 patients were included (75% male, 41 ±17 years). MACE occurred in 29 patients (18%, ACM n = 18, HFH n = 7, LTA n = 11) during a median follow-up of 5.5 (2.2-8.3) years. Forty-six percent had a STEMI-like presentation (combination of chest pain, elevated troponin, and ST-elevation, n = 74). LGE was present in 90% of patients and mean LVEF was 51 ± 12%. Patients with LVEF &amp;lt;50% had a significantly worse prognosis compared to patients with LVEF ≥50% (p &amp;lt; 0.0001, Figure A). When we categorized the study population into subgroups of quartile values of LV GLS, patients with LV GLS worse than 18% had a significant worse outcome compared to the other subgroups (p &amp;lt; 0.05, Figure B). Subgroups of LGE extent did not show significantly different associations with outcome (p = 0.458, Figure C). Cox regression analysis showed that LV strain and LA phasic function were univariably associated with MACE, whereas RV GLS and LGE extent were not. All univariable associated strain parameters were separately included in a multivariable model, including age, sex, STEMI-like presentation, and LVEF. LV GLS (HR 1.08, p = 0.01), LV GCS (HR 1.15, p = 0.02), and LV GRS (HR 0.98, p = 0.02) were independent predictors of MACE. Conclusions LV strain parameters are independent and incremental predictors of prognosis in patients with acute myocarditis, while RV strain and LA phasic function are not. Therefore, LV strain is a promising novel parameter for risk stratification in acute myocarditis. </jats:sec

Clinical impact of re-evaluating genes and variants implicated in dilated cardiomyopathy

Purpose Accurate interpretation of variants detected in dilated cardiomyopathy (DCM) is crucial for patient care but has proven challenging. We applied a set of proposed refined American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria for DCM, reclassified all detected variants in robust genes, and associated these results to patients' phenotype. Methods The study included 902 DCM probands from the Maastricht Cardiomyopathy Registry who underwent genetic testing. Two gene panel sizes (extended n = 48; and robust panel n = 14) and two standards of variant classification (standard versus the proposed refined ACMG/AMP criteria) were applied to compare genetic yield. Results A pathogenic or likely pathogenic (P/LP) variant was found in 17.8% of patients, and a variant of uncertain significance (VUS) was found in 32.8% of patients when using method 1 (extended panel (n = 48) + standard ACMG/AMP), compared to respectively 16.9% and 12.9% when using method 2 (robust panel (n = 14) + standard ACMG/AMP), and respectively 14% and 14.5% using method 3 (robust panel (n = 14) + refined ACMG/AMP). Patients with P/LP variants had significantly lower event-free survival compared to genotype-negative DCM patients. Conclusion Stringent gene selection for DCM genetic testing reduced the number of VUS while retaining ability to detect similar P/LP variants. The number of genes on diagnostic panels should be limited to genes that have the highest signal to noise ratio

Precision phenotyping of dilated cardiomyopathy using multidimensional data.

BACKGROUND: Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction. OBJECTIVES: The purpose of this study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification. METHODS: Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years). RESULTS: In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005). CONCLUSIONS: Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to traditional risk models. They may improve patient selection for novel interventions, thereby enabling precision medicine