Neutrophil degranulation biomarkers characterize restrictive echocardiographic pattern with diastolic dysfunction in patients with diabetes.

OBJECTIVE: To investigate the potential association between neutrophil degranulation and patterns of myocardial dysfunction in a cohort of patients with type 2 diabetes mellitus (T2DM). BACKGROUND: Two distinct phenotypes of diabetic cardiomyopathy have been described: a restrictive phenotype with diastolic dysfunction (restrictive/DD) and a dilative phenotype with systolic dysfunction (dilative/SD). However, the underlying determinants of these two patterns are not yet recognized. METHODS: In this single-centre, observational, cross-sectional study, 492 patients were recruited. Ultrasonographic measurements were performed by two experienced sonographers, blinded to the clinical data of the participants. Serum biomarkers of neutrophil degranulation were measured by enzyme-linked immunosorbent sandwich assay (ELISA). RESULTS: After adjustment for confounders, resistin, myeloperoxidase, matrix metalloproteinase 8 and matrix metalloproteinase 9/tissue inhibitor of metalloproteinases 1 complex were positively associated with the restrictive/DD pattern compared with the normal pattern. Similarly, MPO was positively associated with the dilative/SD pattern compared with the normal pattern, and resistin was negatively associated with the dilative/SD pattern compared with the restrictive/DD pattern. CONCLUSIONS: Neutrophil degranulation is associated with the restrictive/DD echocardiographic pattern in patients with T2DM, but not with the normal pattern and dilative/SD patterns. Neutrophils could have a pivotal role in the pathogenesis of myocardial dysfunction, and particularly diastolic dysfunction, in patients with T2DM.

Amiloidose cardíaca: cardiomiopatia infiltrativa com comportamento hemodinâmico restritivo ­ relato de caso / Cardiac amyloidosis: infiltrative cardiomyopathy with restrictive hemodynamic behavior ­ case report

A amiloidose é uma condição rara que descreve um grupo heterogêneo de distúrbios que cursam com a deposição extracelular de agregados proteicos fibrilares em tecidos e órgãos. Relata-se aqui o caso de paciente do sexo masculino, com 76 anos de idade, que, há 2 meses, iniciou quadro progressivo de dispneia aos mínimos esforços. Na investigação, observou-se aumento cardíaco global, e o ecocardiograma evidenciou cardiopatia restritiva infiltrativa e derrame pericárdico. Pela elevada suspeição clínica, foi solicitada ressonância magnética cardíaca, que foi altamente sugestiva de amiloidose cardíaca. Dessa forma, assim como no caso relatado, o acometimento cardíaco possui como principal forma de manifestação o tipo miocardiopatia restritivo, sendo um quadro de insuficiência cardíaca crônica com etiologia de difícil diagnóstico em pacientes acima de 50 anos, com prognóstico bastante reservado. Assim, apesar de permanecer como um desafio diagnóstico para o clínico, sua hipótese deve sempre ser aventada na ausência de outra causa que justifique tais achados (AU)

Twenty-four-hour ambulatory (Holter) electrocardiographic findings in 13 cats with non-hypertrophic cardiomyopathy.

Detection and characterisation of cardiac arrhythmias in cats with hypertrophic cardiomyopathy (HCM) has already been documented in various studies. However, similar studies have not been reported for other forms of feline cardiomyopathy. The clinical records of 13 client-owned cats diagnosed with restrictive cardiomyopathy (RCM), arrhythmogenic right ventricular cardiomyopathy (ARVC) and non-specific cardiomyopathy (NSCM) that underwent Holter recording at the time of diagnosis were reviewed retrospectively. Eight cats had signs of congestive heart failure at presentation, one cat had a history of recurrent syncope and the remaining four cats were asymptomatic. The average heart rate was 138 ± 22 (range 97-181) beats per minute (bpm) with the lowest value (97 bpm) recorded in a cat with third degree atrioventricular block (3-AVB) and the highest value (181 bpm) observed in a cat with atrial fibrillation (AF). The median number of ventricular ectopic beats (VEB) over 24 h was 2031 (338-8305), mostly represented by single isolated VPCs (803, 123-2221). Cardiac pauses were observed in three cats, with the longest pause lasting more than 6 s. A survival analysis was not performed due to the small number of cats and limited follow-up information. Holter recording revealed cardiac arrhythmias in all 13 cats, while 8/13 cats (61.5%) had an unremarkable resting electrocardiogram (ECG). The average daily heart rate in these cats did not appear affected by the presence of heart failure, although periods of sinus arrhythmia were absent in all individuals.

Variant R94C in TNNT2-Encoded Troponin T Predisposes to Pediatric Restrictive Cardiomyopathy and Sudden Death Through Impaired Thin Filament Relaxation Resulting in Myocardial Diastolic Dysfunction.

Background Pediatric-onset restrictive cardiomyopathy (RCM) is associated with high mortality, but underlying mechanisms of disease are under investigated. RCM-associated diastolic dysfunction secondary to variants in TNNT2-encoded cardiac troponin T (TNNT2) is poorly described. Methods and Results Genetic analysis of a proband and kindred with RCM identified TNNT2-R94C, which cosegregated in a family with 2 generations of RCM, ventricular arrhythmias, and sudden death. TNNT2-R94C was absent among large, population-based cohorts Genome Aggregation Database (gnomAD) and predicted to be pathologic by in silico modeling. Biophysical experiments using recombinant human TNNT2-R94C demonstrated impaired cardiac regulation at the molecular level attributed to reduced calcium-dependent blocking of myosin's interaction with the thin filament. Computational modeling predicted a shift in the force-calcium curve for the R94C mutant toward submaximal calcium activation compared within the wild type, suggesting low levels of muscle activation even at resting calcium concentrations and hypercontractility following activation by calcium. Conclusions The pathogenic TNNT2-R94C variant activates thin-filament-mediated sarcomeric contraction at submaximal calcium concentrations, likely resulting in increased muscle tension during diastole and hypercontractility during systole. This describes the proximal biophysical mechanism for development of RCM in this family.

Hemodynamics of constrictive pericarditis and restrictive cardiomyopathy.

Constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM) are indolent disabling diseases of diastolic function. The two conditions share common pathophysiologic features, resulting in similar and overlapping clinical presentations, echocardiographic findings, and hemodynamic characteristics. However, their clinical course differs, as CP is surgically curable whereas RCM is a chronic condition managed medically. Separating these two entities is based on delineation of anatomic and physiologic derangements employing multimodality hemodynamic interrogation by advanced imaging techniques (Echo-Doppler, CT, and especially MRI) combined with sophisticated invasive hemodynamics.

Heart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology.

Cardiomyopathies are a heterogeneous group of heart muscle diseases and an important cause of heart failure (HF). Current knowledge on incidence, pathophysiology and natural history of HF in cardiomyopathies is limited, and distinct features of their therapeutic responses have not been systematically addressed. Therefore, this position paper focuses on epidemiology, pathophysiology, natural history and latest developments in treatment of HF in patients with dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies. In DCM, HF with reduced ejection fraction (HFrEF) has high incidence and prevalence and represents the most frequent cause of death, despite improvements in treatment. In addition, advanced HF in DCM is one of the leading indications for heart transplantation. In HCM, HF with preserved ejection (HFpEF) affects most patients with obstructive, and ∼10% of patients with non-obstructive HCM. A timely treatment is important, since development of advanced HF, although rare in HCM, portends a poor prognosis. In RCM, HFpEF is common, while HFrEF occurs later and more frequently in amyloidosis or iron overload/haemochromatosis. Irrespective of RCM aetiology, HF is a harbinger of a poor outcome. Recent advances in our understanding of the mechanisms underlying the development of HF in cardiomyopathies have significant implications for therapeutic decision-making. In addition, new aetiology-specific treatment options (e.g. enzyme replacement therapy, transthyretin stabilizers, immunoadsorption, immunotherapy, etc.) have shown a potential to improve outcomes. Still, causative therapies of many cardiomyopathies are lacking, highlighting the need for the development of effective strategies to prevent and treat HF in cardiomyopathies.

De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy.

Mutations in FLNC for a long time are known in connection to neuromuscular disorders and only recently were described in association with various cardiomyopathies. Here, we report a new clinical phenotype of filaminopathy in four unrelated patients with early-onset restrictive cardiomyopathy (RCM) in combination with congenital myopathy due to FLNC mutations (NM_001458.4:c.3557C>T, p.A1186V, rs1114167361 in three probands and c.[3547G>C; 3548C>T], p.A1183L, rs1131692185 in one proband). In all cases, concurrent myopathy was confirmed by neurological examination, electromyography, and morphological studies. Three of the patients also presented with arthrogryposis. The pathogenicity of the described missense variants was verified by cellular and morphological studies and by in vivo modeling in zebrafish. Combination of in silico and experimental approaches revealed that FLNC missense variants localized in Ig-loop segments often lead to development of RCM. The described FLNC mutations associated with early-onset RCMP extend cardiac spectrum of filaminopathies and facilitate the differential diagnosis of restrictive cardiac phenotype associated with neuromuscular involvement in children.

Spirometric impairments, cardiovascular outcomes, and noncardiovascular death in older persons.

BACKGROUND: In prior work involving older persons, the reported associations of spirometric impairments with cardiovascular outcomes may have been confounded by age-related changes in lung function. Hence, using more age-appropriate spirometric criteria from the Global Lung Function Initiative (GLI), we have evaluated the associations of spirometric impairments, specifically restrictive-pattern and airflow-obstruction, with cardiovascular death (CV-death) and hospitalization (CV-hospitalization). In these analyses, we also evaluated the competing outcome of noncardiovascular death (nonCV-death) and calculated measures of relative and absolute risk. METHODS: Our study sample was drawn from the Cardiovascular Health Study (CHS), including 4232 community-dwelling white persons aged ≥65 years. Multivariable regression models included the following baseline predictors: GLI-defined restrictive-pattern and airflow-obstruction, age, male gender, obesity, waist circumference, current smoker status, ≥10 pack-years of smoking, hypertension, dyslipidemia, diabetes, and cardiovascular and cerebrovascular disease. Outcomes included adjudicated CV-death, CV-hospitalization, and nonCV-death, ascertained over 10 years of follow-up. Measures of association included hazard ratios (HRs), rate ratios (RRs), and average attributable fraction (AAF), each with 95% confidence intervals. RESULTS: Restrictive-pattern and airflow-obstruction were associated with CV-death (adjusted HRs: 1.57 [1.18, 2.09] and 1.29 [1.04, 1.60]) and with nonCV-death (adjusted HRs: 2.10 [1.63, 2.69] and 1.79 [1.51, 2.12]), respectively. Airflow-obstruction, but not restrictive-pattern, was also associated with CV-hospitalization (adjusted RRs: 1.18 [1.02, 1.36] and 1.20 [0.96, 1.50], respectively). The adjusted AAFs of restrictive-pattern and airflow-obstruction were 1.68% (0.46, 3.06) and 2.35% (0.22, 4.72) for CV-death, and 3.44% (1.97, 5.08) and 7.77% (5.15, 10.60) for nonCV-death, respectively. CONCLUSION: Assessment of GLI-defined spirometric impairments contributes to broad geriatric risk stratifications for both cardiovascular and non-cardiovascular outcomes.

Spectrum of Restrictive and Infiltrative Cardiomyopathies: Part 1 of a 2-Part Series.

Restrictive cardiomyopathies are the least common form of heart muscle disease. They are characterized as infiltrative and noninfiltrative, storage diseases, and endomyocardial disorders. Genetic diseases commonly present during childhood or adolescence. However, a growing percentage of elderly patients with heart failure with preserved ejection fraction are being recognized as having forms of restrictive cardiomyopathy, particularly cardiac amyloidosis. Noninvasive evaluation has replaced endomyocardial biopsy in the diagnostic evaluation of most suspected etiologies. The detection of infiltrative cardiomyopathies, including lysosomal and glycogen storage disorders, iron overload, and amyloidosis (both light chain amyloidosis and transthyretin amyloidosis variants), as well as inflammatory diseases such as sarcoidosis has slowly led to improved outcomes via disease-specific therapies.

Spectrum of Restrictive and Infiltrative Cardiomyopathies: Part 2 of a 2-Part Series.

Restrictive cardiomyopathies are the least common form of heart muscle disease. They are characterized as infiltrative and noninfiltrative, storage diseases, and endomyocardial disorders. Genetic diseases commonly present during childhood or adolescence. However, a growing percentage of elderly patients with heart failure with preserved ejection fraction are being recognized as having forms of restrictive cardiomyopathy, particularly cardiac amyloidosis. Noninvasive evaluation has replaced endomyocardial biopsy in the diagnostic evaluation of most suspected etiologies. The detection of infiltrative cardiomyopathies, particularly primary and secondary forms of iron overload, as well as inflammatory diseases such as sarcoidosis has slowly led to improved outcomes via disease-specific therapies.

Idiopathic Restrictive Cardiomyopathy in Children and Young Adults.

Idiopathic restrictive cardiomyopathy (IRC) is a rare condition characterized by reduced ventricular compliance. Children with IRC have poor outcomes with most patients proceeding to cardiac transplantation. We sought to analyze our institutional experience and assess contemporary outcomes for children with IRC. We reviewed the medical record for patients (<21 years old) evaluated for a primary diagnosis of IRC between 1975 and 2013 at our institution. Demographic, clinical, echocardiographic, and catheterization data were abstracted. The patients were divided into 2 groups comprising a historical cohort (HC) (diagnosis: 1975 to 1993, n = 8) and a contemporary cohort (CC) (diagnosis: 1994 to 2013, n = 12). Twenty children were identified with IRC (mean age at presentation 9.7 ± 6.5 years, 55% female). Mean length of follow-up was 6.5 ± 8.4 years (range 0.1 to 35.6 years). In the CC, 7 of 12 patients (58%) progressed to cardiac transplantation (mean age of 9 ± 4 years at transplant, mean interval from diagnosis of IRC: 1.5 ± 0.9 years). Overall survival was improved significantly in the CC compared with the HC (80% vs. 38%, p = 0.02), but transplantation free survival was no different between the CC and HC over 5 years (38% vs 38%, p = 0.65). In the CC, elevation of mitral valve Doppler E/e' ratio on echocardiography was associated with increased mortality (p = 0.01). In conclusion, IRC continues has a poor prognosis. Early referral for transplantation was associated with improved overall survival in the modern era. Patients with markedly elevated E/e' ratio may have increased risk of death.

Cardiac amyloidosis: An update on pathophysiology, diagnosis, and treatment.

The amyloidoses are a group of systemic diseases characterized by organ deposition of misfolded protein fragments of diverse origins. The natural history of the disease, involvement of other organs, and treatment options vary significantly based on the protein of origin. In AL amyloidosis, amyloid protein is derived from immunoglobulin light chains, and most often involves the kidneys and the heart. ATTR amyloidosis is categorized as mutant or wild-type depending on the genetic sequence of the transthyretin (TTR) protein produced by the liver. Wild-type ATTR amyloidosis mainly involves the heart, although the reported occurrence of bilateral carpal tunnel syndrome, spinal stenosis and biceps tendon rupture in these patients speaks to more generalized protein deposition. Mutant TTR is marked by cardiac and/or peripheral nervous system involvement. Cardiac involvement is associated with symptoms of heart failure, and dictates the clinical course of the disease. Cardiac amyloidosis can be diagnosed noninvasively by echocardiography, cardiac MRI, or nuclear scintigraphy. Endomyocardial biopsy may be needed in the case of equivocal imaging findings or discordant data. Treatment is aimed at relieving congestive symptoms and targeting the underlying amyloidogenic process. This includes anti-plasma cell therapy in AL amyloidosis, and stabilization of the TTR tetramer or inhibition of TTR protein production in ATTR amyloidosis. Cardiac transplantation can be considered in highly selected patients in tandem with therapy aimed at suppressing the amyloidogenic process, and appears associated with durable long-term survival.

Clinical features of idiopathic restrictive cardiomyopathy: A retrospective multicenter cohort study over 2 decades.

Idiopathic restrictive cardiomyopathy (RCMP) has not been fully understood because this disease is difficult to diagnose. The present study aimed to assess the clinical profile and outcome of idiopathic RCMP from a multicenter cohort.This investigation is a retrospective study of consecutive patients with idiopathic RCMP at 10 centers in Korea between 1990 and 2010. We evaluated the clinical characteristics of the patients and prognostic factors associated with mortality using multivariate Cox proportional hazards regression analyses.The study included 53 patients (26 men, 49.1%). During a median follow-up of 1.7 years, 17 patients (32.1%) died and 5 patients (9.4%) received a heart transplant. The 5-year survival rate of the overall patients was 64.4% ±â€Š7.8%. In multivariable analyses, the predictors of mortality were tricuspid regurgitation (TR) ≥ moderate (hazard ratio [HR] 32.55, P < .001) and left ventricular end-diastolic diameter (LVEDD) (HR 0.85, P < .001).Idiopathic RCMP showed unfavorable prognosis. Advanced TR and lower LVEDD are independent adverse predictors of mortality in patients with idiopathic RCMP.

Restrictive Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy.

Restrictive cardiomyopathy (RCM) is characterized by nondilated left or right ventricle with diastolic dysfunction. The restrictive cardiomyopathies are a heterogenous group of myocardial diseases that vary according to pathogenesis, clinical presentation, diagnostic evaluation and criteria, treatment, and prognosis. In this review, an overview of RCMs will be presented followed by a detailed discussion on 3 major causes of RCM, for which tailored interventions are available: cardiac amyloidosis, cardiac sarcoidosis, and cardiac hemochromatosis. Each of these 3 RCMs is challenging to diagnose, and recognition of each disease entity is frequently delayed. Clinical clues to promote recognition of cardiac amyloidosis, cardiac sarcoidosis, and cardiac hemochromatosis and imaging techniques used to facilitate diagnosis are discussed. Disease-specific therapies are reviewed. Early recognition remains a key barrier to improving survival in all RCMs.

Molecular mechanisms in cardiomyopathy.

Cardiomyopathies represent a heterogeneous group of diseases that negatively affect heart function. Primary cardiomyopathies specifically target the myocardium, and may arise from genetic [hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), mitochondrial cardiomyopathy] or genetic and acquired [dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM)] etiology. Modern genomics has identified mutations that are common in these populations, while in vitro and in vivo experimentation with these mutations have provided invaluable insight into the molecular mechanisms native to these diseases. For example, increased myosin heavy chain (MHC) binding and ATP utilization lead to the hypercontractile sarcomere in HCM, while abnormal protein-protein interaction and impaired Ca2+ flux underlie the relaxed sarcomere of DCM. Furthermore, expanded access to genetic testing has facilitated identification of potential risk factors that appear through inheritance and manifest sometimes only in the advanced stages of the disease. In this review, we discuss the genetic and molecular abnormalities unique to and shared between these primary cardiomyopathies and discuss some of the important advances made using more traditional basic science experimentation.