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Previous randomized clinical trials investigated therapeutic role of exogenous relaxin in patients with acute-on-chronic heart failure HF and failed to meet clinical endpoints. Here, we aimed to assess endogenous, circulating RLN1 levels in patients with heart failure with reduced ejection fraction HFrEF of ischemic origin.

Furthermore, we analyzed relation of RLN1 and left ventricular diastolic function, left and right ventricular fibrosis, and invasive hemodynamic measurements. Unique feature of our study is the availability of ex vivo human myocardial tissue.

Tissue was collected immediately after heart explantations; peripheral blood was collected before induction of anesthesia. Medical records were analyzed ECG, anthropometry, blood tests, medication, echocardiography, and invasive hemodynamic measurements.

Conclusion: Increased RLN1 levels were accompanied by lower myocardial fibrosis rate, which is a novel finding in our patient population with coronary artery disease 1 June Volume 10 Article Simon et al. RLN1 can have a biomarker role in ventricular fibrosis; furthermore, it may influence hemodynamic and vasomotor activity via neurohormonal mechanisms of action. Given these valuable findings, RLN1 may be targeted in anti-fibrotic therapeutics and in perioperative care of heart transplantation.

We aimed to evaluate perioperative blood tests, echocardiography, and invasive hemodynamic measurements in comparison with circulating RLN1 arthrosis rizskezelés. We hypothesized that circulating RLN1 levels affect the degree of left and right ventricular myocardial fibrosis and act via the Notch signaling pathway in the failing human myocardium. To underpin our hypothesis, we quantified left and right ventricular myocardial fibrosis and its correlation with circulating RLN1 and investigated gene expression levels of RLN1 and Notch-1 signaling.

Furthermore, we aimed to compare relaxin levels with echocardiography results and hemodynamic parameters in the context of postoperative vasoplegia syndrome as well.


Relaxin RLN is a polypeptide hormone that was first examined for its potential role in reproduction and pregnancy. RLN1 and 2 were reported to increase the collagen solubility in the cervix of the uterine, as well as to soften the pubic symphysis in the pregnant women Hansell et al. The RLN peptide family consists of seven members and produced by interstitial cells of various organs Dschietzig and Stangl, ; Park et al.

Further studies reported that cardiac cells are able to produce and secrete RLN and their receptors were identified in the heart Taylor and Clark, ; Hsu et al.

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This fact has been underpinned by several studies in which RLN1-knock out mice were studied Du et al. In these animals, large-scale fibrosis was reported in the lungs, kidneys, and left ventricle of the heart Dschietzig et al.

This fibrosis was reversible by administrating exogenous RLN Huang et al. Ischemic heart disease is one of the most important causes of heart failure HF. A key mechanism of HF is cardiac remodeling caused by myocardial fibrosis and cardiomyocyte injury Heusch et al.

There are two types of myocardial fibrosis: interstitial fibrosis and replacement myocardial fibrosis Ambale-Venkatesh and Lima, Myocardial interstitial fibrosis is defined by diffuse, disproportionate accumulation of collagen Gonzalez et al. Replacement myocardial fibrosis is the result of post-myocardial infarction necrosis and scar formation.

Cardiomyocyte injury activates fibroblasts resulting in collagen turnover and extracellular fiber deposition. Even if these mechanisms are essential in the stabilization and relative function of the injured area, they can cause abnormal stiffening and impaired ventricular function, HF, arrhythmia or even sudden cardiac death Weber et al.

Clinical trials have shown that higher endogenous RLN1 levels are present in patients with HF, but these elevated levels proved to be not enough to compensate the above mentioned pathologic mechanisms Gu et al. RLN produced by cardiac myocytes and interstitial cells has been shown to stimulate myocardial cell growth in neonatal mice.

Other studies have shown that deficiency of RLN1 gene leads to cardiac pvr prostate normal range in cc with ageing Samuel et al. All of our patients were active on heart transplantation waiting list upon recruitment.

The Heart and Vascular Center at Semmelweis University runs pvr prostate normal range in cc detailed database for the Transplantation Biobank, in which full medical history, anthropometry, clinical data, medications, blood tests, echocardiography results, pharmacologic, and device therapy such as pacemaker PMimplantable cardioverter defibrillator ICDcardiac resynchronization therapy CRTand mechanical circulatory support MCS data are available upon retrospective collection.

For this study, end-stage HF patients with ischemic etiology were recruited. For control subjects, healthy volunteers of a cross-sectional voluntary cardiovascular screening program Budakalász Health Examination Survey Kiss et al. Blood sampling for all HFrEF patients was performed immediately before induction of the anesthesia for heart transplantation surgery.

Blood sampling among healthy controls was performed at random time a kézízület fáj a hidegtől on their visit of our epidemiology study.

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Echocardiography was performed by various number of investigators from the Heart and Vascular Center and other cardiology centers. Echocardiography data were obtained from the database of the Transplantation Biobank.

Given the wide range of referring institutes for a heart transplantation, incomplete echocardiography reports existed, which limits interpretation of advanced imaging such as TDI or speckle tracking.

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Frontiers in Physiology www. Relaxin-1 in Myocardial Fibrosis scanned and analyzed at 20× magnification images taken at full resolution with a single image dimension set at 1, × pixels, pixel size is 0.

The digital pictures were taken by Zeiss Axio microscope. In order to assess average myocardial fibrosis, two sections were processed from each sample and pictures of five different areas were scanned from each section strictly capturing the right and left upper and lower extremities and the center of each sectionthus altogether 20 independent images per sample were taken. The quantitative analyzes of the images were carried out with software ImageJ bundled with bit Java 1.

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Invasive hemodynamic measurements were carried out via pulmonary artery catheterization PAC to assess eligibility for heart transplantation within 1 month of referral, and pvr prostate normal range in cc multiple time points in the perioperative period.

All patients had PAC and invasive hemodynamic measurements at 24 h follow-up, post-operatively. Biobanking Procedure In the Transplantation Biobank of the Heart and Vascular Center at Semmelweis University, we gather various samples of the patients with end-stage heart disease who undergo heart transplantation at the Heart and Vascular Center at Semmelweis University.

These samples include the explanted heart for histology and molecular biology probes, and blood samples. The main steps of the biobanking procedure are the following: first, whole blood is drawn from recipients.

Experimental procedure strictly followed product catalog guides. Experimental steps strictly followed product catalog guide.

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To further assess levels of standard and novel cardiac biomarkers, NT-pro-BNP, CA and cholinesterase were measured in our blood laboratory, on site. Both methods are gold standard in the examination of tissue fibrosis, however, they are not specific for interstitial myocardial fibrosis. Tissue was fixed for 24 h, room temperature. Later on, ventricular samples were dehydrated in ethanol baths, embedded in paraffin, and mounted on salinized plates.

For the washing, 0. The stained sections were Frontiers in Physiology www. All subjects gave written informed consent in keeping fájdalomcsillapítók a csípőízület fájdalmaira the Declaration of Helsinki.

Statistical Analyses Samples from 47 independent patients and 36 age and sex matched healthy volunteers were used. Relaxin-1 in Myocardial Fibrosis experiments were performed with at least three technical replicates. Statistics and diagrams were established in GraphPad Prism 7. Blood Samples and Biomarkers Detailed laboratory test results can be seen in Table 1.

Beside a general cardiac biomarker NT-pro-BNP we have also measured novel cardiac biomarkers CA and RLN ; furthermore, cholinesterase levels from serum collected right before heart transplantation surgery were evaluated. Figure 1 shows cardiac biomarkers and cholinesterase levels in the HFrEF population compared with the healthy control subjects.

Survival at 1 year post-operatively was studied in the HFrEF population. Survival was independent of all blood sample results and biomarkers. Only All patients were on maximal tolerable doses of evidence based medications of chronic HF.

Demographics, medical history are reported in Table 1.

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Medications are reported in Table 2. Echocardiography and invasive hemodynamic measurements were obtained upon referral for heart transplantation list. Blood samples were drawn after the induction of anesthesia for heart transplantation surgery. Whisker dot plots show levels of A Relaxin-1 and B Relaxin-2 measured from serum drawn immediately before heart transplantation surgery.

Control healthy subjects were age and sexed matched, bloods were drawn at individual time points. Of note, most of the patients required down-grading of doses and medications due to intolerance in end-stage heart failure.

ACE, angiotensin converting enzyme. Parameter CA pre-op Mean Comparing pre- and postoperative 24, 48, and 72 h blood samples, RLN and cholinesterase levels were in correlation with acute phase proteins and invasive hemodynamic Frontiers in Pvr prostate normal range in cc www. Relaxin-1 in Myocardial Fibrosis wall motion abnormalities or valve disease. Megnagyobbodott nyirokcsomók és fájó ízületek ventricular dimensions, as well as systolic and diastolic volumes were increased, showing dilation and remodeling of the left ventricle.

Average right ventricular diameters were also dilated and TAPSE showed decreased longitudinal contraction of right ventricle. Interestingly, average values of pulmonary arterial pressures and pulmonary vascular resistance were increased, referring to chronic pathological remodeling in the pulmonary arterial vasculature, which is common in HFrEF.

According the definition of pre- post-capillary and combined pulmonary arterial hypertension most of our patients had combined pulmonary hypertension pulmonary capillary wedge pressure: Table 4 shows correlation of echocardiography and hemodynamic parameters with circulating RLN1 levels. Furthermore, circulating RLN1 levels showed significant negative correlation with a morphology parameter left ventricular end-systolic diameter and diastolic pulmonary artery pressure.

A,C Sections depict severe fibrosis of the left anterior segment of the left ventricle and B,D sections show mild myocardial fibrosis in the same area.

Severely fibrotic tissues were derived from a patient with low Relaxin-1 level, while mild fibrosis was associated with high Relaxin All myocardial tissues were collected upon explant of the failing heart in the operation theater and were immediately processed for histology.

E Quantification of fibrotic tissue in histology sections was performed in ImageJ. Image processing comprised of color transformation followed by threshold adjustment and pixel assessments. Rodeheffer et al. The proper pathogenesis of ischemic myocardial remodeling is still obscure. In the literature, there is only a limited amount of data regarding the diastolic function of the left ventricle and the systolic function of the right ventricle in ischemic cardiomyopathy Schinkel et al.

The latter can play a prominent role in the prognosis of patients after heart-transplantation by influencing pulmonary circulatory conditions.

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Furthermore, the function of the right ventricle is important in the acute decompensation of the patients with chronic HF Frea et al.