Intrinsic Cardiomyopathy Research Articles

Intrinsic cardiomyopathy in pediatric Marfan syndrome: predictive factors and risk assessments.

Marfan syndrome (MFS) is associated with cardiovascular complications, particularly valvulopathies; however, its association with primary cardiomyopathy remains unclear. This retrospective cohort study examined the cardiomyopathy characteristics (CMCs) in pediatric patients with MFS. CMCs were defined as meeting at least one of the following echocardiography or clinical parameters: (1) cardiac index (CI) too low for patient's age, (2) ejection fraction (EF) <50%, and (3) diastolic dysfunction. The predictive factors for CMCs were determined using a multivariable logistic regression model. Among 83 patients with MFS (age, median [range], 12.5 [0.4-22.3] years), 39.8% exhibited CMCs. Only 4 patients (5%) showed heart failure symptoms (NYHA > 1). Independent predictors for CMCs included a systemic score of ≥7 (revised Ghent criteria) and likely pathogenic or pathogenic variants in FBN1, including variants that introduce a premature stop codon, splice site variants, and missense variants involving cysteine. A multivariable score was constructed with an AUC of 0.733. This study offers valuable insights into the prevalence and predictors of CMC in pediatric patients with MFS and presents potential strategies for risk assessment of cardiomyopathy. The objective of this study was to elucidate the contentious issue of intrinsic cardiomyopathy in Marfan syndrome and demonstrate its notable occurrence even in pediatric patients who do not exhibit heart failure symptoms or valvular complications. We highlighted the importance of specific FBN1 variants and higher systemic scores in identifying the potential for intrinsic cardiomyopathy in pediatric patients with Marfan syndrome.

EVIDENCE OF CARDIOMYOPATHY ASSOCIATED WITH MARFAN SYNDROME IN CHILDREN

Adults with Marfan syndrome (MFS) have demonstrated increased biventricular volumes and decreased left ventricular (LV) ejection fraction (EF), consistent with an intrinsic cardiomyopathy. This study evaluated ventricular size and function in pediatric MFS using cardiac magnetic resonance (CMR).

A Machine Learning Model for the Systematic Identification of Wild-Type Transthyretin Cardiomyopathy

Introduction Wild-type transthyretin (TTR) amyloid cardiomyopathy (ATTRwt)—a life-threatening but now treatable disease—is often misdiagnosed as more common etiologies of heart failure (HF). As a strategy to identify undiagnosed patients, we sought to develop and validate a machine learning (ML) model to identify ATTRwt patients using medical claims data. Methods We developed an ML model for the identification of ATTRwt using ICD codes from US medical claims data sourced from IQVIA (n =∼300 million patients, up to 10 years of medical history). An ATTRwt cohort was derived using an ICD code for ATTRwt and compared to a random sample of HF patients matched by age, gender, and medical histories [cohort 1a (ATTRwt): N=373, cohort 1b (HF): N=373]. The classification model employed the Random Forest algorithm to learn from data from 80% of the patients (training set) and tested the learnings on the remaining 20% of patients (test set). Model validation was performed by predicting ATTRwt in 3 additional cohorts: ATTRwt and non-ATTRwt HF patients in electronic medical record (EMR) data [cohort 2a (ATTRwt): N=100, cohort 2b (HF): N=100], cardiac amyloidosis (CA) and HF patients in medical claims data [cohort 3a (CA): N=4,485, cohort 3b (HF): N=4,485, and CA and HF patients in EMR data [cohort 4a (CA): N=1,789, cohort 4b (HF): N=1,789]. EMR data was sourced from Optum (n= 88 million US patients, up to 10 years of medical history). The CA cohort comprised patients with organ-specific amyloidosis and HF diagnoses. Results The model delivered robust performance in correctly predicting ATTRwt and HF patients with sensitivity/specificity/accuracy of 94/94/91%, AUC 0.97 (derivation cohort 1, test set). External validation was also successful: cohort 2, 96/95/88%; cohort 3, 64/72/77%; and cohort 4, 75/76/80%. Model output revealed key clinical features associated with ATTRwt patients: pericardial disease (OR 11.8 CI 5.3-30.1), primary intrinsic cardiomyopathy (OR 6.1 CI 4.4-8.5), carpal tunnel (OR 5.7 CI 4.3-11.8), diastolic HF (OR 5.3 CI 3.8-7.4), atrial fibrillation (OR 4.9 CI 3.4-7.2), RBBB (OR 4.5 CI 2.5-5.6), synovitis (OR 3.9 CI 2.4-6.8), pleural effusion (OR 2.7 CI 2.0-3.7), osteoarthrosis (OR 2.5 CI 1.8-3.5), lumbar spinal stenosis (OR 2.1 CI 1.5-3.1), chronic kidney disease (OR 2.1 CI 1.5-2.8), and senile cataract (OR 2.0 CI 1.5-2.8). Conclusion Our findings from a robust ML analysis confirm the clinical profile of ATTRwt patients consistent with published literature and provide additional novel insights to aid in identifying undiagnosed patients. This is the first ML approach that provides a systematic framework to identify ATTRwt patients with a high degree of accuracy among large patient-level databases.

Effect and safety of treatment with ACE-inhibitor Enalapril and \u03b2-blocker metoprolol on the onset of left ventricular dysfunction in Duchenne muscular dystrophy - a randomized, double-blind, placebo-controlled trial

BackgroundX-linked Duchenne muscular dystrophy (DMD), the most frequent human hereditary skeletal muscle myopathy, inevitably leads to progressive dilated cardiomyopathy. We assessed the effect and safety of a combined treatment with the ACE-inhibitor enalapril and the β-blocker metoprolol in a German cohort of infantile and juvenile DMD patients with preserved left ventricular function.Methods Trial designSixteen weeks single-arm open run-in therapy with enalapril and metoprolol followed by a two-arm 1:1 randomized double-blind placebo-controlled treatment in a multicenter setting. Inclusion criteria: DMD boys aged 10–14 years with left ventricular fractional shortening [LV-FS] ≥ 30% in echocardiography. Primary endpoint: time from randomization to first occurrence of LV-FS < 28%. Secondary: changes of a) LV-FS from baseline, b) blood pressure, c), heart rate and autonomic function in ECG and Holter-ECG, e) cardiac biomarkers and neurohumeral serum parameters, f) quality of life, and g) adverse events.ResultsFrom 3/2010 to 12/2013, 38 patients from 10 sites were centrally randomized after run-in, with 21 patients continuing enalapril and metoprolol medication and 17 patients receiving placebo. Until end of study 12/2015, LV-FS < 28% was reached in 6/21 versus 7/17 patients. Cox regression adjusted for LV-FS after run-in showed a statistically non-significant benefit for medication over placebo (hazard ratio: 0.38; 95% confidence interval: 0.12 to 1.22; p = 0.10). Analysis of secondary outcome measures revealed a time-dependent deterioration of LV-FS with no statistically significant differences between the two study arms. Blood pressure, maximal heart rate and mean-NN values were significantly lower at the end of open run-in treatment compared to baseline. Outcome analysis 19 months after randomization displayed significantly lower maximum heart rate and higher noradrenalin and renin values in the intervention group. No difference between treatments was seen for quality of life. As a single, yet important adverse event, the reversible deterioration of walking abilities of one DMD patient during the run-in period was observed.ConclusionsOur analysis of enalapril and metoprolol treatment in DMD patients with preserved left ventricular function is suggestive to delay the progression of the intrinsic cardiomyopathy to left ventricular failure, but did not reach statistical significance, probably due to insufficient sample size.Clinical trial registrationDRKS-number 00000115, EudraCT-number 2009–009871-36.

Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans.

Mild intrinsic cardiomyopathy in patients with Marfan syndrome (MFS) has consistently been evidenced by independent research groups. So far, little is known about the long-term evolution and pathophysiology of this finding. To gain more insights into the pathophysiology of MFS-related cardiomyopathy, we performed in-vivo and ex-vivo studies of 11 Fbn1(C1039G/+) mice and 9 wild-type (WT) littermates. Serial ultrasound findings obtained in mice were correlated to the human phenotype. We therefore reassessed left ventricular (LV) function parameters over a 6-y follow-up period in 19 previously reported MFS patients, in whom we documented mild LV dysfunction. Fbn1(C1039G/+) mice demonstrated LV contractile dysfunction. Subsequent ex-vivo studies of the myocardium of adult mutant mice revealed upregulation of TGFβ-related pathways and consistent abnormalities of the microfibrillar network, implicating a role for microfibrils in the mechanical properties of the myocardium. Echocardiographic parameters did not indicate clinical significant deterioration of LV function during follow-up in our patient cohort. In analogy with what is observed in the majority of MFS patients, the Fbn1(C1039G/+) mouse model demonstrates mild intrinsic LV dysfunction. Both extracellular matrix and molecular alterations are implicated in MFS-related cardiomyopathy. This model may now enable us to study therapeutic interventions on the myocardium in MFS.

Left Ventricular Cardiomyopathy in Mitral Valve Prolapse: Fact or Fiction?

In most patients with mitral valve prolapse (MVP) without severe mitral regurgitation (MR), left ventricular (LV) function is preserved. There are, however, patients with MVP who have unexplained LV dilatation and/or decreased LV function. An association between MVP and sudden cardiac death has also been reported. LV size and function may be affected by the type of MVP, severity of regurgitation, and cause of MVP (myxomatous degeneration versus fibroelastic deficiency). There is increasing evidence suggesting an intrinsic cardiomyopathy associated with MVP. The cardiomyopathy associated with MVP can also affect the right ventricle (RV). Although the impact on ventricular dimensions and function are usually subtle, these abnormalities can affect clinical and echocardiographic estimation of the severity of MR and may thus have an impact on therapeutic decisions. Particularly in patients with the most extreme forms of MVP (Barlow disease), and in patients with Marfan syndrome or other connective tissue disorders, a cardiomyopathy affecting the LV and RV may thus occur occasionally. A better understanding of LV impairment associated with MVP is important for risk assessment and clinical decision-making.

Real Time Three‐Dimensional Echocardiography for the Evaluation of Cardiomyopathy

Cardiomyopathy refers to a set of diseases that are characterized by myocardial dysfunction. Classically, two-dimensional echocardiography has been used in the diagnosis of these disorders and to help guide their management. Three-dimensional transthoracic echocardiography is now increasingly being used in the diagnosis, management, and prognostication of intrinsic cardiomyopathies. In this article, we summarize the available data on the use of three-dimensional transthoracic echocardiography in various forms of intrinsic cardiomyopathy as well as some of its advantages over traditional two-dimensional transthoracic echocardiography.

Model‐specific selection of molecular targets for heart failure gene therapy

Heart failure (HF) is a complex multifaceted problem of abnormal ventricular function and structure. In recent years, new information has been accumulated allowing for a more detailed understanding of the cellular and molecular alterations that are the underpinnings of diverse causes of HF, including myocardial ischemia, pressure-overload, volume-overload or intrinsic cardiomyopathy. Modern pharmacological approaches to treat HF have had a significant impact on the course of the disease, although they do not reverse the underlying pathological state of the heart. Therefore gene-based therapy holds a great potential as a targeted treatment for cardiovascular diseases. Here, we survey the relative therapeutic efficacy of genetic modulation of β-adrenergic receptor signaling, Ca(2+) handling proteins and angiogenesis in the most common extrinsic models of HF.

Signalosomes as therapeutic targets

Cardiac hypertrophy is the predominant compensatory response of the heart to a wide variety of biomechanical stressors, including exercise, hypertension, myocardial infarction, intrinsic cardiomyopathy or congenital heart disease. Although cardiac hypertrophy can maintain cardiac output in response to elevated wall stress, sustained cardiac hypertrophy is often accompanied by maladaptive remodeling which can ultimately lead to heart failure. Cultured cardiac myocytes, transgenic and knock-out animal models, and pharmacological studies have not only revealed key molecules involved in hypertrophic signaling, but have also highlighted the redundancy in the hypertrophic signaling cascade. Currently, the majority of existing therapies for inhibition of pathologic cardiac hypertrophy and heart failure target molecules on the surface of cardiac myocytes, such as G-protein coupled receptors (GPCRs) and ion channels. Because these molecules are upstream of multiple intracellular signaling pathways, however, current therapy is often accompanied by significant off-target effects and toxicity. More recently, research has focused on identifying the intracellular effectors of these signaling cascades in the hope that more selective drugs may be rationally designed for therapeutic intervention. Within the cardiac myocyte, the formation of discrete multimolecular complexes, or ‘signalosomes’, is an important mechanism for increasing the specificity and efficiency of hypertrophic signal transduction. In response to extracellular stimuli, these signalosomes can alter gene and protein expression, cell size, and chamber remodeling, such as in the case of the signalosomes formed by the mAKAPβ and AKAP-lbc scaffold proteins. A better understanding of the basic molecular mechanisms regulating the compartmentation and scaffolding of signaling molecules could lead to the development of new clinical tools that may prevent the development of heart failure and minimize negative impacts on physiological processes.

Calcineurin Inhibition and Cardiac Hypertrophy

Mark A. Sussman et al . ([1][1]) report that the immunosuppressants cyclosporin (CsA) and FK506 prevent the development of hypertrophy in transgenic mouse models of intrinsic cardiomyopathy and, of more general import, in a rat model of extrinsic pressure-overload hypertrophy caused by banding of