John Marshall Cowan: An appreciation.

John Marshall Cowan (1870-1947) descended from a long line of Glasgow medical practitioners. He was at the forefront in the great advances made in cardiology during the first quarter of the 20th century. He was a founder member of the Cardiac Club and the principal author of a major text book Diseases of the Heart, first published in 1914. He had a distinguished military career and was physician in charge of wards in the Royal Infirmary, Glasgow and Professor of Medicine at Anderson's College, Glasgow. This article outlines Cowan's life, career and publications and also provides an examination of his magnum opus, Diseases of the Heart.

Hypertension, Left Ventricular Hypertrophy, and Myocardial Ischemia.

The risks associated with hypertension emerge through a series of complex interactions. Myocardial ischemia is the major contributor to this risk. The mechanisms driving ischemia reflect many of the key factors in hypertension, including endothelial and neurohumoral factors, fibrosis, and hemodynamics. Left ventricular hypertrophy and fibrosis are of fundamental importance and together with hemodynamics provide an optimal template for myocardial ischemia. Understanding the pathophysiology has aided a more rational management approach but challenges remain which, if surmounted, will have an impact on the morbidity and mortality caused by myocardial ischemia in patients with hypertension.

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.

Hypertension and myocardial ischemia.

Detailed studies over the past 30 years have built up an impressive evidence base for the presence of myocardial ischemia in patients who have hypertension. This relationship ranges from the obvious association with obstructive coronary artery disease to mechanisms related to hemodynamic, microcirculatory, and neuroendocrine abnormalities. All of these factors serve to destabilize the critical balance between myocardial oxygen supply and demand. We have at our disposal a range of sophisticated investigations that allow us to demonstrate the presence and extent of the ischemia and therefore to target specific therapies to reduce the risk to these patients. Achieving target BP and managing all reversible components of the patient's cardiovascular risk status reduce to a minimum the clinical sequelae of myocardial ischemia in this vulnerable population..

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.

Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology.

Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are global epidemics incurring significant morbidity and mortality. The combination presents many diagnostic challenges. Clinical symptoms and signs frequently overlap. Evaluation of cardiac and pulmonary function is often problematic and occasionally misleading. Echocardiography and pulmonary function tests should be performed in every patient. Careful interpretation is required to avoid misdiagnosis and inappropriate treatment. Airflow obstruction, in particular, must be demonstrated when clinically euvolaemic. Very high and very low concentrations of natriuretic peptides have high positive and negative predictive values for diagnosing HF in those with both conditions. Intermediate values are less informative. Both conditions are systemic disorders with overlapping pathophysiological processes. In patients with HF, COPD is consistently an independent predictor of death and hospitalization. However, the impact on ischaemic and arrhythmic events is unknown. Greater collaboration is required between cardiologists and pulmonologists to better identify and manage concurrent HF and COPD. The resulting symptomatic and prognostic benefits outweigh those attainable by treating either condition alone.

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.

Biochemical evidence of myocardial fibrosis in veteran endurance athletes.

BACKGROUND: Studies on exercise-induced left ventricular hypertrophy (LVH) in veteran athletes suggest the presence of abnormal diastolic filling and incomplete regression of LVH on cessation of exercise. HYPOTHESIS: Myocardial fibrosis occurs in exercise induced LVH in veteran athletes. AIM: To document non-invasively the presence of fibrosis in veteran athletes DESIGN: Prospective case-control study. SETTING: City centre district general hospital. PARTICIPANTS: 45 normotensive elite veteran athletes and 45 normal sedentary subjects. INTERVENTIONS: Echocardiographic assessment was made of LV mass, LV systolic and LV diastolic function. Plasma carboxyterminal propeptide of collagen type I (PICP), carboxyterminal telopeptide of collagen type I (CITP) and tissue inhibitor of matrix metalloproteinase type I (TIMP-1) were measured as markers of collagen synthesis, degradation and inhibition of degradation, respectively. RESULTS: Veteran athletes had significant elevation in LV dimensions and calculated LV mass index (LVMI). Diastolic and systolic function was normal. Plasma PICP (259 vs 166 microg/l, p<0.001), CITP (5.4 vs 2.9 microg/l, p<0.001) and TIMP-1 (350 vs 253 ng/ml, p = 0.01) were elevated in the cohort of athletes. There was a further elevation of TIMP-1 in athletes with echocardiographic LVH, defined as an LVMI >130 g/m(2) (417 vs 266 ng/ml, p = 0.02). CONCLUSION: There is biochemical evidence of disruption of the collagen equilibrium favouring fibrosis in veteran athletes with LVH. This may suggest that fibrosis occurs as part of the hypertrophic process in veteran athletes.

Prevalence and prognostic impact of bundle branch block in patients with heart failure: evidence from the CHARM programme.

BACKGROUND: Bundle branch block (BBB) is a powerful independent predictor of cardiovascular mortality in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). The prognostic implications in HF with preserved systolic function (HF-PSF) are less well understood. METHODS: The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme randomised 7599 patients with symptomatic HF to receive candesartan or placebo. The primary outcome comprised cardiovascular death or HF hospitalisation. The relative risk conveyed by BBB relative to a normal electrocardiogram was examined. RESULTS: The prevalence of BBB was significantly lower in patients with preserved compared with reduced systolic function (CHARM-Preserved 14.4%, Alternative 29.6%, Added 30.5%), p<0.0001. Overall, the adjusted hazard ratio for the primary outcome was 1.48 (95% confidence interval 1.22-1.78), p<0.0001, reflecting increased risk in patients with reduced LVEF (1.72 [1.28-2.31], p=0.0003). The apparently more modest risk among patients with HF-PSF was significant in unadjusted (1.80 [1.37-2.37], p<0.0001) but not adjusted analysis (1.16 [0.88-1.54], p=0.2897). However, no formal statistical difference was observed between the two cohorts, and interpretation is limited by the unknown prevalence of left and right BBB morphologies in each. Comparing BBB presence with absence yielded qualitatively similar results. CONCLUSION: The simple clinical finding of BBB is a powerful independent predictor of worse clinical outcomes in patients with HF and reduced LVEF. It is less frequent, with a more modest predictive effect, in patients with preserved systolic function.

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.

Serological evidence of altered collagen homeostasis reflects early ventricular remodeling following acute myocardial infarction.

BACKGROUND: Infarct expansion characterises early ventricular remodeling following myocardial infarction (AMI) and is a product of the balance between collagen degradation and synthesis. Serological markers of collagen turnover may help in predicting those at risk of remodeling. C-propeptide for type-I collagen (PICP) and C-telopeptide for type-I collagen (CITP) are markers of collagen synthesis and degradation, respectively. METHODS: Fifty-one patients with AMI were recruited and dichotomised by echocardiographic wall motion index (WMI). Sequential measurements of plasma PICP and CITP were correlated to this and other echocardiographic variables of remodeling. RESULTS: Twenty-three normal WMI, 28 abnormal WMI. Both groups showed increases in PICP and CITP over time. However, mean admission CITP higher in abnormal WMI group, 4.5 vs. 3.1 ng/ml (p<0.05) as was peak, 6.3 vs. 4.8 ng/ml (p<0.05). Conversely, admission PICP was lower in abnormal WMI group 114 vs. 143 ng/ml (p<0.05). Admission CITP correlated with WMI, r=0.53, p<0.001. CITP>3.2 ng/ml (normal mean+2S.D.) had 74% positive predictive value for abnormal WMI, negative predictive value 65%. Admission CITP negatively correlated with mitral deceleration time (Dt), r=-0.38, p=0.01. CITP>3.2 was associated with lower Dt-183 vs. 221 ms, p<0.05. CONCLUSION: There is serological evidence of sequential increases in both collagen synthesis and degradation following AMI. However, the balance between these differs in patients who undergo remodeling, manifested by abnormal WMI and reduced Dt, compared to those with no evidence. They have relatively increased degradation and reduced synthesis, favouring net collagen breakdown. These changes occur early with evidence of increased breakdown on admission predicting early remodeling and support the role of serological markers to identify patients at risk of this.

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.

Treatment of hypertensive patients with coexisting coronary arterial disease.

Despite clear guidelines and an array of available antihypertensive medications, patients with hypertension and coronary artery disease are often inadequately treated. New data from HOPE, LIFE, and ALLHAT underscores the importance of blood pressure reduction for patients with coronary artery disease. Despite our improved understanding of the mechanism by which the various classes of antihypertensive medications achieve their effect, it remains the case that blood pressure reduction remains more important than the medication used to achieve the reduction. For most patients with coronary artery disease, combination therapy will be required to achieve a target blood pressure of less than 140/80. When tolerated, this therapy should include a beta-blocker and ACE inhibitor, both of which are of prognostic benefit for patients with coronary artery disease. There are also attractions in choosing calcium antagonists because of their efficacy in controlling anginal symptoms (Dihydropyridine calcium channel blockers if already on a beta-blocking agent and rate-limiting calcium channel blockers if beta blockers are contraindicated). Thiazide diuretics have proven themselves effective again in the ALLHAT study and are likely to be an integral part of treatment for the great majority of patients with coronary artery 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.