Cardiac Genetic Test Yields and Genotype-Phenotype Correlations from Large Cohort Investigated by Medical Examiner's Office.

BACKGROUND: Few reports describe the yield of postmortem genetic testing from medical examiners' offices or correlate genetic test results with autopsy-confirmed phenotypes from a large cohort. OBJECTIVES: To report results from cardiomyopathy- and cardiac arrhythmia-associated genetic testing in conjunction with autopsy findings of cases investigated at the United States' largest medical examiner office. METHODS: Postmortem cases tested from 2015 to 2022 with a cardiomyopathy- and cardiac arrhythmia-associated gene panel were reviewed. American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines were used to classify variant pathogenicity. Correlations of pathogenic/likely pathogenic variants (P/LPVs) with cardiac pathology were evaluated. RESULTS: The cohort included 1107 decedents of diverse ages and ethnicities. P/LPVs were detected in 87 (7.9%) cases, with 73 and 14 variants in cardiomyopathy and cardiac arrhythmia genes, respectively. Variants of uncertain significance were detected in 437 (39.5%) cases. The diagnostic yield (percentage of P/LPV) in decedents with cardiomyopathy (26.1%) was significantly higher than those without (P < 0.0001). The diagnostic yield was significantly lower in infants (0.7%) than older age groups (ranging from 1 to 74 years old, 5.7%-25.9%), which had no statistical difference between their yields. The diagnostic yields by cardiac autopsy findings were 54.0% for hypertrophic cardiomyopathy, 47.1% for arrhythmogenic cardiomyopathy, 20.0% for myocardial fibrosis, 19.0% for dilated cardiomyopathy, and 11.3% for myocarditis. Most P/LPVs were in MYBPC3, TTN, PKP2, SCN5A, MYH7, and FLNC. Ten P/LPVs were novel. CONCLUSIONS: Our results support the importance of performing postmortem genetic testing on decedents of all ages with cardiomyopathy, cardiac lesions insufficient to diagnosis a specific cardiomyopathy (e.g., myocardial fibrosis), and myocarditis. Combined postmortem cardiac examination and genetic analysis are advantageous in accurately determining the underlying cause of death and informing effective clinical care of family members.

Frequency and Clinical Implications of Referrals to Heart Failure Among Patients with Peripartum Cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is a rare but significant cause of new-onset heart failure (HF) during the peri- and post-partum periods. Advances in GDMT for HF with reduced ventricular function have led to substantial improvements in survival and quality of life, yet few studies examine the longitudinal care received by patients with PPCM. The aim of this research is to address this gap by retrospectively characterizing patients with PPCM across a multihospital health system and investigating the frequency of cardiology and HF specialty referrals. Understanding whether surveillance and medical management differ among patients referred to HF will help to underscore the importance of referring patients with PPCM to HF specialists for optimal care.

Dysautonomia, but Not Cardiac Dysfunction, Is Common in a Cohort of Individuals with Long COVID.

Despite the prevalence of dysautonomia in people with Long COVID, it is currently unknown whether Long COVID dysautonomia is routinely accompanied by structural or functional cardiac alterations. In this retrospective observational study, the presence of echocardiographic abnormalities was assessed. Left ventricular (LV) chamber sizes were correlated to diagnostic categories and symptoms via standardized patient-reported outcome (PRO) questionnaires. A total of 203 individuals with Long COVID without pre-existing cardiac disease and with available echocardiograms were included (mean age, 45 years; 67% female). Overall, symptoms and PRO scores for fatigue, breathlessness, quality of life, disability, anxiety and depression were not different between those classified with post-COVID dysautonomia (PCD, 22%) and those unclassified (78%). An LV internal diameter at an end-diastole z score < -2 was observed in 33 (16.5%) individuals, and stroke volume (SV) was lower in the PCD vs. unclassified subgroup (51.6 vs. 59.2 mL, 95% C.I. 47.1-56.1 vs. 56.2-62.3). LV end-diastolic volume (mean diff. (95% CI) -13 [-1--26] mL, p = 0.04) and SV (-10 [-1--20] mL, p = 0.03) were smaller in those individuals reporting a reduction in physical activity post-COVID-19 infection, and smaller LVMI was weakly correlated with worse fatigue (r = 0.23, p = 0.02). The majority of individuals with Long COVID report shared symptoms and did not demonstrate cardiac dysfunction on echocardiography.

Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine-associated myocarditis.

Rare immune-mediated cardiac tissue inflammation can occur after vaccination, including after SARS-CoV-2 mRNA vaccines. However, the underlying immune cellular and molecular mechanisms driving this pathology remain poorly understood. Here, we investigated a cohort of patients who developed myocarditis and/or pericarditis with elevated troponin, B-type natriuretic peptide, and C-reactive protein levels as well as cardiac imaging abnormalities shortly after SARS-CoV-2 mRNA vaccination. Contrary to early hypotheses, patients did not demonstrate features of hypersensitivity myocarditis, nor did they have exaggerated SARS-CoV-2-specific or neutralizing antibody responses consistent with a hyperimmune humoral mechanism. We additionally found no evidence of cardiac-targeted autoantibodies. Instead, unbiased systematic immune serum profiling revealed elevations in circulating interleukins (IL-1ß, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix metalloproteases (MMP1, MMP8, MMP9, and TIMP1). Subsequent deep immune profiling using single-cell RNA and repertoire sequencing of peripheral blood mononuclear cells during acute disease revealed expansion of activated CXCR3+ cytotoxic T cells and NK cells, both phenotypically resembling cytokine-driven killer cells. In addition, patients displayed signatures of inflammatory and profibrotic CCR2+ CD163+ monocytes, coupled with elevated serum-soluble CD163, that may be linked to the late gadolinium enhancement on cardiac MRI, which can persist for months after vaccination. Together, our results demonstrate up-regulation in inflammatory cytokines and corresponding lymphocytes with tissue-damaging capabilities, suggesting a cytokine-dependent pathology, which may further be accompanied by myeloid cell-associated cardiac fibrosis. These findings likely rule out some previously proposed mechanisms of mRNA vaccine--associated myopericarditis and point to new ones with relevance to vaccine development and clinical care.

Approaches to Genetic Screening in Cardiomyopathies: Practical Guidance for Clinicians.

Patients and families benefit when the genetic etiology of cardiomyopathy is elucidated through a multidisciplinary approach including genetic counseling and judicious use of genetic testing. The yield of genetic testing is optimized when performed on a proband with a clear phenotype, and interrogates genes that are validated in association with that specific form of cardiomyopathy. Variants of uncertain significance are frequently uncovered and should not be overinterpreted. Identifying an impactful genetic variant as the cause of a patient's cardiomyopathy can have important prognostic impact, and enable streamlined cascade testing to highlight at risk relatives. Certain genotypes are associated with unique potential cardiac and noncardiac risk factors and may dictate personalized approaches to treatment.

Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation.

COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.

Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain.

Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection - without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

Cardiovascular manifestations of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders.

Introduction: Mitral valve prolapse and aortic root dilatation are reported in association with hypermobile Ehlers-Danlos syndrome (hEDS), but the full phenotypic spectrum of cardiovascular complications in this condition has not been studied in the aftermath of updated nosology and diagnostic criteria. Methods: We performed a retrospective review of 258 patients (> 94% adults) referred to a multidisciplinary clinic for evaluation of joint hypermobility between January 2017 and December 2020 and diagnosed with hEDS or a hypermobility spectrum disorder (HSD) to determine the incidence and spectrum of cardiovascular involvement. Results: Mitral valve prolapse was present in 7.5% and thoracic aortic dilatation in 15.2%. Aortic dilatation was more frequent in individuals with hEDS (20.7%) than with HSD (7.7%) and similarly prevalent between males and females, although was mild in > 90% of females and moderate-to-severe in 50% of males. Five individuals (1.9%) with hEDS/HSD had extra-aortic arterial involvement, including cervical artery dissection (CeAD, n = 2), spontaneous coronary artery dissection (SCAD, n = 2), and SCAD plus celiac artery pseudoaneurysm (n = 1). This is the first series to report the prevalence of CeAD and SCAD in hEDS/HSD. Conclusions: Cardiovascular manifestations in adults with hEDS/HSD, especially females, are typically mild and readily assessed by echocardiography. Since the risk of progression has not yet been defined, adults with hEDS/HSD who are found to have aortic dilatation at baseline should continue ongoing surveillance to monitor for progressive dilatation. Cardiovascular medicine specialists, neurologists, and neurosurgeons should consider hEDS/HSD on the differential for patients with CeAD or SCAD who also have joint hypermobility.

Post-acute COVID-19 Syndrome Negatively Impacts Physical Function, Cognitive Function, Health-Related Quality of Life, and Participation.

OBJECTIVE: This report describes persistent symptoms associated with post-acute COVID-19 syndrome (PACS) and the impact of these symptoms on physical function, cognitive function, health-related quality of life, and participation. DESIGN: This study used a cross-sectional observational study design. Patients attending Mount Sinai's post-acute COVID-19 syndrome clinic completed surveys containing patient-reported outcomes. RESULTS: A total of 156 patients completed the survey, at a median (range) time of 351 days (82-457 days) after COVID-19 infection. All patients were prevaccination. The most common persistent symptoms reported were fatigue (n = 128, 82%), brain fog (n = 105, 67%), and headache (n = 94, 60%). The most common triggers of symptom exacerbation were physical exertion (n = 134, 86%), stress (n = 107, 69%), and dehydration (n = 77, 49%). Increased levels of fatigue (Fatigue Severity Scale) and dyspnea (Medical Research Council) were reported, alongside reductions in levels of regularly completed physical activity. Ninety-eight patients (63%) scored for at least mild cognitive impairment (Neuro-Qol), and the domain of the EuroQol: 5 dimension, 5 level most impacted was Self-care, Anxiety/Depression and Usual Activities. CONCLUSIONS: Persistent symptoms associated with post-acute COVID-19 syndrome seem to impact physical and cognitive function, health-related quality of life, and participation in society. More research is needed to further clarify the relationship between COVID-19 infection and post-acute COVID-19 syndrome symptoms, the underlying mechanisms, and treatment options.

Myopathic Cardiac Genotypes Increase Risk for Myocarditis.

Impairments in certain cardiac genes confer risk for myocarditis in children. To determine the extent of this association, we performed genomic sequencing in predominantly adult patients with acute myocarditis and matched control subjects. Putatively deleterious variants in a broad set of cardiac genes were found in 19 of 117 acute myocarditis cases vs 34 of 468 control subjects (P = 0.003). Thirteen genes classically associated with cardiomyopathy or neuromuscular disorders with cardiac involvement were implicated, including >1 associated damaging variant in DYSF, DSP, and TTN. Phenotypes of subjects who have acute myocarditis with or without deleterious variants were similar, indicating that genetic testing is necessary to differentiate them.

Burden of Cardiomyopathic Genetic Variation in Lethal Pediatric Myocarditis.

BACKGROUND: Acute myocarditis (AM) is a well-known cause of sudden death and heart failure, often caused by prevalent viruses. We previously showed that some pediatric AM correlates with putatively damaging variants in genes related to cardiomyocyte structure and function. We sought to evaluate whether deleterious cardiomyopathic variants were enriched among fatal pediatric AM cases in New York City compared with ancestry-matched controls. METHODS: Twenty-four children (aged 3 weeks to 20 years) with death due to AM were identified through autopsy records; histologies were reviewed to confirm that all cases met Dallas criteria for AM and targeted panel sequencing of 57 cardiomyopathic genes was performed. Controls without cardiovascular disease were identified from a pediatric database and matched by genetic ancestry to cases using principal components from exome sequencing. Rates of putative deleterious variations (DV) were compared between cases and controls. Where available, AM tissues underwent viral analysis by polymerase chain reaction. RESULTS: DV were identified in 4 of 24 AM cases (16.7%), compared with 2 of 96 age and ancestry-matched controls (2.1%, P=0.014). Viral causes were proven for 6 of 8 AM cases (75%), including the one DV+ case where tissue was available for testing. DV+ cases were more likely to be female, have no evidence of chronic inflammation, and associate with sudden cardiac death than DV- cases. CONCLUSIONS: Deleterious variants in genes related to cardiomyocyte integrity are more common in children with fatal AM than controls, likely conferring susceptibility. Additionally, genetically mediated AM may progress more rapidly and be more severe.

Dysautonomia in hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders is associated with exercise intolerance and cardiac atrophy.

Dysautonomia is a recognized manifestation in patients with joint hypermobility (JH) disorders. Symptoms can be highly debilitating and commonly include physical deconditioning and poor aerobic fitness. In this study, the prevalence of dysautonomia, range of associated symptoms, patient-reported physical activity levels, and echocardiographic features were assessed retrospectively in a cohort of 144 patients (94% female) with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorder (HSD). Echocardiographic parameters of left ventricular size and function were compared between patients with and without dysautonomia as well as to reported values from healthy controls. Dysautonomia was identified in 65% of female and 44% of male subjects and was associated with a high burden of symptomatology, most commonly exercise intolerance (78%). Exercise capacity was limited by dysautonomia, often postural symptoms, in half of all patients. We observed a reduction in physical activity following the onset or significant flare of hEDS/HSD, most strikingly noting the proportion of dysautonomic patients with sedentary lifestyle, which increased from 44% to 85%. JH-related dysautonomia was associated with smaller cardiac chamber sizes, consistent with the previous reports in positional orthostatic tachycardia syndrome. Dysautonomia is prevalent in patients with hEDS/HSD, and exercise intolerance is a key feature and leads to drastic decline in physical activity. Unfavorable cardiac geometry may underlie dysautonomia symptoms and may be due to cardiac atrophy in the setting of aerobic deconditioning.

Precision Medicine Approaches to Vascular Disease: JACC Focus Seminar 2/5.

In this second of a 5-part Focus Seminar series, we focus on precision medicine in the context of vascular disease. The most common vascular disease worldwide is atherosclerosis, which is the primary cause of coronary artery disease, peripheral vascular disease, and a large proportion of strokes and other disorders. Atherosclerosis is a complex genetic disease that likely involves many hundreds to thousands of single nucleotide polymorphisms, each with a relatively modest effect for causing disease. Conversely, although less prevalent, there are many vascular disorders that typically involve only a single genetic change, but these changes can often have a profound effect that is sufficient to cause disease. These are termed "Mendelian vascular diseases," which include Marfan and Loeys-Dietz syndromes. Given the very different genetic basis of atherosclerosis versus Mendelian vascular diseases, this article was divided into 2 parts to cover the most promising precision medicine approaches for these disease types.

Genomic Screening Identifies Individuals at High Risk for Hereditary Transthyretin Amyloidosis.

The TTR V142I variant associated with hereditary transthyretin amyloidosis (hATTR) is present in up to 4% of African American (AA) and 1% of Hispanic/Latinx (HL) individuals and increases risk for heart failure. Delayed and missed diagnoses could potentiate health disparities in these populations. We evaluated whether population-based genomic screening could effectively identify individuals at risk for hATTR and prompt initiation of risk management. We identified participants of the BioMe Biobank in New York City who received TTR V142I results through a pilot genomic screening program. We performed a retrospective medical record review to evaluate for the presence hATTR-related systemic features, uptake of recommended follow-up, and short-term outcomes. Thirty-two AA (N = 17) and HL (N = 15) individuals received a TTR V142I result (median age 57, 81% female). None had a previous diagnosis of hATTR. Eighteen (56%) had hATTR-related systemic features, including 4 (13%) with heart failure, 10 (31%) with carpal tunnel syndrome, and 10 (31%) with spinal stenosis. Eighteen (56%) pursued follow-up with a cardiologist within 8 months. One person received a diagnosis of hATTR. Thus, we found that the majority of V142I-positive individuals had hATTR-related systemic features at the time of result disclosure, including well-described red flags. Genomic screening can help identify hATTR risk and guide management early on, avoiding potential delays in diagnosis and treatment.