Ectopic trypsin in the myocardium promotes dilated cardiomyopathy after influenza A virus infection.

We have previously reported that ectopic trypsin in the myocardium triggers acute myocarditis after influenza A virus (IAV) infection. As myocarditis is a common precursor to dilated cardiomyopathy (DCM), the aim of the present study was to investigate the influence of trypsin on the progression of DCM after IAV infection. IAV-infected mice treated with saline or trypsin inhibitor were euthanized on days 0, 9, 20, 40 and 60 postinfection. Trypsin expression colocalized with myocardial inflammatory loci and IAV-induced myocarditis peaked on day 9 postinfection and alleviated by day 20 but persisted until day 60 postinfection, even though replication of IAV was not detected from day 20 postinfection. Similar time courses were observed for the activation of pro-matrix metalloproteinase (pro-MMP)-9 and expression of the proinflammatory cytokines IL-6, IL-1ß, and TNF-α. Degradation of collagen type I, proliferation of ventricular interstitial collagen, and expression of collagen type I and III mRNA increased significantly during acute and chronic phases; collagen type III mRNA increased more significantly than collagen type I mRNA. Cardiac function progressively deteriorated with progressive left ventricular dilation. The trypsin inhibitor aprotinin suppressed pro-MMP-9 activation and cytokine release, alleviated myocardial inflammation, and restored collagen metabolism during acute and chronic phases of myocarditis. This effectively prevented ventricular dilation and improved cardiac function. These results suggest that ectopic trypsin in the myocardium promoted DCM through chronic activation of pro-MMP-9, persistent induction of cytokines, and mediation of collagen remodeling. Pharmacological inhibition of trypsin activity might be a promising approach for the prevention of viral cardiomyopathy.

Time-course of diastolic dysfunction in different stages of chronic HCV related liver diseases.

AIM: A hyperdynamic circulatory pattern in advanced liver disease is known since a long time. The first studies evaluating cardiac function in cirrhosis were performed in patients with alcoholic liver disease and thus this condition was attributed to the toxic effects of ethanol. A reduced performance of the left ventricle after physical and pharmacological strains along with an altered diastolic function has been demonstrated also in postviral cirrhosis. Many factors are involved in advanced cirrhosis whereas little is known in the earlier stages of disease. METHODS: To this aim we have investigated patients with different stages of hepatitis C virus (HCV)-related liver disease to detect the time-course of diastolic dysfunction. An impaired relaxation and increased thickness of left ventricular walls along with an altered pattern of transmitral flow can be easily detected by means of echocardiography. RESULTS: In chronic hepatitis diastolic function is preserved but increased thickness of left ventricle parietal walls can be detected in patients with fibrosis on liver biopsy. The typical pattern of diastolic dysfunction is observed in Child A cirrhotic patients and in Child C ascitic patients but thickness of parietal walls is more relevant in the former group. Chronic aldosterone blockade could exert favourable effects in heart remodeling suggesting a potential role of these drugs in cirrhotic cardiomyopathy. CONCLUSIONS: The presence of increased thickness of left ventricle parietal walls in chronic hepatitis C in the precirrhotic stage point to a putative role of HCV in this heart structural abnormality that can become a co-factor in the more advanced stages of cirrhosis when portal hypertension and its deleterious effects on systemic hemodynamics, cardiac function and structure become manifest.

Core protein of hepatitis C virus induces cardiomyopathy.

Hepatitis C virus (HCV) has been reported to be associated with cardiomyopathy. However, the mechanism of cardiomyopathy in chronic HCV infection is still unclear. Therefore, we investigate the development of cardiomyopathy in mice transgenic for the HCV-core gene. After the age of 12 months, mice developed cardiomyopathy that appeared as left ventricular dilatation, and systolic and diastolic dysfunction assessed by Doppler echocardiography. Histologically, hypertrophy of cardiomyocytes, cardiac fibrosis, disarray and scarcity of myofibrils, vacuolization and deformity of nuclei, myofibrillar lysis, streaming of Z-bands, and an increased number of bizarre-shaped mitochondria were found in HCV-core transgenic mice. These histological changes are just consistent with cardiomyopathy. In conclusion, the HCV-core protein directly plays an important role in the development of cardiomyopathy.

Absence of viral nucleic acids in early and late dilated cardiomyopathy.

OBJECTIVE: To investigate whether viral infection acts as a trigger factor for the development of dilated cardiomyopathy in genetically predisposed individuals with a family history of disease. SETTING: Patients attending the cardiomyopathy unit in a cardiac tertiary referral centre. DESIGN: Nested polymerase chain reaction (nPCR) was used to determine whether enteroviral, adenoviral, or cytomegaloviral nucleic acids were detectable in the myocardium of 19 asymptomatic relatives of patients with dilated cardiomyopathy; all these relatives had echocardiographic abnormalities thought to represent early disease. Explanted hearts from patients with end stage dilated cardiomyopathy were also studied and were compared with 25 controls (ischaemic heart disease (21), valvar heart disease (2), hypertrophic cardiomyopathy (1), restrictive cardiomyopathy (1)). Myocardial tissue from two fatal cases of culture positive coxsackie myocarditis was used as a positive control. RESULTS: No viral nucleic acid was detected in any group other than in those with myocarditis. Spiking of random wells with purified recombinant viral nucleic acids confirmed the sensitivity and reproducibility of the assays. CONCLUSIONS: Myocardial viral infection is not detectable in relatives of patients with dilated cardiomyopathy who are suspected of having early disease. There is no evidence that viruses act as a trigger factor for initiating the dilated cardiomyopathy in these patients.