Showing papers by "Philip A. Poole-Wilson published in 1998"

Downregulation of Immunodetectable Connexin43 and Decreased Gap Junction Size in the Pathogenesis of Chronic Hibernation in the Human Left Ventricle

Abstract: Background—The regional wall motion impairment and predisposition to arrhythmias in human ventricular hibernation may plausibly result from abnormal intercellular propagation of the depolarizing wave front. This study investigated the hypothesis that altered patterns of expression of connexin43, the principal gap junctional protein responsible for passive conduction of the cardiac action potential, contribute to the pathogenesis of hibernation. Methods and Results—Patients with poor ventricular function and severe coronary artery disease underwent thallium scanning and MRI to predict regions of normally perfused, reversibly ischemic, or hibernating myocardium. Twenty-one patients went on to coronary artery bypass graft surgery, during which biopsies representative of each of the above classes were taken. Hibernation was confirmed by improvement in segmental wall motion at reassessment 6 months after surgery. Connexin43 was studied by quantitative immunoconfocal laser scanning microscopy and PC image softw...

Design and current status of ACTION: A Coronary disease Trial Investigating Outcome with Nifedipine GITS. Gastro-Intestinal Therapeutic System.

Abstract: AIMS To present the design of ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS), an ongoing multicentre clinical outcome trial with nifedipine GITS (Gastro-Intestinal Therapeutic System) in patients with stable angina pectoris. METHODS At least 6000 patients with optimally treated stable angina without depressed left ventricular function are randomized in equal proportions to either nifedipine GITS or matching placebo (starting dose 30 mg, maintenance dose 60 mg once daily). Patients are followed for at least four years. The primary end-point, to be analyzed by assigned treatment, includes all-cause mortality, acute myocardial infarction, emergency coronary angiography for refractory angina, overt heart failure, debilitating stroke and peripheral revascularization. For this end-point, the trial has a power of 95% to detect a relative risk reduction of 18% at the 5%, level of significance, and is large enough to exclude an excess mortality caused by nifedipine GITS of 3.1 deaths per 1000 years of treatment or greater. The pre-specified early termination rule is more conservative in the case of a beneficial effect than in the case of an adverse effect of nifedipine GITS. The first patient was randomized on 29 November, 1996. By the end of April 1998, about 5200 patients had been started on study medication. CONCLUSIONS Results will be available in the autumn of 2003.

Impaired baroreflex sensitivity and sympathovagal balance in syndrome X.

Abstract: Alterations of autonomic nervous control of cardiac function have been described in syndrome X. The characteristics, however, of the autonomic control of the cardiovascular system in patients with syndrome X have not been adequately studied; thus, the aim of the present study was to investigate the role of baroreceptor sensitivity and sympathovagal balance in syndrome X. The study group included 12 patients with syndrome X, 12 age- and sex-matched control patients with coronary artery disease, and 12 age- and sex-matched controls with no evidence of heart disease. Baroreceptor sensitivity was evaluated by calculating the regression line relating phenylephrine-induced increases in systolic blood pressure to the attendant changes in the RR interval. Sympathovagal balance was assessed by using heart rate variability in the time and frequency domain and measuring plasma norepinephrine at rest and during incremental bicycle exercise. Baroreceptor sensitivity was significantly reduced in syndrome X compared with that in control normal subjects (7.4 +/- 1.2 vs 16.8 +/- 2.3 ms/mm Hg; p 50 ms, lower root-mean-square of the difference of adjacent RR intervals, and lower logarithmic value of the high-frequency component in patients with syndrome X compared with normal subjects. A nonsignificant trend toward lower baroreceptor sensitivity was found in patients with syndrome X compared with control ischemic patients (7.4 +/- 2 vs 12.2 +/- 1.3 ms/mm Hg). A nonsignificant trend toward a higher value of the low- to high-frequency ratio was also observed in patients with syndrome X than in both control groups. No difference was detected in norepinephrine levels either at rest or during exercise or in the exercise-induced norepinephrine increase between the 3 groups. No difference was also observed between ischemic patients and normal subjects in either baroreceptor sensitivity or heart rate variability measurements. A significant correlation (r = 0.80, p < 0.01) was found between baroreceptor sensitivity and the high-frequency component in normal controls but not for other measurements of autonomic function in the 3 groups. In conclusion, patients with syndrome X have an altered autonomic control of the cardiovascular system characterized by impaired baroreceptor sensitivity and reduced heart rate variability. Abnormal autonomic regulation of the cardiovascular system may be of pathophysiologic importance in syndrome X.

Quantitation of left ventricular volumes and ejection fraction in post-infarction patients from biplane and single plane two-dimensional echocardiograms. A prospective longitudinal study of 371 patients

Abstract: Aims To determine whether left ventricular volumes and ejection fractions calculated from single plane two-dimensional echocardiograms using the algorithm (0·85A 2 L) correlate with those calculated using the biplane Simpson’s method, and whether small changes in volumes and ejection fraction occurring post-infarction could be detected from single-plane as well as from biplane two-dimensional echocardiograms. Methods and Results Serial two-dimensional echocardiograms were obtained in 371 patients from the DEFIANT II trial a mean of 2 days, 1 week and 6 months post-infarction. Single plane volumes from the apical four chamber and apical long axis correlated closely with biplane Simpson’s left ventricular volumes. Both single-plane left ventricular volumes significantly over-estimated biplane Simpson’s volumes. Biplane Simpson’s ejection fractions were consistently slightly under-estimated from the single-plane images. DiVerences between biplane Simpson’s and single-plane volumes increased independently with increasing left ventricular size and distortion. The small changes in left ventricular volumes and ejection fraction over time were as reliably detected from single plane as from biplane images. Conclusion Single-plane left ventricular volumes overestimate biplane Simpson’s volumes and under-estimate ejection fraction, and these discrepancies are amplified in dilated hearts with abnormal shape. (Eur Heart J 1998; 19: 808‐816)

Design and current status of ACTION : A coronary disease Trial Investigating Outcome with Nifedipine GITS

Abstract: Aims To present the design of ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS). an ongoing multicentre clinical outcome trial with nifedipine GITS (Gastro-Intestinal Therapeutic System) in patients with stable angina pectoris. Methods At least 6000 patients with optimally treated stable angina without depressed left ventricular function are randomized in equal proportions to either nifedipine GITS or matching placebo (starting dose 30 mg, maintenance dose 60 mg once daily). Patients are followed for at least four years. The primary end-point, to be analyzed by assigned treatment, includes all-cause mortality, acute myocardial infarction, emergency coronary angiography for refractory angina, overt heart failure, debilitating stroke and peripheral revascularization. For this end-point, the trial has a power of 95% to detect a relative risk reduction of 18% at the 5% level of significance, and is large enough to exclude an excess mortality caused by nifedipine GITS of 3.1 deaths per 1000 years of treatment or greater. The pre-specified early termination rule is more conservative in the case of a beneficial effect than in the case of an adverse effect of nifedipine GITS. The first patient was randomized on 29 November, 1996. By the end of April 1998, about 5200 patients had been started on study medication. Conclusions Results will be available in the autumn of 2003.

Cardiovascular specialty societies and the emerging global burden of cardiovascular disease: a call to action.

Abstract: Recently available data on the global burden of disease document, perhaps for the first time, that cardiovascular disease (CVD) has achieved the dubious status of the leading cause of death worldwide.1 Coronary heart disease and stroke have dominated the mortality figures for Western Europe, North America, and Australia/New Zealand for many decades, extending to Eastern Europe more recently. However, the emergence of CVD as the major cause of death in the world’s most populous regions, such as China and India, along with falling death rates from infectious and parasitic diseases in these countries are clearly the reasons for the elevation of CVD as the leading cause of death globally. Additional data from South and Central America, the Middle East and North Africa, and Southeast Asia confirm these trends. Moreover, projections of mortality based on population increases and increased life expectancy suggest that CVD will be the leading cause of mortality in all parts of the world by the year 2020, with the exception of sub-Saharan Africa.2 Some of us believe that even these estimates may be optimistic, with additional CVD occurring due to the increase in tobacco use, obesity, sedentary lifestyle, and an atherogenic diet in countries of increasing affluence; interaction of these new risk factors with presently prevalent risk factors such as hypertension; and the genetic predisposition of certain subgroups (such as South Asians) to CVD when placed in industrial societies.3 Indeed, conversations with colleagues from far-flung corners of the globe confirm the rising numbers of patients with coronary disease and stroke at relatively young ages now populating hospital wards and intensive care units. These cardiovascular specialists in lesser developed countries will likely not only be faced with increasing numbers of patients with acute and chronic manifestations of CVD but will also lack the extensive (and …

An inhibitor of nitric oxide synthase does not increase contraction or β-adrenoceptor sensitivity of ventricular myocytes from failing human heart

Abstract: Objective: Nitric oxide (NO) has been implicated in the depression of cardiac function in human heart failure. Some reports have identified iNOS (inducible nitric oxide synthase) within the myocyte component of the failing human heart, and NO is known to decrease the contraction amplitude of isolated ventricular myocytes. We have treated myocytes from failing human ventricle with a NOS inhibitor, N G-monomethyl-l-arginine (L-NMMA), in an attempt to restore contractile function. Methods and Results : Myocytes were isolated from failing and non-failing human ventricles and their contraction amplitude was measured during superfusion (32°C, 1–2 mmol/l Ca2+) and electrical stimulation (0.1–2 Hz). The contraction amplitude of myocytes from failing hearts was depressed in a frequency-dependent manner. At 1 Hz, the contraction amplitude of cells from non-failing heart was 4.70±0.53% cell shortening (mean±SEM, n =13 subjects), compared with 2.18±0.27% ( P <0.01, 11 patients) from patients with ischaemic heart disease (IHD) or 2.56±0.74% ( P <0.02, six patients) with dilated cardiomyopathy (DCM). Superfusion with 0.1 mmol/l L-NMMA did not increase contraction amplitude in myocytes from failing heart at either 0.2 Hz ( n =11) or 1 Hz ( n =7). Responses to β-adrenoceptor stimulation were reduced in myocytes from failing human heart, with contraction amplitude in maximum isoprenaline 0.47±0.11 of that in high Ca2+ in the same cell ( n =6), compared to 0.99±0.07 in non-failing heart ( n =14, P <0.01). The presence of 0.1 mmol/l L-NMMA did not increase the isoprenaline/Ca2+ ratio in myocytes from failing heart (0.40±0.09, P =NS). Conclusion: These results do not suggest a functional role for tonic NO production in the frequency-dependent depression of contraction or β-adrenoceptor desensitisation in myocytes from failing human ventricle.

The role of cAMP in the frequency-dependent changes in contraction of guinea-pig cardiomyocytes.

Abstract: Objectives : β-Receptor desensitisation, low basal cAMP, and a negative force–frequency relationship are characteristic changes in human heart failure. Isolated cardiomyocytes from noradrenaline-treated guinea pigs also show these features. We tested the hypothesis that low basal cAMP underlies the loss of contractile response to increasing stimulation frequency in this model. Methods : Isolated cardiomyocytes were obtained from noradrenaline-treated (NA) and sham-operated (SHAM) guinea pigs. They were stimulated from 0.1–2 Hz and contraction amplitude was monitored with a video edge-detection system. Results : NA cells had less positive amplitude–frequency responses (AFR) compared to SHAMs at 2 mM ( P =0.002, n =17), or midrange Ca2+ concentrations (EC40-EC60) ( P <0.001, n=13). When the cAMP agonist, 8-CPT-cAMP (CPT, 10 μM) or high Ca2+ (above EC75) was added to NA cells the AFR was normalised to that of SHAM myocytes (NA vs. SHAM P =ns). In control experiments the cAMP antagonists, Rp-cAMPS (Rpc) and Rp-8-CPT-cAMPS (Rp8, 100 μM), blocked the positive inotropic effects of CPT at 0.5 Hz (control pD2=4.36±0.06, Rp8 pD2=3.68±0.08, P <0.0001, n =6 paired). Rpc (100 μM) completely but reversibly blocked the effect of maximal isoprenaline in control experiments ( P <0.0001). Neither antagonist reduced the AFR compared to time-matched controls ( P =ns, n =6). Blockade of SERCA2a with thapsigargin resulted in a significant reduction in the AFR (ANOVA P <0.0001). Conclusions : The results are consistent with sarcoplasmic reticulum (SR) function being a more important determinant of the amplitude–frequency relationship than tonic levels of cAMP under basal conditions. Reversal of AFR depression by CPT may result from stimulation of SR Ca2+ uptake.

Use of magnetic resonance imaging to demonstrate a fistula from the aorta to the right atrium

Abstract: A 74-year-old woman was admitted with a 1-month history of fever, malaise, cough, and anorexia On examination, she had the signs of mixed aortic valve disease Blood cultures were positive for Streptococcus viridans, and a diagnosis of infective endocarditis was made The electrocardiogram showed sinus rhythm with first-degree heart block (PR interval, 300 ms) Transthoracic Doppler echocardiography showed severe aortic stenosis (gradient of 90 mm Hg) and mild aortic regurgitation Vegetations were present …

Mitochondrial DNA in idiopathic cardiomyopathy

Abstract: Aims To investigate the frequency of pathogenic mitochondrial DNA mutations in idiopathic cardiomyopathy. Methods and Results We investigated the occurrence of seven previously reported pathogenic mitochondrial DNA point mutations in 52 patients with idiopathic dilated cardiomyopathy (blood n=33, myocardium n=19), 10 patients with hypertrophic cardiomyopathy (blood n=7, myocardium n=3), 67 controls with ischaemic heart disease (blood n=53, myocardium n=14) and eight controls with no overt cardiac disease (blood n=4, myocardium n=4). Total DNA or cell lysates were studied by polymerase chain reaction amplification and restriction fragment length polymorphism analysis for the identification of the following mitochondrial DNA point mutations: A3243G, A3252G, A3260G, A4269G, A8344G, T8993G/C and T9997C. None of these point mutations were detected in the blood or myocardium of any of the individuals with dilated or hypertrophic cardiomyopathy or in the controls. In addition we investigated the occurrence of major deletions of mitochondrial DNA in eight patients with dilated cardiomyopathy (myocardium n=7, skeletal muscle n=1), three patients with ischaemic heart disease (myocardium n=3) and one control myocardium by Southern blot analysis. Deletions were not detected in any of the patients. Conclusion The results suggest that although these mutations are known to be associated with specific cardio-myopathies, they are not a common feature of idiopathic cardiomyopathy. The European Society of Cardiology

Function of Cardiac Myocytes in Ischemicheart Disease: Comparative Changes in Right and Left Ventricular Cells

Abstract: The contraction and relaxation velocities of single myocytes isolated from failing and nonfailing left and right human ventricles have been compared in order to investigate the possible contribution of cellular changes to the diastolic dysfunction seen in vivo. Myocytes from the failing right ventricle (RV) showed slowed relaxation compared to those from nonfailing, and the change was quantitatively similar to that seen in the failing left ventricle (LV). Poor relaxation was observed in RV myocytes from patients with ischemic heart disease, idiopathic dilated cardiomyopathy, and congenital heart disease. Division of patients into groups with high and low pulmonary artery pressure (PAP) showed a significant relation between raised PAP and slow relaxation of RV myocytes. Cells from the high PAP group were also longer, but not wider, than those from the low PAP group. β-adrenoceptor desensitization was evident in RV myocytes from failing heart, but did not diger in magnitude between high and low PAP groups. As we have previously shown for the LV, diastolic dysfunction in the RV may be related to changes in myocyte function.

ATP-Sensitive Potassium Channels and Myocardial Ischemia

Abstract: The KATP channel plays an important role in mediating a variety of pathophysiological responses during myocardium ischemia and exhibits cardioprotective effects. As a consequence of the recent cloning of the subunits of the KATP, channel, efforts are being made to understand its properties, regulation, and physiological role in coupling the metabolic state of a cell to excitability. Advances are anticipated in the understanding of the cellular and molecular mechanisms underlying the role of the KATP channel during myocardial ischemia. The modulators of the KATP channel are of great value as therapeutic agents for the treatment of ischemic heart disease. Newly identified tissue-selective KATP channel openers may result in important advances in the treatment of cardiovascular disease.