MiR-185-5p regulates the development of myocardial fibrosis

Background: Cardiac fibrosis stiffens the ventricular wall, predisposes to cardiac arrhythmias and contributes to the development of heart failure. In the present study, our aim was to identify novel miRNAs that regulate the development of cardiac fibrosis and could serve as potential therapeutic targets for myocardial fibrosis. Methods and results: Analysis for cardiac samples from sudden cardiac death victims with extensive myocardial fibrosis as the primary cause of death identified dysregulation of miR-185-5p. Analysis of resident cardiac cells from mice subjected to experimental cardiac fibrosis model showed induction of miR-185-5p expression specifically in cardiac fibroblasts. In vitro, augmenting miR-185-5p induced collagen production and profibrotic activation in cardiac fibroblasts, whereas inhibition of miR-185-5p attenuated collagen production. In vivo, targeting miR-185-5p in mice abolished pressure overload induced cardiac interstitial fibrosis. Mechanistically, miR-185-5p targets apelin receptor and inhibits the anti-fibrotic effects of apelin. Finally, analysis of left ventricular tissue from patients with severe cardiomyopathy showed an increase in miR-185-5p expression together with pro-fibrotic TGF-beta 1 and collagen I. Conclusions: Our data show that miR-185-5p targets apelin receptor and promotes myocardial fibrosis.Peer reviewe

Gender differences in prevalence and prognostic value of fragmented QRS complex

Background: Fragmented QRS (fQRS) on 12-lead electrocardiogram(ECG) is associated with scarred myocardium and adverse outcome. However, the data on gender differences in terms of its prevalence and prognostic value is sparse. The aim of this study was to evaluate whether gender differences in fQRS exist among subjects drawn from populations with different risk profiles. Methods: We analyzed fQRS from 12-lead ECG in 953 autopsy-confirmed victims of sudden cardiac death (SCD) (78% men; 67.0 +/- 11.4 yrs), 1900 coronary artery disease (CAD) patients with angiographically confirmed stenosis of >= 50% (70% men; 66.6 +/- 9.0 yrs, 43% with previous myocardial infarction [MI]), and in 10,904 adults drawn from the Finnish adult general population (52% men; 44.0 +/- 8.5 yrs). Results: Prevalence of fQRS was associated with older age, male sex and the history and severity of prior cardiac disease of subjects. Among the general population fQRS was more commonly found among men in comparison to women (20.5% vs. 14.8%, p <0.001). The prevalence of fQRS rose gradually along with the severity of prior cardiac disease in both genders, yet remained significantly higher in the male population: subjects with suspected or known cardiac disease (25.4% vs. 15.8% p <0.001), CAD patients without prior MI (39.9% vs. 26.4%, p <0.001), CAD patients with prior MI (42.9% vs. 31.2%, p <0.001), and victims of SCD (56.4% vs. 44.4%, p <0.001). Conclusions: The prevalence of QRS fragmentation varies in different populations. The fragmentation is clearly related to the underlying cardiac disease in both genders, however women seem to have significantly lower prevalence of fQRS in each patient population in comparison to men. (C) 2020 The Authors. Published by Elsevier Inc.Peer reviewe

Liver X Receptor Agonist 4β‐Hydroxycholesterol as a Prognostic Factor in Coronary Artery Disease

Background Regardless of progress in treatment of coronary artery disease (CAD), there is still a significant residual risk of death in patients with CAD, highlighting the need for additional risk stratification markers. Our previous study provided evidence for a novel blood pressure–regulating mechanism involving 4β‐hydroxycholesterol (4βHC), an agonist for liver X receptors, as a hypotensive factor. The aim was to determine the role of 4βHC as a prognostic factor in CAD. Methods and Results The ARTEMIS (Innovation to Reduce Cardiovascular Complications of Diabetes at the Intersection) cohort consists of 1946 patients with CAD. Men and women were analyzed separately in quartiles according to plasma 4βHC. Basic characteristics, medications, ECG, and echocardiography parameters as well as mortality rate were analyzed. At baseline, subjects with a beneficial cardiovascular profile, as assessed with traditional markers such as body mass index, exercise capacity, prevalence of diabetes, and use of antihypertensives, had the highest plasma 4βHC concentrations. However, in men, high plasma 4βHC was associated with all‐cause death, cardiac death, and especially sudden cardiac death (SCD) in a median follow‐up of 8.8 years. Univariate and comprehensively adjusted hazard ratios for SCD in the highest quartile were 3.76 (95% CI, 1.6–8.7; P=0.002) and 4.18 (95% CI, 1.5–11.4; P=0.005), respectively. In contrast, the association of cardiac death and SCD in women showed the lowest risk in the highest 4βHC quartile. Conclusions High plasma 4βHC concentration was associated with death and especially SCD in men, while an inverse association was detected in women. Our results suggest 4βHC as a novel sex‐specific risk marker of cardiac death and especially SCD in chronic CAD. Registration Information clinicaltrials.gov. Identifier NCT01426685

Serum PINP, PIIINP, galectin-3 and ST2 as Surrogates of Myocardial Fibrosis and Echocardiographic Left Venticular Diastolic Filling Properties

Objectives and Background. Serum biomarkers have been proposed to reflect fibrosis of several human tissues, but their specific role in the detection of myocardial fibrosis has not been well established. We studied the association between N-terminal propeptide of type I and III procollagen (PINP, PIIINP, respectively), galectin-3 (gal-3), soluble ST2 (ST2) and myocardial fibrosis measured by late gadolinium enhanced cardiac magnetic resonance imaging (LGE CMR) and their relation to left ventricular diastolic filling properties measured by tissue Doppler echocardiography (E/e´) in patients with stable coronary artery disease (CAD).Methods and Results. We determined the PINP, PIIINP, gal-3 and ST2 serum levels and performed LGE CMR and echocardiography on 63 patients with stable CAD without a history of prior myocardial infarction. Myocardial late gadolinium enhancement T1 relaxation time was defined as a specific marker of myocardial fibrosis. ST2, PINP and PIIINP did not have a significant correlation with the post-LGE T1 relaxation time tertiles (NS for all), but the lowest post-LGE T1 relaxation time tertile had significantly higher gal-3 values than the other two tertiles (p= 0,002 and 0.002) and higher E/é values (p= 0,009) compared to the highest T1 relaxation time tertile. ST2 (p= 0.025 and 0.029), gal-3 (p= 0.003 and < 0.001) and PIIINP (p= 0.001 and 0.007) levels were also significantly higher in the highest E/é tertile, compared to the other two tertiles.Conclusions. Elevated serum levels of gal-3 reflect the degree of myocardial fibrosis assessed by LGE CMR. Gal-3, ST2 and PIIINP are also elevated in patients with impaired LV diastolic function, suggesting that these biomarkers are useful surrogates of structural and functional abnormality of the myocardium

Endothelin-1 is associated with mortality that can be attenuated with high intensity statin therapy in patients with stable coronary artery disease

Abstract Background All coronary artery disease (CAD) patients do not benefit equally of secondary prevention. Individualized intensity of drug therapy is currently implemented in guidelines for CAD and diabetes. Novel biomarkers are needed to identify patient subgroups potentially benefitting from individual therapy. This study aimed to investigate endothelin-1 (ET-1) as a biomarker for increased risk of adverse events and to evaluate if medication could alleviate the risks in patients with high ET-1. Methods A prospective observational cohort study ARTEMIS included 1946 patients with angiographically documented CAD. Blood samples and baseline data were collected at enrollment and the patients were followed for 11 years. Multivariable Cox regression was used to assess the association between circulating ET-1 level and all-cause mortality, cardiovascular (CV) death, non-CV death and sudden cardiac death (SCD). Results Here we show an association of circulating ET-1 level with higher risk for all-cause mortality (HR: 2.06; 95% CI 1.5–2.83), CV death, non-CV death and SCD in patients with CAD. Importantly, high intensity statin therapy reduces the risk for all-cause mortality (adjusted HR: 0.05; 95% CI 0.01–0.38) and CV death (adjusted HR: 0.06; 95% CI 0.01–0.44) in patients with high ET-1, but not in patients with low ET-1. High intensity statin therapy does not associate with reduction of risk for non-CV death or SCD. Conclusions Our data suggests a prognostic value for high circulating ET-1 in patients with stable CAD. High intensity statin therapy associates with reduction of risk for all-cause mortality and CV death in CAD patients with high ET-1

Presence of atrial fibrillation is associated with liver stiffness in an elderly Finnish population

Abstract Background: Chronic liver injury from different etiologies drives liver fibrosis. However, little is known about the associated factors, systemic factors in particular. Recently, non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation have been shown to be associated with each other. Thereby, we aimed to study the association between atrial fibrillation and liver stiffness. Study: Extensive clinical measurements including echocardiography of the heart, transient elastography (TE) of the liver and the presence of atrial fibrillation were determined in elderly Finnish study subjects (n = 76, mean age 73 years) from OPERA (Oulu Project Elucidating the Risk of Atherosclerosis) study cohort. Half of the study subjects had non-alcoholic fatty liver disease, whereas others did not have any known hepatic morbidity. The present study was cross-sectional by nature. Results: The subjects with atrial fibrillation had higher TE values (with atrial fibrillation TE = 9.3kPa, without atrial fibrillation TE = 6.3kPa, p = 0.018). When the cohort was divided to four subgroups (those without NAFLD or atrial fibrillation, with NAFLD but without atrial fibrillation, with both conditions, and with atrial fibrillation but without NAFLD), the TE value was the highest in the subjects with both conditions (5.3kPa, 7.4kPa, 10.8kPa and 7.8kPa, respectively, p = 0.019). Moreover, the higher the TE value, the more prevalent atrial fibrillation was (the atrial fibrillation prevalence by tertiles of TE 27% / 36% / 77%, p = 0.001). Likewise, the greater the TE value, the greater the left atrial diameter, a collateral of atrial fibrillation (left atrial diameters by tertiles of TE 39mm / 45mm / 48mm, p"&lt;"0.001) was. All these p-values for continuous variables remained statistically significant even after adjustment for common clinically relevant risk factors. Conclusions: There is an association between atrial fibrillation and liver stiffness. This novel association may have multiple explanations and mechanistic links, which are discussed here and need further studies, prospective studies in particular

The left atrial diameter (mm) by transient elastography tertiles.

<p>The mean LAD in the first TE tertile (n = 21) was 39mm (SD ±7mm), in the second tertile (n = 28) 45mm (SD ± 7mm) and in the third tertile (n = 26) 48mm (SD ± 8mm) (p<0.001). After adjustments (BMI, age, gender, amount of alcohol intake (g/week), smoking (pack years), Quick index, systolic blood pressure) the statistical significance prevailed (p = 0.012). Abbreviations: LAD, left atrial diameter; TE, transient elastography; BMI, body mass index.</p

The characteristics of the subjects with transient elastography (n = 76) by subgroups used in the study selection.

<p>The characteristics of the subjects with transient elastography (n = 76) by subgroups used in the study selection.</p