Biomarkers of fibrosis in heart failure and relations to left ventricular size, function and outcome

Abstract: Background: Heart failure (HF) is a syndrome with impaired quality of life and higher mortality than most forms of cancer. The excessive accumulation of collagen in the myocardial extracellular matrix is called myocardial fibrosis, which is a reaction to myocardial stress, myocardial injury and a part of the remodeling process that alters the shape, size, and function of the heart. Aims: To study (aims 1-3) myocardial fibrosis assessed by biomarkers at baseline in HF patients and their associations with 1) clinical variables, B-type natriuretic peptide (BNP), and echocardiographic findings at baseline 2) clinical variables, BNP, and echocardiographic findings in HF with or without atrial fibrillation 3) mortality outcomes 4) associations between temporal changes in biomarkers of myocardial fibrosis with clinical and echocardiographic findings and outcome. Methods and results: The OPTIMAL study consisted of 208 patients ≥60 years and hospitalized for HF with depressed systolic function. Patients were included from January 1996 to December 1999 and randomized to either follow-up at a nurse-led outpatient HF clinic or conventional follow-up in primary care. The main objective was to evaluate if the nurse-led outpatient HF clinic was associated with improved quality of life. The patients in this thesis are a cohort from the original study, with varying numbers of study objects due to the available numbers of echocardiographic examinations, long-term ambulatory ECG recordings, blood samples, and patients who survived the first year after inclusion. Paper I: Echocardiography and biomarkers of type I collagen synthesis (PICP) and degradation (CITP) were available for 132 patients. Both increasing levels of PICP and CITP were independently associated with increasing levels of BNP. Increasing levels of PICP were also independently associated with increasing left ventricular size and decreasing isovolumic relaxation time. Paper II: Long-term ambulatory ECG monitoring was available in 143 patients in addition to echocardiography, PICP, and CITP. Direct relations between levels of PICP and CITP to left atrial size were seen. Increasing levels of PICP and decreasing left ventricular end-diastolic volume were independently associated with atrial fibrillation. Paper III: Same cohort as in paper I. PICP and CITP predicted all-cause and cardiovascular mortality after adjustment for possible confounders in two different models. CITP was also a predictor of non-cardiovascular death and directly related to NYHA functional class. Paper IV: Sixty-eight patients from the cohort in paper I were analyzed at baseline and 12 months for PICP, CITP, matrix metalloproteinase-1 ([MMP-1], a collagenase), amino- terminal propeptide of type III collagen ([PIIINP], reflects type III collagen metabolism), and the CITP to MMP-1 ratio was calculated (an inverse index of collagen cross-linking). Pharmacotherapy was optimized over 12 months. Improved left ventricular ejection fraction (LVEF), decreased left ventricular mass index, better NYHA functional class, and lower BNP were parallel with lower levels of PICP, CITP, and CITP:MMP-1 in all patients after 12 months. Follow-up at ten years showed the later deceased (n=42) to be older and with a longer duration of HF compared with survivors. CITP at baseline and 12 months, and CITP:MMP-1 at 12 months were higher in the later deceased compared with the survivors. The temporal changes from baseline to 12 months were in favor of the survivors versus the later deceased regarding improved left ventricular dimensions and function, better NYHA functional class, lower BNP, and lower PICP. Conclusions: Higher levels of the biomarkers of type I collagen metabolism in HF patients with depressed EF are associated with increased cardiac size, increased BNP, atrial fibrillation, and worse outcomes. Pharmacotherapy improved cardiac function and functional capacity along with decreasing biomarkers of collagen metabolism. A reduction in the biomarker of type I collagen breakdown and an increase in type I collagen cross-linking seem to be prognostically favorable.