Around 399,000 individuals die every year from HCV or from complications linked to its chronic infection including liver cirrhosis, liver failure, or hepatocellular carcinoma (HCC). Six major HCV genotypes have been identified in the Middle East and Africa including Egypt, HCV genotype 4 is the most prevalent .
Besides the widely known harmful effects of HCV on the liver structure and function, its chronic infection is connected with different extra-hepatic manifestations, such as glomerulonephritis, non-Hodgkin B cell lymphoma, mixed cryoglobulinemia, pulmonary fibrosis, autoimmune diseases, and ocular and dermatological diseases, whose mechanisms blamed in its pathogenesis are persistent immune system stimulation in addition to the tropism of the HCV virus for other tissues .
Moreover, chronic HCV has been also associated with higher risk of cardiovascular diseases. In reality, some authors have been hypothesized that chronic HCV infection could take part in the atheromatous process basically by means of increased oxidative stress, chronic inflammation, and insulin resistance (IR) as well as replication of HCV virus on the pre-existing plaques. Furthermore, few studies have investigated the potential hazardous effects of HCV infection on both right and left heart; nevertheless, the findings are conflicting. Hypertrophic and dilated cardiomyopathies have been depicted as extra-hepatic morbidity linked to chronic HCV; however, their true frequency is quiet unknown .
Compared to interferon-based therapy (IBT), DAAs have demonstrated outstanding efficacy safety and revolutionized paradigms for HCV towards wider approaches for cure . It has been shown that HCV virologic cure invariably diminish liver inflammation, indicated by improved aminotransferase levels and decreased rates of liver fibrosis progression. SVR also contributes to regression of liver cirrhosis and improves the clinical signs of portal hypertension as well as end-stage liver disease in some patients. Additionally, it has been reported eradication of HCV was linked with general improvement in extra-hepatic comorbidities such as cryoglobulinemia, insulin sensitivity, and non-Hodgkin’s lymphoma . However, few studies have investigated the effects of the DAAs on cardiovascular biomarkers after HCV elimination.
The aim of our study was to investigate plasma B-type natriuretic peptide (BNP) in chronic HCV Egyptian patients prior and after sofosbuvir and daclatasvir with or without ribavirin therapy and to highlight the effect of HCV eradication on plasma BNP levels.
The present study was performed on 89 chronic HCV participants; they received DAAs therapy in the form of sofosbuvir 400 mg/day and daclatasvir 60 mg/day with or without ribavirin for 12 weeks. All patients showed undetected HCV RNA in week 4, end of treatment (EOT), and SVR12. We observed that achieving SVR12 was associated with lowering ALT and AST levels, besides lowering of FIB-4 and APRI scores, and this was agreed with previous reports .
BNP as well as other structurally linked peptides, which are C-type natriuretic peptide (CNP), atrial natriuretic peptide (ANP), and urodilatin, is a member of the natriuretic peptide family. The natriuretic peptides possess a typical biochemical structure consisting of a 17 amino acid ring together with a bridge of disulfide in-between two molecules of cysteine. It was found that the ventricular myocardium is considered to be the main source of BNP synthesis and secretion. ANP is stowed in granules, and after stimulation, it could be released immediately, while only little amounts of BNP are stowed in granules and the implied mechanism for the organization of BNP secretion is speedy gene expression accompanied by de novo synthesis of the peptide. It was reported that BNP is synthesized as a prohormone (proBNP) containing 108 amino acids. When proBNP is released in the circulation, it is cleaved to egalitarian proportions into the biologically active 32 amino acid BNP, which represents the C-terminal part and a 76 amino acid N-terminal part that is biologically inactive .
Myocardial wall stress was notified to be the crucial stimulus for increasing the synthesis and secretion of BNP and NT-proBNP. Additionally, other stimulating agents like cytokines, myocardial ischaemia, and endocrine (paracrine) modulation by other neurohormones are also essential .
We displayed noteworthy outcomes, where overall plasma BNP changes in studied HCV patients prior and post eradication of HCV showed a non-significant difference of its plasma mean values in post-treatment compared to prior treatment indicating, to some extent, the cardiovascular safety of used drugs. These results were in accordance with previous literature, where mean values of BNP were found to be not changed before and 3 months after HCV eradication .
In a former study, it was stated that plasma BNP offers prognostic details in chronic heart failure patients as well as in patients with asymptomatic or symptomatic left ventricular dysfunction . Furthermore, it has been shown that plasma NT-proBNP independently foretells long-term death risk due to congestive heart failure . In the general population, both biomarkers were identified as accurate diagnostic and prognostic cardiac markers that correlate with both CHF symptoms and the severity of systolic and diastolic dysfunction . Moreover, these biomarkers have been shown to be associated with the extent of circulatory dysfunction in patients with liver cirrhosis .
In the present study we noticed a non-significant relation found between BNP levels and BMI. These results disagree with those of Wang and his colleagues who have elucidated a consistent inverse relationship between circulating BNP levels and BMI . This difference can be attributed to the difference in the population samples as they classified the patients as obese defined as having a BMI of 30 or greater and non-obese with BMI less than 30. We planned in our study to exclude patients with BMI equal or more than 30 to evade the influence of obesity on BNP levels.
Our study demonstrated significant positive correlations among BNP levels and FIB4 and APRI scores together with a considerable negative correlation among BNP levels and platelets. Additionally, we observed that higher baseline BNP levels were detected in patients with liver cirrhosis than in patients with normal liver echogenicity.
A body of evidence suggests that the impact of HCV-associated inflammation on cardiovascular risk could be higher in patients with more liver damage. The profibrogenic and proinflammatory environment driving liver fibrogenesis in HCV patients may likewise be systemically activated, over and above enhancing the development of cardiovascular lesions . Consistent with these data, a cohort study has found that chronic HCV patients with higher liver stiffness values had a substantial hazard for development of cardiovascular events compared to those with lower stiffness values . Additionally, Maruyama and his colleagues have reported that in chronic HCV patients a considerable link was present between myocardial injury and both the severity of necroinflammatory activity and subsequent liver damage . Several factors were also suggested to mediate the link between HCV infection and risk of CVD development including augmented oxidative stress, modified iron homeostasis, activation of immunological, and/or inflammatory processes leading to a disrupted cytokine imbalance as well as induction of hepatic steatosis, a risk factor in insulin sensitivity and related metabolic abnormalities .
To the best of our knowledge, there were no considerable data available demonstrating the correlations between the change in BNP levels and the severity of liver disease. In our study, we observed that delta BNP was considerably related to liver echogenicity where BNP was significantly decreased in patients with advanced liver disease as determined by pretreatment presence of liver cirrhosis and higher FIB4 or APRI scores than its baseline values before starting treatment, as we previously reported that these patients showed baseline higher BNP levels. These results reflected the beneficial cardiac effects of HCV eradication as one of its extra-hepatic manifestations.
It was formerly illustrated by Dalbeni and his colleagues that HCV is accountable for cardiac and vascular remodeling via direct cytotropic toxicity in addition to an indirect immune-mediated mechanism, most likely both are eliminated when HCV is eradicated. Moreover, they found that in participants with a detectable high cytokines concentration, they observed a significant decrease of TNF-α . TNF-α has been considered to be a potent proinflammatory molecule, which is associated with cardio-toxic effect, is secreted via the activated monocytes and macrophages in response to diverse infections. It stimulates the release of acute phase proteins in the liver driving lymphocyte and endothelial activation ; however, Dalbeni et al. found non-significant differences in mean values of both HS-TnT and NT-proBNP as cardiac biomarkers between pretreatment and post-treatment . The difference in the results of cardiac biomarkers and those we obtained may be related to the biomarker used as well as they did not calculate the delta BNP for correlating it with baseline levels or degree of liver disease