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Biomedical subjects

R J MacFadyen

Publications and source records attributed to R J MacFadyen.

At least 19 recordsLinked to original sources
PubMed2006

Extracellular matrix turnover and disease severity in Anderson-Fabry disease.

BACKGROUND: Anderson-Fabry Disease (AFD) is an inherited metabolic disease associated with premature death secondary to cardiovascular and renal disease. Patients with AFD develop progressive left ventricular (LV) remodelling and heart failure. We hypothesized that altered extracellular matrix (ECM) turnover contributes to the pathophysiology of cardiac disease in AFD. METHODS AND RESULTS: Twenty-nine consecutive patients (44.1 +/- 11.7 years, 15 male) with AFD and 21 normal controls (39.7 +/- 11.3 years, 10 male) had serum analysed for matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of matrix metalloproteinase-1 and -2 (TIMP-1, TIMP-2). All patients underwent clinical assessment, echocardiography and Mainz Severity Score Index (MSSI) measurement, a validated severity score in AFD. MMP-9 levels were significantly higher in patients than controls (1003.8 +/- 337.8 ng/ml vs 576.7 +/- 276.3 ng/ml respectively, p < 0.001). There were no differences in TIMP levels between patients and controls. There was a positive correlation between MMP-9 levels and MSSI (r = 0.5, p = 0.01). There was a negative correlation between MMP-9 and endocardial fractional shortening (FS) (r = -0.5, p = 0.01) and mid-wall FS (r = -0.6, p = 0.001). There was no correlation between other echocardiographic parameters and MMP-9 levels. These relations were independent of age and sex using stepwise linear regression analysis. CONCLUSIONS: Patients with AFD have abnormal ECM turnover compared to normal controls. The correlation between MMP-9 levels and systolic function suggests that altered ECM turnover is important in cardiac remodelling. The association between MMP-9 and overall disease severity suggests that circulating levels of MMP-9 may provide a useful marker for assessing the response of patients with AFD to enzyme replacement treatment.

Adult↗
PubMed2006

Contemporary referral of patients from community care to cardiology lack diagnostic and clinical detail.

The quantity of referrals to secondary care is increasing. That the quality of medical referrals is decreasing is a common allegation yet has rarely been assessed. We report a time-limited, cross-sectional survey evaluating cardiological referral information quality. Referral letters (n = 218, excluding direct access pro formas) from GPs to the Cardiology Department at City Hospital, Birmingham, were collated and analysed over 2 months. A subset (n = 49) of these patients completed questionnaires assessing their knowledge and patient communication of the referral. Information quality was poor (length, diagnosis, expectation, prior treatment and investigation) with almost half of all letters containing only outline symptomatic complaints without diagnosis. The majority of patients referred had not been investigated or treated in any way before referral. Despite lack of understanding of the reason for referral, typically the majority of patients expressed themselves as satisfied with the process. Given most referrals are seen as appropriate, information exchange between secondary and primary care is crucial. By contrast, the standard of even basic clinical assessment communicated between primary care and secondary care was severely limited. The reason(s) why medical assessment is lacking are unclear but must be explored to give more support to primary care to complete basic medical task particularly if investment is to flow into this source.

Cardiology Service, Hospital↗
PubMed2005

Tissue inhibitor of metalloproteinse-1 is a marker of diastolic dysfunction using tissue doppler in patients with type 2 diabetes and hypertension.

BACKGROUND: Tissue inhibitor of metalloproteinase-1 (TIMP-1) is associated with increased fibrosis of the extracellular matrix (ECM). Myocardial stiffness is a feature of diastolic dysfunction. We assessed circulating TIMP-1 as a marker of diastolic dysfunction in patients with type 2 diabetes mellitus (DM) and hypertension, who were compared with healthy controls. METHODS: We recruited 54 patients (43 males; mean age 68 +/- 5 years) with treated type 2 DM (i.e. controlled glycaemia, hypertension, hyperlipidaemia), 35 (30 males; 69 +/- 8 years) treated nondiabetic hypertensives, and 31 healthy controls (18 males; 66 +/- 5 years). Circulating TIMP-1 was measured by ELISA. Using transthoracic echocardiography, the early (E) diastolic mitral inflow velocity was measured with pulse wave Doppler, and the early mitral annular velocity (e'), a recognized index of diastolic relaxation, was measured with tissue Doppler. The E/A ratio was also calculated and isovolumic relaxation time measured. RESULTS: Mean e' levels differed significantly between controls, diabetics and hypertensives (P < 0.0001). Circulating TIMP-1 was significantly different between patients and controls (P = 0.006), but there was no statistically significant difference between the DM and hypertension group. In both groups, only e' was negatively correlated with TIMP-1 levels, with a stronger correlation among the hypertensive patients (Spearman r = -0.544, P = 0.001) when compared with the diabetic group (r = -0.341, P = 0.011). CONCLUSION: Diastolic relaxation is impaired in diabetes and hypertensive patients. The relationship between TIMP-1 and e' may reflect increased myocardial fibrosis and consequent diastolic dysfunction, which may be more prominent in hypertension.

Aged↗
PubMed2005

Abnormal circulating levels of metalloprotease 9 and its tissue inhibitor 1 in angiographically proven peripheral arterial disease: relationship to disease severity.

BACKGROUND: Peripheral arterial disease (PAD) is associated with adaptive changes in the vascular and muscle extracellular matrix (ECM) in response to reduced blood flow. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), are key modulators of ECM turnover. We hypothesized that patients with intermittent claudication (with low ankle-brachial blood pressure index, <0.8), and critical ischaemia would have raised circulating levels of MMP-9, TIMP-1 and TIMP-2 compared with healthy controls, reflecting an increase in proteolytic activity which may be related to ECM turnover in PAD. METHODS: We studied 36 patients (23 males; 65 +/- 9 years) with intermittent claudication and 43 (25 males; 68 +/- 12) patients with critical ischaemia. All patients had angiographic evidence confirming significant PAD. RESULTS: Circulating levels of MMP-9 and TIMP-1 were higher (both P < 0.0001) in the PAD patient groups compared with the controls. Patients with critical ischaemia had MMP-9 and TIMP-1 levels that were significantly higher than those with intermittent claudication. There were no differences in circulating TIMP-2 levels between patients and controls. There was a modest positive correlation between the white cell count (WCC) and MMP-9, both patients with intermittent claudication (Spearman, r = 0.398, P = 0.016) and critical ischaemia (r = 0.378, P = 0.014). CONCLUSION: We demonstrate higher levels of circulating MMP-9 and TIMP-1 in patients with intermittent claudication and critical ischaemia. Circulating concentrations of both markers can be related to disease severity, being higher in critical ischaemia compared with levels in intermittent claudication.

Aged↗
PubMed2005

What role do extracellular matrix changes contribute to the cardiovascular disease burden of diabetes mellitus?

Matrix metalloproteinases (MMP) and their inhibitors (TIMP) are central factors in the control of extracellular matrix turnover. They are important in normal physiology and also during a range of pathological states. In this review, we have systematically identified clinical articles relevant to cardiovascular disease in diabetes from the last 10 years. Our aim was to outline the structure, function and regulation of metalloproteinases and their key roles in cardiomyopathy and vasculopathy in diabetes. We also explore the effects of drug intervention on both human subjects with diabetes and experimental animal models. The modulation of MMP and TIMP activity using drugs that affect the expression and function of these proteins may provide us with new ways to treat this serious and disabling disease, and we explore potential mechanisms and treatments.

Animals↗
PubMed2004

Collateralization and the response to obstruction of epicardial coronary arteries.

Occlusive coronary disease is an important cause of global morbidity and mortality. While mechanical revascularization is effective, some individuals are not amenable to such interventions, and have a poorer prognosis. However, collateral circulation can protect and preserve myocardium around the time of coronary occlusion, contribute to better residual myocardial contractility, and lessen symptoms. We describe the anatomy and physiology of coronary collateralization, its component parts (angiogenesis and arteriogenesis), the current methods for definition of the collateral response and how this might be manipulated. The manipulation of this process is a realistic possibility for future adjuvant treatment of coronary artery disease.

Collateral Circulation↗
PubMed2004

Sudden unexpected death in heart failure may be preceded by short term, intraindividual increases in inflammation and in autonomic dysfunction: a pilot study.

OBJECTIVE: To see whether sudden unexpected death in chronic heart failure is preceded by intraindividual worsening in inflammation and in ECG criteria. DESIGN AND SETTING: Prospective cohort study conducted in the community. PATIENTS: 34 patients with chronic heart failure were studied. Their mean (SD) age was 68 (8) years, 29 were men, mean (SD) left ventricular ejection fraction was 29 (9)%, and they were in New York Heart Association functional class II (n = 20), III (n = 11), and IV (n = 3). The patients were examined monthly over 24 months, with sequential measurement of C reactive protein and neutrophil counts and 24 hour ambulatory ECG monitoring measuring heart rate variability, mean heart rate, and arrhythmias. Intraindividual changes in these parameters were related to subsequent cardiac deaths. RESULTS: During follow up, nine patients died: five patients had a sudden unexpected death (SUD) and four died of progressive heart failure (PHF). There were significant intraindividual changes in neutrophil counts (p = 0.02), C reactive protein (p = 0.039), and heart rate variability (p < or = 0.018) in those who died of SUD and PHF. In contrast no significant changes were seen in ventricular extrasystoles, ventricular tachycardia episodes, brain natriuretic peptide, or aldosterone in the SUD group, but all of these parameters did increase as expected in those who died of PHF. CONCLUSIONS: This is preliminary evidence that SUD may be preceded by intraindividual increases in both inflammation and autonomic dysfunction. Both may be causal in genesis but, even if they are not, intraindividual increases in either may be convenient markers to identify patients at high risk of impending SUD. Larger studies are needed to confirm the observation from this pilot study.

Aged↗
PubMed2004

Routine unselected access to day case electrical cardioversion of persistent atrial fibrillation: anticoagulant preparation is the key factor.

OBJECTIVES: To determine the routine efficacy of a day case cardioversion system operating in a remote geographical area with an unselected case referral base and a proportion of direct GP access. DESIGN: Prospective analysis of all admitted cases in a 13 week period. PARTICIPANTS: 47 consecutive patients admitted for 49 planned episodes of electrical cardioversion. MEASUREMENTS: Pre procedural investigations and preparation, immediate and three-month outcome of rhythm following ECV. RESULTS: We found a predominant use by the cardiac unit despite working within a general medical service unit suggesting low case selection from non-cardiac sources. We suspected and confirmed a high rate of point of care treatment cancellation. Poor management of anticoagulation was the dominant reason for canceling planned treatment. Procedural preparation in terms of anti arrhythmic drug therapy and investigations seemed well preserved. CONCLUSION: New strategies for initiating and sustaining adequate outpatient warfarin therapy are needed to allow such systems to operate efficiently.

Aged↗
PubMed2003

Repeated measures of blood pressure and correlations between systolic pressure, pulse pressure and LV mass: a circular debate?

This month's edition of the Journal contains an interesting contribution from Mule and colleagues from Palermo. The structure of the piece is very simple relating ambulatory blood pressure (ABP) measures for systolic, diastolic and pulse pressure to LV mass in hypertensive patients. The technique employed is linear correlation analysis. Pulse pressure is an area of interest of many of the readers, contributors and editorial board of the Journal. This is not a new area nor is this a new approach. The strategy of deriving biological inference from such data relevant to the individual by correlation analysis from a population sample deserves a closer and broader comment.

Blood Pressure↗
PubMed2001

Isolated diastolic heart failure as a cause of breathlessness in the community: the Arbroath study.

The aim of this study was to examine the prevalence of exercise limitation due to diastolic heart failure among patients felt to have cardiac breathlessness by their general medical practitioner but not referred to hospital. We found that 18% of patients had a simple investigated profile compatible with isolated diastolic dysfunction as a cause of their symptoms. Symptoms appeared to pre-date major cardiac events (infarction; stroke; arrhythmia) that dominated the subsequent clinical course. The patients in this group have adverse cardiovascular risk profiles. Obesity was a common co-morbidity which may impair detailed 2-D echocardiographic assessment.

Adult↗
PubMed2001

A placebo-controlled study examining the effect of allopurinol on heart rate variability and dysrhythmia counts in chronic heart failure.

AIMS: Allopurinol improves endothelial function in chronic heart failure by reducing oxidative stress. We wished to explore if such an effect would attenuate autonomic dysfunction in CHF in line with many other effective therapies in CHF. METHODS: We performed a prospective, randomized, double-blind cross-over study in 16 patients with NYHA Class II-IV chronic heart failure (mean age 67 +/- 10 years, 13 male, comparing allopurinol (2 months) at a daily dose of 300 mg (if creatinine < 150 micromol l-1) or 100 mg (if creatinine > 150 micromol l-1) with matched placebo. Mean heart rate and dysrhythmia counts were recorded from 24 h Holter tapes at monthly intervals for 6 months. We assessed autonomic function using standard time domain heart rate variability parameters (HRV): SDNN, SDANN, SDNN index, rMSSD and TI. RESULTS: Allopurinol had no significant effect on heart rate variability compared with placebo; the results are expressed as a difference in means +/- s.d. with 95% confidence interval (CI) between allopurinol and placebo: SDNN mean = 6.5 +/- 4.8 ms, P = 0.18 and 95% CI (-3.7, 17); TI mean = -2.1 +/- 1.4, P = 0.16 and 95% CI (-5.2, 0.8); SDANN mean = -2.8 +/- 7 ms, P = 0.68 and 95% CI (-18, 12); SDNNi mean = 2 +/- 6.6, P = 0.7 and 95% CI (-12, 16); RMSSD mean = -0.9 +/- 2, P = 0.68 and 95% CI (-5.6, 3.7). For mean heart rate the corresponding results were 0.9 +/- 1.4, P = 0.5 and 95% CI (-2, 3.8). Log 24 h ventricular ectopic counts (VEC) were 0.032 +/- 0.37, P = 0.7 and 95% CI (-0.1, 0.2). Patient compliance with study medication was good since allopurinol showed its expected effect of reducing plasma uric acid (P < 0.001). CONCLUSIONS: Allopurinol at doses, which are known to reduce oxidative stress appear to have no significant effect on resting autonomic tone, as indicated by time domain heart rate variability or on dysrhythmia count in stable heart failure patients.

Aged↗
PubMed2001

Lessons to be learned: a case study approach a case study of the temporal onset of pulmonary hypertension with pre-existent cirrhotic portal hypertension.

We report the occurrence of pulmonary hypertension in a 37-year-old male patient with cirrhosis of the liver, portal hypertension and oesophageal varices. Although this is a rare combination, previous reports have shown that the association of portal and pulmonary hypertension is not coincidental; the temporal onset of primary pulmonary hypertension is hard to predict and our patient was asymptomatic for a number of years. The pathogenesis of portal hypertension leading to pulmonary hypertension is not known. Diagnosis is difficult because the clinico-pathological symptoms in both conditions are similar. Treatment is limited to calcium channel blockers, vasodilators, nitrous oxide and prostacyclin, although most patients will eventually require visceral transplantation.

Adult↗