Although there is general agreement on the favorable effect of immunosuppression in eosinophilic, granulomatous, giant-cell myocarditis and in lymphocytic myocarditis associated with connective ...tissue disorders and with rejection of a transplanted heart, its therapeutic role in lymphocytic inflammatory cardiomyopathy (ICM) is still debated. Previous retrospective studies reported a relevant clinical benefit in 90% of patients with virus-negative ICM and no response or cardiac impairment in 85% of those with virus-positive ICM following immunosuppression. Other studies identified cardiomyocyte HLA upregulation as an additional indicator of ICM susceptibility to immunosuppressive therapy. Recently in a single-center randomized prospective double-blind trial using a combination of prednisone and azathioprine in addition to supportive treatment in 85 virus-negative ICM patients, a significant improvement in left ventricular (LV) ejection fraction and a significant reduction in LV dimensions in 88% of 43 treated patients compared with 42 patients receiving placebo who showed a cardiac impairment in 83% of cases (TIMIC study) was reported. These data confirm the efficacy of immunosuppression in virus-negative ICM. Lack of response in 12% of cases suggests the presence of unscreened viruses or mechanisms of damage and inflammation not susceptible to immunosuppression. Recovery of cardiac function in responders to immunosuppression was associated with inhibition of cardiomyocyte death, increased cell proliferation and with newly synthesized contractile material. (Circ J 2015; 79: 4–7)
To investigate the contribution of unaffected cardiomyocytes in Fabry disease cardiomyopathy.
Left ventricular (LV) endomyocardial biopsies from twenty-four females (mean age 53 ± 11 ys) with Fabry ...disease cardiomyopathy were studied. Diagnosis of FD was based on the presence of pathogenic GLA mutation, Patients were divided in four groups according with LV maximal wall thickness (MWT): group 1 MWT ≤ 10.5 mm, group 2 MWT 10.5-15 mm, group 3 MWT 16-20 mm, group 4 MWT > 20 mm. At histology mosaic of affected and unaffected cardiomyocytes was documented. Unaffected myocytes' size ranged from normal to severe hypertrophy. Hypertrophy of unaffected cardiomyocytes correlated with severity of MWT (p < 0.0001, Sperman r 0,95). Hypertrophy of unaffected myocytes appear to concur to progression and severity of FDCM. It is likely a paracrine role from neighboring affected myocytes.
MicroRNAs (miRNAs/miRs) are small conserved RNA molecules of 22 nucleotides that negatively modulate gene expression primarily through base paring to the 3' untranslated region of target messenger ...RNAs. The muscle-specific miR-1 has been implicated in cardiac hypertrophy, heart development, cardiac stem cell differentiation, and arrhythmias through targeting of regulatory proteins. In this study, we investigated the molecular mechanisms through which miR-1 intervenes in regulation of muscle cell growth and differentiation.
On the basis of bioinformatics tools, biochemical assays, and in vivo models, we demonstrate that (1) insulin-like growth factor-1 (IGF-1) and IGF-1 receptor are targets of miR-1; (2) miR-1 and IGF-1 protein levels are correlated inversely in models of cardiac hypertrophy and failure as well as in the C2C12 skeletal muscle cell model of differentiation; (3) the activation state of the IGF-1 signal transduction cascade reciprocally regulates miR-1 expression through the Foxo3a transcription factor; and (4) miR-1 expression correlates inversely with cardiac mass and thickness in myocardial biopsies of acromegalic patients, in which IGF-1 is overproduced after aberrant synthesis of growth hormone.
Our results reveal a critical role of miR-1 in mediating the effects of the IGF-1 pathway and demonstrate a feedback loop between miR-1 expression and the IGF-1 signal transduction cascade.
The functional interdependencies between the molecular components of a biological process demand for a network medicine platform that integrates systems biology and network science, to explore the ...interactions among biological components in health and disease. Access to large-scale omics datasets (genomics, transcriptomics, proteomics, metabolomics, metagenomics, phenomics, etc.) has significantly advanced our opportunity along this direction. Studies utilizing these techniques have begun to provide us with a deeper understanding of how the interaction between the intestinal microbes and their host affects the cardiovascular system in health and disease. Within the framework of a multiomics network approach, we highlight here how tryptophan metabolism may orchestrate the host-microbes interaction in cardiovascular diseases and the implications for precision medicine and therapeutics, including nutritional interventions.
Objectives The aim of this study was to determine whether clinical presentation and type of cell death in acute myocarditis might contribute to cardiac magnetic resonance (CMR) sensitivity. ...Background Growing evidence indicates CMR is the reference noninvasive tool for the diagnosis of acute myocarditis. However, factors affecting CMR sensitivity are still unclear. Methods We retrospectively evaluated 57 consecutive patients with a diagnosis of acute myocarditis made on the basis of clinical history (≤3 months) and endomyocardial biopsy evidence of lymphocytic infiltrates (≥14 infiltrating leukocytes/mm2 at immunohistochemistry) in association with damage of the adjacent myocytes and absence or minimal evidence of myocardial fibrosis. CMR acquisition protocol included T2-weighted (edema), early (hyperemia), and late (fibrosis/necrosis) gadolinium enhancement sequences. Presence of ≥2 CMR criteria denoted myocarditis. Type of cell death was evaluated by using in situ ligation with hairpin probes. Results Three clinical myocarditis patterns were recognized: infarct-like (pattern 1, n = 21), cardiomyopathic (pattern 2, n = 21), and arrhythmic (pattern 3, n = 15). Tissue edema was observed in 81% of pattern 1, 28% of pattern 2, and 27% of pattern 3. Early enhancement was evident in 71% of pattern 1, 67% of pattern 2, and 40% of pattern 3. Late gadolinium enhancement was documented in 71% of pattern 1, 57% of pattern 2, and 47% of pattern 3. CMR sensitivity was significantly higher in pattern 1 (80%) compared with pattern 2 (57%) and pattern 3 (40%) (p < 0.05). Cell necrosis was the prevalent mechanism of death in pattern 1 compared with pattern 2 (p < 0.001) and pattern 3 (p < 0.05), whereas apoptosis prevailed in pattern 2 (p < 0.001 vs. pattern 1 and p < 0.05 vs. pattern 3). Conclusions In acute myocarditis, CMR sensitivity is high for infarct-like, low for cardiomyopathic, and very low for arrhythmic clinical presentation; it correlates with the extent of cell necrosis–promoting expansion of interstitial space.
Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported.
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.
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.
The limited ability of enzyme replacement therapy (ERT) in removing globotriaosylceramide from cardiomyocytes is recognized for advanced Fabry disease cardiomyopathy (FDCM). Prehypertrophic FDCM is ...believed to be cured or stabilized by ERT. However, no pathologic confirmation is available. We report here on the long-term clinical-pathologic impact of ERT on prehypertrophic FDCM.
Fifteen patients with Fabry disease with left ventricular maximal wall thickness ≤10.5 mm at cardiac magnetic resonance required endomyocardial biopsy because of angina and ventricular arrhythmias. Endomyocardial biopsy showed coronary small-vessel disease in the angina cohort, and vacuoles in smooth muscle cells and cardiomyocytes ≈20% of the cell surface containing myelin bodies at electron microscopy. Patients received α-agalsidase in 8 cases, and β-agalsidase in 7 cases. Both groups experienced symptom improvement except 1 patients treated with α-agalsidase and 1 treated with β-agalsidase. After ERT administration ranging from 4 to 20 years, all patients had control cardiac magnetic resonance and left ventricular endomyocardial biopsy because of persistence of symptoms or patient inquiry on disease resolution. In 13 asymptomatic patients with FDCM, left ventricular maximal wall thickness and left ventricular mass, cardiomyocyte diameter, vacuole surface/cell surface ratio, and vessels remained unchanged or minimally increased (left ventricular mass increased by <2%) even after 20 years of observation, and storage material was still present at electron microscopy. In 2 symptomatic patients, FDCM progressed, with larger and more engulfed by globotriaosylceramide myocytes being associated with myocardial virus-negative lymphocytic inflammation.
ERT stabilizes storage deposits and myocyte dimensions in 87% of patients with prehypertrophic FDCM. Globotriaosylceramide is never completely removed even after long-term treatment. Immune-mediated myocardial inflammation can overlap, limiting ERT activity.
Primary aldosteronism (PA) causes a cardiomyopathy (CM) which substrate and evolution after aldosterone normalization are unreported.
Four male patients with aldosterone-secreting adrenal adenoma and ...cardiomyopathy (PACM, group A) were evaluated with 2D-echo, Magnetic Resonance (CMR), coronary angiography and left ventricular endomyocardial biopsy. Biopsy samples were processed for histology, electron microscopy, immunohistochemistry, and Western Blot analysis of myocardial aldosterone receptors and aquaporin 1 and 4.
Results were compared with endomyocardial samples from 5 patients with hypertensive cardiomyopathy of equivalent severity and normal plasma aldosterone (group B) and surgical samples from 5 controls (group C). One PACM patient was re-examined with CMR and endomyocardial biopsy 12 months after adrenalectomy with aldosterone and cardiac normalization.
Coronary arteries were normal in all. Group A showed prominent myocardial hypertrophy and fibrosis, with water accumulation in the cytosol and organelles of cardiomyocytes and microvascular smooth muscle cells, associated to reduced myofibril concentration and 2.8-fold increase in myocardial aldosterone receptors and aquaporin 1. At CMR, LGE areas were diffusely present. After aldosterone normalization, cardiomyocyte diameter reduced with disappearance of intracellular vacuoles, recovery of electron-density of cytosol and cell organelles, and myofibrillar content, persisting fibrosis and down-regulation of aldosterone receptors and aquaporin 1 channels. At CMR, myocardial mass reduced with recovery of cardiac contractility. LGE signal remained unchanged.
PACM is a reversible entity characterized by over-expression of aldosterone receptors and aquaporin 1. It induces a reversible intracellular water overloading causing impaired cardiomyocyte relaxation, contraction and ultrastructural integrity.
•Primary aldosteronism•Cardiomyopathy•Endomyocardial biopsy
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