Time course of early changes in plasma markers of collagen turnover following percutaneous transluminal coronary angioplasty.

INTRODUCTION: Marked changes occur in the collagen framework of the heart following acute ischemia, which is associated with adverse ventricular remodelling. Plasma markers of collagen turnover are useful in the assessment of remodelling and have predictive value, but their exact temporal dynamics following ischemia are unclear. OBJECTIVE: To characterize the early temporal dynamics of plasma markers of collagen turnover in a human model of coronary artery occlusion. METHODS: Fourteen patients undergoing elective percutaneous coronary intervention (PCI) to a single coronary artery were recruited in addition to a control group of eight patients undergoing elective diagnostic coronary arteriography. Sequential assessment of plasma levels of procollagen type I carboxyterminal propeptide and C-telopeptide for type I collagen (CITP) as markers of synthesis and degradation, respectively, was performed over a 16 h period. RESULTS: The ischemic burden in the PCI group was high, with 13 of the 14 patients demonstrating transient ST segment shift or positive troponin. Mean plasma levels of CITP on admission were 3.1 ng/mL and 3.0 ng/mL in the PCI and control groups, respectively (P value nonsignificant). There was a sequential increase in plasma CITP following PCI, peaking at 4.7 ng/mL at 16 h (P<0.01), with no change in the control group. There were no significant changes in plasma levels of procollagen type I carboxyterminal propeptide in either group. CONCLUSIONS: Plasma levels of CITP demonstrated early temporal dynamics of collagen degradation following transient coronary artery occlusion supporting the use of plasma markers of collagen turnover as an early tool in the assessment of the remodelling process following myocardial ischemia.

Primary care burden and treatment of patients with heart failure and chronic obstructive pulmonary disease in Scotland.

AIMS: Heart failure (HF) and chronic obstructive pulmonary disease (COPD) frequently coexist and present major challenges to healthcare providers. The epidemiology, consultation rate, and treatment of patients with HF and COPD in primary care are ill-defined. METHODS AND RESULTS: This was an analysis of cross-sectional data from 61 primary care practices (377 439 patients) participating in the Scottish Continuous Morbidity Recording scheme. The prevalence of COPD in patients with HF increased from 19.8% in 1999 to 23.8% in 2004. In 2004, the prevalence was similar in men and women (24.8% vs. 22.9%, P = 0.09), increased with age up to 75 years, and increased with greater socioeconomic deprivation (most deprived 31.3% vs. least deprived 18.6%, P = 0.01). Contact rates for HF or COPD in those with both conditions were greater than disease-specific contact rates in patients with either condition alone. Although overall beta-blocker prescribing increased over time; the adjusted odds of beta-blocker prescription in patients with COPD was low and failed to improve [odds ratio 0.30 (0.28-0.32), P < 0.001]. In 2004, only 18% of individuals with HF and COPD were prescribed beta-blockers vs. 41% in those without COPD. CONCLUSION: Chronic obstructive pulmonary disease is a frequent comorbidity in patients with HF and represents a significant healthcare burden to primary care. Although beta-blocker prescribing in the community has increased, less than a fifth of patients with HF and COPD received beta-blockers.

Bisoprolol in patients with heart failure and moderate to severe chronic obstructive pulmonary disease: a randomized controlled trial.

AIMS: Heart failure (HF) and chronic obstructive pulmonary disease (COPD) frequently coexist. No study has prospectively examined the effects of beta-blockade in those with both conditions. METHODS AND RESULTS: We randomized 27 patients with HF and coexistent moderate or severe COPD to receive bisoprolol or placebo, titrated to maximum tolerated dose over 4 months. The primary outcome was forced expiratory volume in 1 s (FEV(1)). The study is registered with ClinicalTrials.gov, number: NCT00702156. Patients were elderly and predominantly male. Cardiovascular comorbidity, smoking history, and pulmonary function were similar in each group (mean FEV(1) 1.37 vs. 1.26 L, P = 0.52). A reduction in FEV(1) occurred after 4 months following treatment with bisoprolol compared with placebo (-70 vs. +120 mL, P = 0.01). Reversibility following inhaled beta(2)-agonist and static lung volumes were not impaired by bisoprolol. All measures of health status exhibited a consistent non-significant improvement, including the Short Form 36 physical and mental component scores (2.6 vs. 0.5 and 0.8 vs. -0.3, respectively), Minnesota Living with Heart Failure Questionnaire (-2.5 vs. 3.5) and Chronic Respiratory Questionnaire (0.07 vs. -0.24). The mean number of COPD exacerbations was similar in the bisoprolol and placebo groups (0.50 and 0.31, respectively, P = 0.44). CONCLUSION: Initiation of bisoprolol in patients with HF and concomitant moderate or severe COPD resulted in a reduction in FEV(1). However, symptoms and quality of life were not impaired.

Serological evidence of early remodeling in high-risk non-ST elevation acute coronary syndromes.

INTRODUCTION: Non-ST elevation acute coronary syndrome (ACS) represents a spectrum of risk, with electrocardiographic (ECG) changes and a positive troponin being associated with higher morbidity and mortality. Ischaemia produces alterations in the collagenous component of the heart, even in the absence of myocyte necrosis. Collagen turnover can be assessed biochemically with C-propeptide for type I collagen (PICP) and C-telopeptide for type I collagen (CITP) being markers of collagen synthesis and degradation respectively. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is a marker of inhibition of degradation. METHODS: Fifty-two patients with non-ST elevation acute ACS were recruited and dichotomised into high- and low-risk groups based on ECG and troponin level. Sequential measurements of plasma PICP, CITP and TIMP-1 were performed over a 48 hour period. RESULTS: Twenty were classified as low-risk (negative troponin and normal ECG) and 32 as high-risk. PICP was within the normal range at all time points in both groups. However, admission CITP was higher in the high-risk group (3.7 vs. 2.6 ng/ml, p<0.001) and, unlike the low-risk group, demonstrated a further rise over 48 h. Similarly, mean TIMP-1 displayed a sequential change over time in the high-risk group only, and admission level was higher compared to the low-risk group (302 vs. 221 ng/ml, p<0.01). DISCUSSION: There is serological evidence of time-dependent altered collagen metabolism in high-risk ACS, which is not present in the low-risk group. This may reflect a degree of remodeling and may aid risk stratification of patients presenting with non-ST elevation ACS.

Increase in serum adiponectin concentration in patients with heart failure and cachexia: relationship with leptin, other cytokines, and B-type natriuretic peptide.

AIMS: Adiponectin is a fat-derived hormone involved in the regulation of metabolism. Adiponectin concentration is inversely related to body weight and, in animals, causes weight loss. We, therefore, measured adiponectin concentration in patients with heart failure (HF) and cachexia. METHODS AND RESULTS: Serum adiponectin concentrations were measured in three groups of patients with coronary artery disease (CAD): (i) HF, reduced left ventricular systolic function, and cachexia (n = 10); (ii) HF, reduced systolic function but no cachexia (n = 20); (iii) HF-controls-patients with CAD, no HF, and preserved systolic function (n = 10); and in a healthy control group (n = 7). Patients with HF and cachexia had higher concentrations of adiponectin [23.8 (10.2-37.2) microg/mL] than all other groups: HF-no cachexia 8.1 (0.5-16.6) microg/mL; CAD-controls 7.1 (0.4-13.5) microg/mL; and healthy controls 8.7 (2.5-16.8) microg/mL) (P < 0.05 for each comparison). Adiponectin correlated negatively with body mass index, percentage of body fat, waist circumference and insulin resistance, and positively with B-type natriuretic peptide (BNP) and tumour necrosis factor-alpha. CONCLUSION: Cachexia in HF is associated with an increase in adiponectin concentration. This may represent preservation of the physiological response to change in body fat but might also suggest that adiponectin plays a role in the pathogenesis of cachexia. The correlation between BNP and adiponectin also raises the possibility that the former might increase the secretion of the latter.

The management of hypertension in ischaemic heart disease.

PURPOSE OF REVIEW: Patients with hypertension and coronary artery disease are often inadequately treated. Blood pressure levels remain unacceptably high in about half of such patients. A significant shortfall exists between guidelines and practice in implementing evidence-based drug therapy. RECENT FINDINGS: Recent trials underscore the importance of blood pressure reduction. The purported superiority of specific drug classes, notably angiotensin-converting enzyme inhibitors and beta-blockers, is increasingly debated. Conversely, the benefits of calcium channel blockers are increasingly recognized. Irrespective of differences, all three agents are frequently required to achieve blood pressure targets. Beyond blood pressure reduction, statin therapy is undoubtedly the single most important risk factor intervention. New studies suggest that intensive lipid lowering and greater reductions in low-density lipoprotein cholesterol will further reduce major cardiovascular events. Finally, the impact of smoking cessation, exercise, and diet is often underestimated. SUMMARY: The prognosis for patients is critically dependent on reducing global cardiovascular risk by addressing all modifiable risk factors. The cornerstone of treatment remains blood pressure reduction, using agents with both antihypertensive and antianginal properties.

Hypertensive heart disease and fibrosis.

PURPOSE OF REVIEW: The clinical importance of fibrosis in hypertensive heart disease is now well recognized. However, the precise mechanisms involved in the pathophysiology and therefore the potential cardioreparative strategies are still not fully understood. These areas continue to be the focus of extensive research. This review summarizes the work conducted in this field over the past 12 months. RECENT FINDINGS: This article further confirms the involvement of the renin-angiotensin system in cardiac fibrosis and illustrates the supportive roles of mineralocorticoids, endothelin, and novel signaling pathways. It also summarizes the most recent data examining the genetic aspects of myocardial fibrosis and further clarifies potential cardioreparative strategies. SUMMARY: Myocardial fibrosis in hypertensive heart disease remains an area of intensive research. Whereas recent work has expanded our knowledge of the underlying processes in the development of this fibrosis, additional scientific and clinical research is required to assist clinical risk assessment and to provide evidence that therapeutic intervention confers improved clinical outcome in hypertensive heart disease.

TIMP-1: a marker of left ventricular diastolic dysfunction and fibrosis in hypertension.

This study was designed to document noninvasively the pathological mechanisms responsible for myocardial fibrosis and to assess the clinical utility of plasma markers of collagen synthesis and degradation as screening tools for the assessment of fibrosis in hypertension. We studied 100 never-treated hypertensive patients and 50 normal subjects. Echocardiographic assessment was made of left ventricular (LV) mass and diastolic filling using measurement of E:A ratio, E wave deceleration time (E dec), and isovolumic relaxation time (IVRT). The presence of diastolic dysfunction was taken as a surrogate marker for the presence of myocardial fibrosis. Plasma carboxy-terminal propeptide of collagen type I (PICP), carboxy-terminal telopeptide of collagen type I (CITP), and tissue inhibitor of matrix metalloproteinases type I (TIMP-1) were measured as markers of collagen synthesis, degradation, and inhibition of degradation, respectively. Plasma TIMP-1 was significantly elevated in the hypertensive cohort (358 ng/mL versus 253 ng/mL, P<0.001) as were CITP (5.2 microg/L versus 2.9 microg/L, P<0.001), and PICP (200 microg/L versus 166 microg/L, P<0.05). TIMP-1 was significantly elevated in patients with diastolic dysfunction (421 ng/mL versus 283 ng/mL P<0.01) and correlated with markers of diastolic filling, namely E:A ratio (r=0.26, P<0.05) and E Dec (r=0.41, P<0.01). A plasma TIMP-1 level of >500 ng/mL had a specificity of 97% and a positive predictive value of 96% in predicting diastolic dysfunction. In patients with untreated hypertension, there is evidence of increased collagen synthesis, degradation, and inhibition of degradation resulting in fibrosis. Our results demonstrate that plasma TIMP-1 correlates with markers of LV diastolic filling, is predictive of LV dysfunction, and is a potential noninvasive marker of fibrosis.