Prognostic Utility of Cardiovascular Magnetic Resonance-Based Phenotyping in Patients With Muscular Dystrophy.

Background The prognostic utility of cardiovascular magnetic resonance imaging, including strain analysis and tissue characterization, has not been comprehensively investigated in adult patients with muscular dystrophy. Methods and Results We prospectively enrolled 148 patients with dystrophinopathies (including heterozygotes), limb-girdle muscular dystrophy, and type 1 myotonic dystrophy (median age, 36.0 [interquartile range, 23.0-50.0] years; 51 [34.5%] women) over 7.7 years in addition to an age- and sex-matched healthy control cohort (n=50). Cardiovascular magnetic resonance markers, including 3-dimensional strain and fibrosis, were assessed for their respective association with major adverse cardiac events. Our results showed that markers of contractile performance were reduced across all muscular dystrophy groups. In particular, the dystrophinopathies cohort experienced reduced left ventricular (LV) ejection fraction and high burden of replacement fibrosis. Patients with type 1 myotonic dystrophy showed a 26.8% relative reduction in LV mass with corresponding reduction in chamber volumes. Eighty-two major adverse cardiac events occurred over a median follow-up of 5.2 years. Although LV ejection fraction was significantly associated with major adverse cardiac events (adjusted hazard ratio [aHR], 3.0 [95% CI, 1.4-6.4]) after adjusting for covariates, peak 3-dimensional strain amplitude demonstrated greater predictive value (minimum principal amplitude: aHR, 5.5 [95% CI, 2.5-11.9]; maximum principal amplitude: aHR, 3.3 [95% CI, 1.6-6.8]; circumferential amplitude: aHR, 3.4 [95% CI, 1.6-7.2]; longitudinal amplitude: aHR, 3.4 [95% CI, 1.7-6.9]; and radial strain amplitude: aHR, 3.0 [95% CI, 1.4-6.1]). Minimum principal strain yielded incremental prognostic value beyond LV ejection fraction for association with major adverse cardiac events (change in χ2=13.8; P<0.001). Conclusions Cardiac dysfunction is observed across all muscular dystrophy subtypes; however, the subtypes demonstrate distinct phenotypic profiles. Myocardial deformation analysis highlights unique markers of principal strain that improve risk assessment over other strain markers, LV ejection fraction, and late gadolinium enhancement in this vulnerable patient population.

Cardiac manifestations and clinical management of X-linked Emery-Dreifuss muscular dystrophy: a case series.

Background: Heart disease is an under-recognized cause of morbidity and mortality in patients with Emery-Dreifuss muscular dystrophy (EDMD). Arrhythmias and conduction delays are highly prevalent and given the rarity of this disease the patient care process remains poorly defined. Case summary: This study closely followed four adult patients from the Neuromuscular Multidisciplinary Clinic (Alberta, Canada) that presented with X-linked recessive EDMD. Patients were assessed and managed on a case-by-case basis. Clinical status and cardiac function were assessed through clinical history, physical examination, and investigations (12-lead electrocardiogram, 24 hour Holter monitor, transthoracic echocardiogram, and plasma biomarkers). Conduction disease, requiring permanent pacemaker, was prevalent in all patients. With appropriate medical therapy over a median follow-up period five years the cardiac status was shown to have stabilized in all these patients. Discussion: We demonstrate the presentation of arrhythmias, conduction abnormalities, and chamber dilation in adult patients with X-linked EDMD. Cardiac medications and pacemaker therapy are shown to prevent adverse outcomes from these complications. Patients with EDMD are expected to develop heart disease early and prior to the development of an overt neuromuscular phenotype. These patients should be closely monitored in a multidisciplinary setting for effective management to improve their clinical outcomes.

Trajectory of left ventricular ejection fraction in response to therapies in patients with muscular dystrophy.

BACKGROUND: Patients with muscular dystrophy (MD) are at elevated risk of serious cardiac complications and clinical assessment is limited due to inherent physical limitations. We assessed the utility of left ventricular ejection fraction (LVEF) derived from transthoracic echocardiogram (TTE) as a prognostic marker for major adverse cardiac events (MACE) in a mixed adult MD cohort. METHODS: One hundred and sixty-five MD patients (median age: 36 (interquartile range [IQR]: 23.0-49.0) years; 65 [39.4%] females) were enrolled in our prospective cohort study. Diagnoses included dystrophinopathies (n = 42), limb-girdle MD (n = 31), type 1 myotonic dystrophy (n = 71), and facioscapulohumeral MD (n = 21). Left ventricular ejection fraction, ventricular dimensions at end-diastole and end-systole, and serial measures (n = 124; follow-up period: 2.19 [IQR: 1.05-3.32] years) stratified patients for MACE risk. RESULTS: Cardiomyopathy was diagnosed in 60 (36.4%) patients of the broader cohort (median LVEF: 45.0 [IQR: 35.0-50.0] %). Ninety-eight MACE occurred over the 7-year study period. At baseline, patients with a LVEF < 55.0% had a high risk of MACE (adjusted odds ratio: 8.30; 95% confidence interval [CI]: 3.18-21.7), concordant with the analysis of LV dimensions. Forty-one percent of these patients showed an improvement in LVEF with the optimization of medical and device therapies. Relative to patients with preserved LVEF, patients with reduced LVEF were at an elevated risk of MACE (adjusted hazard ratio [aHR]: 7.21; 95% CI: 1.99-26.1), and improved LVEF resulted in comparable outcomes (aHR: 1.84; 95% CI: .49-6.91) associated with optimization of medical and device therapies. Reduction in QRS duration by CRT therapy was associated with an improvement in LVEF (average improvement: 12.8 [± 2.30] %; p = .04). CONCLUSIONS: Reduction in LVEF indicates an increased risk of cardiovascular events in patients with MD. Baseline and serial LVEF obtained by TTE can prognosticate patients for MACE and guide clinical management.

Low Prevalence of Cardiomyopathy in Patients with Mitochondrial Disease and Neurological Manifestations.

Patients with mitochondrial diseases can develop cardiomyopathy but with variable expressivity and penetrance. Our prospective study enrolled and evaluated a cohort of 53 patients diagnosed with chronic progressive ophthalmoplegia (CPEO, n = 34), Kearns-Sayre syndrome (KSS, n = 3), neuropathy ataxia and retinitis pigmentosa (NARP, n = 1), myoclonic epilepsy with ragged red fibers (MERRF, n = 1), Harel-Yoon Syndrome (HYS, n = 1) and 13 patients with undefined mitochondrial diseases, presenting primarily with neurological symptoms. Over a 4-year period, six patients in our study cohort were diagnosed with heart disease (11.3%), with only three patients having defined cardiomyopathy (5.7%). Cardiomyopathy was present in a 21-year-old patient with HYS and two CPEO patients having mild cardiomyopathy at an older age. Two CPEO patients had congenital heart disease, and a third CPEO had LV hypertrophy secondary to hypertension. In three patients, traditional risk factors for heart disease, including dyslipidemia, hypertension, and respiratory disease, were present. The majority of our adult cohort of patients have normal cardiac investigations with a median left ventricular (LV) ejection fraction of 59.0%, indexed LV mass of 67.0 g/m2, and normal diastolic and valvular function at baseline. A 12-lead electrocardiogram showed normal cardiac conduction across the study cohort. Importantly, follow-up assessments showed consistent cardiac structure and function. Our study shows a low prevalence of cardiomyopathy and highlights the breadth of phenotypic variability in patients with mitochondrial disorders. The presence of cardiovascular risk factors and aging are important comorbidities in our cohort.

Myocardial Iron Deficiency and Mitochondrial Dysfunction in Advanced Heart Failure in Humans.

Background Myocardial iron deficiency (MID) in heart failure (HF) remains largely unexplored. We aim to establish defining criterion for MID, evaluate its pathophysiological role, and evaluate the applicability of monitoring it non-invasively in human explanted hearts. Methods and Results Biventricular tissue iron levels were measured in both failing (n=138) and non-failing control (NFC, n=46) explanted human hearts. Clinical phenotyping was complemented with comprehensive assessment of myocardial remodeling and mitochondrial functional profiles, including metabolic and oxidative stress. Myocardial iron status was further investigated by cardiac magnetic resonance imaging. Myocardial iron content in the left ventricle was lower in HF versus NFC (121.4 [88.1-150.3] versus 137.4 [109.2-165.9] µg/g dry weight), which was absent in the right ventricle. With a priori cutoff of 86.1 µg/g d.w. in left ventricle, we identified 23% of HF patients with MID (HF-MID) associated with higher NYHA class and worsened left ventricle function. Respiratory chain and Krebs cycle enzymatic activities were suppressed and strongly correlated with depleted iron stores in HF-MID hearts. Defenses against oxidative stress were severely impaired in association with worsened adverse remodeling in iron-deficient hearts. Mechanistically, iron uptake pathways were impeded in HF-MID including decreased translocation to the sarcolemma, while transmembrane fraction of ferroportin positively correlated with MID. Cardiac magnetic resonance with T2* effectively captured myocardial iron levels in failing hearts. Conclusions MID is highly prevalent in advanced human HF and exacerbates pathological remodeling in HF driven primarily by dysfunctional mitochondria and increased oxidative stress in the left ventricle. Cardiac magnetic resonance demonstrates clinical potential to non-invasively monitor MID.

Dysregulation of ACE (Angiotensin-Converting Enzyme)-2 and Renin-Angiotensin Peptides in SARS-CoV-2 Mediated Mortality and End-Organ Injuries.

ACE (angiotensin-converting enzyme)-2 as the target for SARS-CoV-2 also negatively regulates the renin-angiotensin system. Pathological activation of ADAM17 (A disintegrin and metalloproteinase-17) may potentiate inflammation and diminish ACE2-mediated tissue protection through proteolytic shedding, contributing to SARS-CoV-2 pathogenesis. We aim to examine plasma soluble ACE2 and angiotensin profiles in relation to outcomes by enrolling consecutive patients admitted for COVID-19 with baseline blood collection at admission and repeated sampling at 7 days. The primary outcome was 90-day mortality, and secondary outcomes were the incidence of end-organ injuries. Overall, 242 patients were included, the median age was 63 (52-74) years, 155 (64.0%) were men, and 57 (23.6%) patients reached the primary end point. Baseline soluble ACE2 was elevated in COVID-19 but was not associated with disease severity or mortality. In contrast, an upward trajectory of soluble ACE2 at repeat sampling was independently associated with an elevated risk of mortality and incidence of acute myocardial injury and circulatory shock. Similarly, an increase in soluble tumor necrosis factor receptor levels was also associated with adverse outcomes. Plasma Ang I, Ang 1-7 (angiotensin 1-7) levels, and the Ang 1-7/Ang II (angiotensin II) ratio were elevated during SARS-CoV-2 infection related to downregulation of ACE activity at baseline. Moreover, patients having an upward trajectory of soluble ACE2 were characterized by an imbalance in the Ang 1-7/Ang II ratio. The observed dysregulation of ACE2 and angiotensin peptides with disease progression suggest a potential role of ADAM17 inhibition and enhancing the beneficial Ang 1-7/Mas axis to improve outcomes against SARS-CoV-2 infection.

Clinical utility of 12-lead electrocardiogram in evaluating heart disease in patients with muscular dystrophy: Assessment of left ventricular hypertrophy, conduction disease, and cardiomyopathy.

INTRODUCTION: Heart disease remains a leading cause of mortality in patients with muscular dystrophy (MD), and cardiac assessment by standard imaging modalities is challenging due to the prominence of physical limitations. METHODS: In this prospective cohort study of 169 MD patients and 34 negative control patients, we demonstrate the clinical utility of a 12-lead electrocardiogram (ECG) as an effective modality for the assessment of cardiac status in patients with MD. We assessed the utility of conventional criteria for electrocardiogram-indicated left ventricular hypertrophy (ECG-LVH) as well as ECG morphologies. RESULTS: Cornell voltage, Cornell voltage-duration, Sokolow-Lyon voltage, and Romhilt-Estes point score criteria demonstrated low sensitivity and minimal positive predictive value for ECG-LVH when compared with cardiac imaging. Patients with LBBB had a high probability of a cardiomyopathy (relative risk [RR], 2.75; 95% confidence interval [CI], 2.14-3.53; p < .001), and patients with QRS fragmentation (fQRS) had a high probability of a cardiomyopathy (RR, 1.76; 95% CI, 1.20-2.59; p = .004), requiring cardiac medication and device intervention. We found that an R/S ratio >1 in V1 and V2 is highly specific (specificity, 0.89; negative predictive value [NPV], 0.89 and specificity, 0.82; NPV, 0.89, respectively) for patients with dystrophinopathies compared with other types of MD. CONCLUSION: The identification of LBBB and fQRS was linked to cardiomyopathy in patients with MD, while ECG-LVH was of limited utility. Importantly, these findings can be applied to effectively screen a broad cohort of MD patients for structural heart disease and prompt further evaluation and therapeutic intervention.

Evaluating the diagnostic and prognostic value of biomarkers for heart disease and major adverse cardiac events in patients with muscular dystrophy.

AIMS: Heart disease is recognized as the leading cause of morbidity and mortality in patients with muscular dystrophy (MD). Our study demonstrates the clinical utility of cardiac biomarkers to improve the diagnosis of cardiomyopathy and prognostication of major adverse cardiac events (MACE) in these vulnerable patients. METHODS AND RESULTS: We prospectively followed 117 patients [median age, 42 [interquartile range (IQR), 26-50) years; 49 (41.9%) women] at the Neuromuscular Multidisciplinary clinic diagnosed with a dystrophinopathy, limb-girdle MD, type 1 myotonic dystrophy, or facioscapulohumeral MD. We determined that B-type natriuretic peptide (BNP) and high-sensitive troponin I (hsTnI) were effective diagnostic markers of cardiomyopathy [area under the curve (AUC), 0.64; P = 0.017; and AUC, 0.69; P = 0.001, respectively]. Patient risk stratification for MACE was based on cut-off values of BNP and hsTnI defined a priori as 30.5000 pg/mL and 7.6050 ng/L, respectively. Over a median follow-up period of 2.09 (IQR, 1.17-2.81) years there were 36 confirmed MACE. Multivariate regression analyses showed that patients with BNP and hsTnI levels above the respective cut-off values had a 3.70-fold (P = 0.001) and 3.24-fold (P = 0.002) greater risk of MACE, respectively, compared with patients with biomarker levels below. Furthermore, patients with biomarker levels above both cut-off values had a 4.08-fold (P = 0.001) greater risk of MACE. Inflammatory biomarkers did not show clinical utility for heart disease in these patients. CONCLUSION: Our study demonstrates important diagnostic and prognostic value of BNP and hsTnI as part of a comprehensive cardiac assessment to augment the management and treatment of heart disease in patients with MD.

The Human Explanted Heart Program: A translational bridge for cardiovascular medicine.

The progression of cardiovascular research is often impeded by the lack of reliable disease models that fully recapitulate the pathogenesis in humans. These limitations apply to both in vitro models such as cell-based cultures and in vivo animal models which invariably are limited to simulate the complexity of cardiovascular disease in humans. Implementing human heart tissue in cardiovascular research complements our research strategy using preclinical models. We established the Human Explanted Heart Program (HELP) which integrates clinical, tissue and molecular phenotyping thereby providing a comprehensive evaluation into human heart disease. Our collection and storage of biospecimens allow them to retain key pathogenic findings while providing novel insights into human heart failure. The use of human non-failing control explanted hearts provides a valuable comparison group for the diseased explanted hearts. Using HELP we have been able to create a tissue repository which have been used for genetic, molecular, cellular, and histological studies. This review describes the process of collection and use of explanted human heart specimens encompassing a spectrum of pediatric and adult heart diseases, while highlighting the role of these invaluable specimens in translational research. Furthermore, we highlight the efficient procurement and bio-preservation approaches ensuring analytical quality of heart specimens acquired in the context of heart donation and transplantation.

Cardiac Intervention Improves Heart Disease and Clinical Outcomes in Patients With Muscular Dystrophy in a Multidisciplinary Care Setting.

Background Patients with muscular dystrophy (MD) represent a vulnerable patient population with no clearly defined care model in modern-day clinical practice to manage a high burden of heart disease and comorbidities. We demonstrate the effectiveness of cardiac interventions, namely the initiation and optimization of medical and device therapies, as part of a multidisciplinary care approach to improve clinical outcomes in patients with MD. Methods and Results We conducted a prospective cohort study at the Neuromuscular Multidisciplinary clinic following patients with dystrophinopathies, limb-girdle MD, type 1 myotonic dystrophy, and facioscapulohumeral MD. A negative control group classified as non-MD myopathies without heart disease, was also tracked. Our cohort of 185 patients (median age: 42 years; 79 [42.7%] women), included 145 patients with MD. Cardiomyopathy was present in 65.6% of the patients with dystrophinopathies (21 of 32) and 27.3% of the patients with limb-girdle MD (9 of 33). Conduction abnormalities were common in type 1 myotonic dystrophy (33.3% [20/60] patients). Cardiac intervention reversed systolic dysfunction, with left ventricular ejection fraction improving from 43% to 50.0% over a 3-year period. A sustained reduction in healthcare utilization was also observed. The number of outpatient clinic visits decreased from 3.0 to 1.5 visits per year, the duration of hospitalizations was reduced from 14.2 to 0.9 days per year, and the number of cardiac-related hospitalizations decreased from 0.4 to 0.1 hospitalizations per year associated with low mortality. Conclusions Our study demonstrates that cardiac intervention as part of a comprehensive multidisciplinary care approach to treating patients with MD leads to a sustained improvement in clinical outcomes.

Screening and Initiating Supportive Care in Patients With Heart Failure.

Background: Patients with heart failure (HF) experience a major symptom burden and an overall reduction of quality of life. However, supportive care (SC) remains an under-utilized resource for these patients. Among the many existing barriers to integrating SC into routine care, identifying patients with SC needs remains challenging. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is an important predictor of SC needs in patients with HF. Methods and Results: We used the shortened version KCCQ-12 as a screening tool for SC need in our ambulatory HF patient population using a KCCQ-12 summary score of <29 as the cut-off. Of the 456 patients who completed the KCCQ-12, 41 (9%) were predicted to have SC needs. Demographics, medical history, biochemical parameters, echocardiographic assessment and medical treatment were similar between the two groups of patients. However, patients with KCCQ-12 <29 were more symptomatic based on both New York Heart Association (NYHA) classification and American Heart Association (AHA) staging with a higher prevalence of depression. We established a multidisciplinary SC clinic and the profile and outcomes of patients with SC needs that were referred and followed at our SC clinic were also evaluated. Twenty-three patients were referred to our SC clinic: 2 died before being seen, 1 refused SC and 20 received SC. Of these 20 patients, 11 died and 9 are currently being followed. Median survival after starting the SC clinic is 3 months. In the original SC cohort of 23, 17 patients had available KCCQ-12 summary scores. However, only 6 out of 17 (35%) had KCCQ-12 scores <29, indicating the need for additional assessment tools in this patient population. Conclusions: The magnitude of unmet supportive care needs in patients with HF is significant. While the KCCQ-12 questionnaire is a useful tool to identify patients with SC, serial clinical evaluation, establishment of a SC clinic and prompt referral are essential for patients needing supportive care.

Comparison of Usefulness of Cardiac Resynchronization Therapy in Patients With Type 1 Myotonic Dystrophy With Versus Without Left Bundle Branch Block.

Patients with type 1 myotonic dystrophy show reduced left ventricular systolic function in the presence of left bundle branch block due to electromechanical dys-synchrony. Our prospective study tracked a cohort of 64 type 1 myotonic dystrophy patients that demonstrated a high burden of atrial and ventricular arrhythmias and conduction delays. Of these patients, 12 (19%) patients had left bundle branch block, which was associated with reduced left ventricular systolic function. Eight of these patients received cardiac resynchronization therapy devices resulting in reduction of median QRS complex duration from 173 to 166 ms (p = 0.04), and improvement in median left ventricular ejection fraction from 37% to 46% (p = 0.007). In conclusion, cardiac resynchronization therapy device therapy is both feasible and effective in treating advanced cardiac disease in this vulnerable group of patients by improving left ventricular function.

Ventricular tachycardia in patients with type 1 myotonic dystrophy: a case series.

BACKGROUND: Type 1 myotonic dystrophy (DM1) is associated with a variety of cardiac conduction abnormalities and the frequent need for permanent pacing. However, the role of ventricular tachycardia (VT) and the implied risk of sudden cardiac death (SCD) is poorly understood. CASE SUMMARY: This study examined a 56-patient DM1 cohort of men and women, and identified five patients (two females and three males) with ventricular arrhythmias (8.9%). Patients were reviewed on a case-by-case basis, with their clinical presentation and management of VT and the associated cardiomyopathy indicated. Patient cardiac function was determined by 12-lead electrocardiogram, 48-h Holter monitor, and transthoracic echocardiography. These patients were therefore suitable candidates for implantable cardioverter-defibrillator implantation and received these devices; four of the five patients also received cardiac resynchronization therapy. Medical therapies included angiotensin converting enzyme inhibition, mineralocorticoid receptor antagonist, and following device implantation, beta-blocker therapy was initiated. DISCUSSION: Our case series demonstrates the prevalence of VT in patients with DM1 highlighting the associated risks of SCD in this patient population. The burden of ventricular arrhythmias, advanced conduction disease, and cardiomyopathy are best treated with a combination of device and medical therapies.

Elevated Inflammatory Plasma Biomarkers in Patients With Fabry Disease: A Critical Link to Heart Failure With Preserved Ejection Fraction.

Background Because systemic inflammation and endothelial dysfunction lead to heart failure with preserved ejection fraction, we characterized plasma levels of inflammatory and cardiac remodeling biomarkers in patients with Fabry disease ( FD ). Methods and Results Plasma biomarkers were studied in multicenter cohorts of patients with FD (n=68) and healthy controls (n=40). Plasma levels of the following markers of inflammation and cardiac remodeling were determined: tumor necrosis factor ( TNF ), TNF receptor 1 ( TNFR 1) and 2 ( TNFR 2), interleukin-6, matrix metalloprotease-2 ( MMP -2), MMP -8, MMP -9, galectin-1, galectin-3, B-type natriuretic peptide ( BNP ), midregional pro-atrial natriuretic peptide ( MR -pro ANP ), and globotriaosylsphingosine. Clinical profile, cardiac magnetic resonance imaging, and echocardiogram were reviewed and correlated with biomarkers. Patients with FD had elevated plasma levels of BNP , MR -pro ANP , MMP -2, MMP -9, TNF , TNFR 1, TNFR 2, interleukin-6, galectin-1, globotriaosylsphingosine, and analogues. Plasma TNFR 2, TNF , interleukin-6, MMP -2, and globotriaosylsphingosine were elevated in FD patients with left ventricular hypertrophy, whereas diastolic dysfunction correlated with higher BNP , MR -pro ANP , and MMP -2 levels. Patients with late gadolinium enhancement on cardiac magnetic resonance imaging had greater levels of BNP , MR -pro ANP , TNFR 1, TNFR 2, and MMP -2. Plasma BNP , MR -pro ANP , MMP -2, MMP -8, TNF , TNFR 1, TNFR 2, galectin-1, and galectin-3 were elevated in patients with renal dysfunction. Patients undergoing enzyme replacement therapy who have more severe disease had higher MMP -2, TNF , TNFR 1, TNFR 2, and globotriaosylsphingosine analogue levels. Conclusions Inflammatory and cardiac remodeling biomarkers are elevated in FD patients and correlate with disease progression. These features are consistent with a phenotype dominated by heart failure with preserved ejection fraction and suggest a key pathogenic role of systemic inflammation in FD .

Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in cardiovascular disease.

The main function of the intestinal barrier is to regulate the absorption of nutrients, electrolytes, and water from the lumen into circulation and to prevent the entry of pathogenic microorganisms and toxic luminal substances. To maintain this function, an ideal microbiota balance is required and gut microbiota are critical for the intestinal epithelial barrier dysfunction and for the maintenance of physiological homeostasis. There is a demonstrable link between dysbiosis and intestinal dysfunction and diseases such as diabetes, obesity, and cardiovascular disease. However, links amongst gut pathology, microbial ecology, and blood pressure remain elusive. In a recent issue of Clinical Science (vol. 132, issue 6, 701-718), Kim et al. demonstrate a crucial link between gut microbiota and bacterial metabolites such as butyrate, gut leakiness, and hypertension.