Myocardial Aldosterone receptors and Aquaporin 1 up-regulation causing cardiomyocyte remodeling in human heart failure

Background: Abnormal aldosterone signaling is a recognized source of cardio-vascular damage. Its influence on cardiomyocyte structure, function and hormonal receptors when associated with heart failure is still unreported. Methods: Twenty-six consecutive patients with heart failure (LVEF < 40%), normal coronaries and valves, underwent a left ventricular endomyocardial biopsy (EMB) for evaluation of myocardial substrate. Biopsy samples were processed for histology, electron microscopy, immunohistochemistry, and Western Blot analysis of myocardial aldosterone receptors and aquaporin-1 correlated with plasma aldosterone (AD) and renin activity (PRA). Eight patients with virus-negative inflammatory cardiomyopathy (ICM), had a control EMB after 6 months of immunosuppressive therapy and recovery of cardiac function with re-evaluation of cardiomyocyte structure and receptor expression. Results: EMB in addition to the diagnosis of myocarditis (15 cases), dilated cardiomyopathy (CM, 6), alcohol CM (2), diabetic CM (3), showed vacuolar degeneration and cloudy swelling of cardiomyocytes corresponding at electron microscopy to ions and water accumulation into cytosol, membrane-bound vesicles, nucleus and other organelles, associated to an increased AD, PRA and myocardial expression of aldosterone receptors (2.3 fold) and aquaporin 1 (2.6 fold). In the 8 pts recovered from ICM, cardiomyocyte diameter reduced with disappearance of intracellular vacuoles, normalization of cytosol, nucleus and cell organelles’ electron-density, along with down-regulation of aldosterone receptors and aquaporin-1. Conclusion: Human heart failure is associated with over-expression of myocyte aldosterone receptors and aquaporin-1 causing intracellular water overloading, swelling and functional compromise of cardiomyocytes. Cardiac recovery is accompanied by down-regulation of hormonal receptors and normalization of cell structure and composition

Removal of cardiac AL-amyloid with positive remodeling of cardiomyocytes and of restrictive cardiomyopathy

Herein, we describe histological mobilization of light chain cardiac amyloid documented by sequential left ventricular endomyocardial biopsies. These findings were associated with positive remodelling of cardiomyocytes and of restrictive cardiomyopathy resulting from 14 courses of chemotherapy over 17 years of time. Histological and ultrastructural findings of light chain cardiac amyloid removal led to increase in cardiomyocyte dimension and electrocardiogram voltages, reduction of biventricular wall thickness with improvement of left ventricular diastolic function, and NYHA class shifting from III to I

False-positive bone scintigraphy denoting transthyretin amyloid in elderly hypertrophic cardiomyopathy

A positive nuclear scintigraphy with hydroxy bisphosphonate bone tracer (99mTc-HPD) is believed to have high sensitivity (>99%) and specificity (91%) for the diagnosis of transthyretin amyloid cardiomyopathy. We report the case of an 85-year-old man with increased thickness of ventricular walls and a positive bone scintigraphy, who was unexpectedly found to have sarcomeric hypertrophic cardiomyopathy at left ventricular endomyocardial biopsy. Congo Red staining, immunohistochemistry, and transmission electronmicroscopy on six left ventricular samples scored negative for amyloidosis but were suggestive for sarcomeric hypertrophic cardiomyopathy. Genetic study did not show TTR and most commonly involved sarcomeric genes mutations. In hypertrophic cardiomyopathy focal cell necrosis related to demand/supply oxygen mismatch, small vessels disease or inflammation could be responsible of a false-positive bone scintigraphy signal for transthyretin amyloidosis. Because of this, especially in view of a possible specific treatment, endomyocardial biopsy is highly recommended for the correct diagnosis of cardiomyopathies with hypertrophic phenotype

Infiltration of conduction tissue is a major cause of electrical instability in cardiac amyloidosis

Abstract: Background: Pathology of conduction tissue (CT) and relative arrhythmias in living subjects with cardiac amyloid have never been reported. Aims: Reporting CT pathology and its arrhythmic correlations in human cardiac amyloidosis. Methods and Results: In 17 out of 45 cardiac amyloid patients, a left ventricular endomyocardial biopsy included conduction tissue sections. It was identified by Aschoff-Monckeberg histologic criteria and positive immunostaining for HCN4. The degree of conduction tissue infiltration was defined as mild when ≤ 30%, moderate when 30-70% and severe when > 70% cell area was replaced. Conduction tissue infiltration was correlated with ventricular arrhythmias, maximal wall thickness and type of amyloid protein. Mild involvement was observed in 5 cases, moderate in 3 and severe in 9. Involvement was associated with a parallel infiltration of conduction tissue artery. Conduction infiltration correlated with severity of arrhythmias (Spearman rho=0.8, p <0.001). In particular, major ventricular tachyarrhythmias requiring pharmacologic treatment or ICD implantation occurred in 7 patients with severe, 1 patient with moderate and none with mild conduction tissue infiltration. Pacemaker implantation was required in 3 patients with complete conduction section replacement. No significant correlation was observed between the degree of conduction infiltration and age, cardiac wall thickness or type of amyloid protein. Conclusion: Amyloid-associated cardiac arrhythmias correlate with extent of conduction tissue infiltration. Its involvement is independent from type and severity of amyloidosis, suggesting a variable affinity of amyloid protein to conduction tissue

Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome

Aims : Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported. Methods and results : Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients. Conclusion : Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression

Pemphigus-associated cardiomyopathy: report of autoimmune myocarditis and review of literature

Pemphigus is a rare disease characterized by bullous lesions of the skin and mucous membranes. The aetiology is autoimmune and related to the formation of IgG autoantibodies against desmogleins, which are structural proteins of desmosomes that ensure the stability of contacts between cells. Cardiac involvement in patients with pemphigus is poorly documented. We report the data in the literature on this topic and a case of pemphigus-associated autoimmune myocarditis with damage of intercalated disc responding to immunosuppressive therapy. The occurrence of cardiomyopathy with left ventricular dysfunction in patients affected by pemphigus should be appropriately screened with endomyocardial biopsy as it could be the myocardial extension of a potentially reversible autoimmune disorder

A proposed strategy for anticoagulation therapy in noncompaction cardiomyopathy

Noncompaction cardiomyopathy (NCCM) is a rare condition characterized by prominent trabeculae, deep intertrabecular recesses, and a left ventricular myocardium with a two-layered structure, characterized by a spongy endocardial layer and a thinner and compacted epicardial one. NCCM can be isolated or associated with other congenital heart diseases and complex syndromes involving neuromuscular disorders and facial dysmorphisms. To date, more than 40 genes coding for sarcomeric, cytoskeletal, ion channels, and desmosomal proteins have been identified. Clinical presentation is also highly variable, ranging from no symptoms to end-stage heart failure (HF), lethal arrhythmias, sudden cardiac death, or thromboembolic events. In particular, the prevalence of thromboembolism in NCCM patients appears to be higher than that of a similar, age-matched population without NCCM. Thromboembolism has a multifactorial aetiology, which is linked to genetic, as well as traditional cardiovascular risk factors. In previous studies, atrial fibrillation (AF) was observed in approximately 25-30% of adult NCCM patients and embolism had a cardiac source in ~63-69% of cases; therefore, AF represents a strong predictor of adverse events, especially if associated to HF and neuromuscular disorders. Left ventricular dysfunction is another risk factor for thromboembolism, as a result of blood stagnation and local myocardial injury. Moreover, it is not completely clarified if the presence of deep intertrabecular recesses causing stagnant blood flow can constitute per se a thrombogenic substrate even in absence of ventricular dysfunction. For the clinical management of NCCM patients, an appropriate stratification of the thromboembolic risk is of utmost importance for a timely initiation of anticoagulant therapy. The aim of the present study is to review the available literature on NCCM with particular attention on thromboembolic risk stratification and prevention and the current evidence for oral anticoagulation therapy. The use of direct oral anticoagulants vs. vitamin K antagonists is also discussed with important implications for patient treatment and prognosis