Manjit Shahi

Myocardial dysfunction in treated adult hypopituitarism: a possible explanation for increased cardiovascular mortality.

OBJECTIVE--To assess cardiac structure and function in patients with treated hypopituitarism and to determine their relation to the degree of growth hormone deficiency and body composition pattern. DESIGN--26 patients with treated hypopituitarism were studied by cross sectional and Doppler echocardiography and by exercise testing. The results were analysed and their relation to the degree of growth hormone deficiency and body composition determined. SETTING--All tests were performed in the department of cardiology and the unit of metabolic medicine at a tertiary referral centre. PATIENTS--Patients with hypopituitarism referred for endocrine assessment. MAIN OUTCOME MEASURES--Left ventricular mass, left ventricular diastolic function, and exercise capacity in patients with hypopituitarism and their relation to growth hormone deficiency. RESULTS--Mean (SD) serum concentration of insulin-like growth factor 1 (IGE-1), a measure of growth hormone deficiency, was 82.4 (45) micrograms/l. Lean body mass calculated by measuring total body potassium was 50 (9) kg. All patients had a normal left ventricular mass index and a normal left ventricular ejection fraction. Eight patients had abnormal left ventricular diastolic function. There was a significant correlation between IGF-1 and left ventricular mass (r = 0.45, p less than 0.02). Lean body mass was also significantly correlated with left ventricular mass (r = 0.78, p less than 0.0001) and left ventricular diastolic function (r = -0.63, p less than 0.01). The mean exercise duration was 8.6 (3.6) minutes. There was a significant correlation between serum IGF-1 and the rate-pressure product on exercise (r = 0.47, p less than 0.01). Seven patients had planar ST segment depression greater than 0.1 mV during exercise testing. In five of these patients there was rapid resolution of ST segment depression immediately after exercise. Two patients developed considerable ST segment depression, and subsequent coronary angiography showed normal coronary arteries. Exercise-induced ST segment depression was not related to the severity or duration of growth hormone deficiency or serum cholesterol concentration. CONCLUSIONS--This study suggests that left ventricular mass and the rate-pressure product are related to the degree of growth hormone deficiency, that left ventricular diastolic dysfunction is frequently seen in hypopituitarism, and that these patients may have ischaemic-like ST segment changes during exercise testing. These findings may explain the increased cardiovascular mortality in patients with hypopituitarism and may also have implications for growth hormone replacement therapy in adults.

THE EFFECTS OF ANTIHYPERTENSIVE THERAPY ON CAROTID VASCULAR STRUCTURE IN MAN

OBJECTIVE An increased carotid intima-media thickness (IMT) has been found to be associated with a number of cardiovascular risk factors such as age, hypertension, cigarette smoking, hypercholesterolaemia and left ventricular hypertrophy. Our objective was to assess whether carotid intima-media thickness in hypertensive patients could be reduced by antihypertensive therapy. METHODS 13 hypertensive patients, 10 previously untreated, were examined using carotid ultrasonography and echocardiography at baseline and then at 8 weeks and 39 weeks after commencement of antihypertensive therapy with ramipril and the second-line addition of felodipine. RESULTS By the end of the study significant regression of IMT (0.1(0.05-0.16) mm, F-value 10.2, P < 0.01) and left ventricular mass index had occurred (25(10.7-39.3) g/m2, F-value 9.7, P < 0.01). The reduction in IMT was significantly related to the reduction in mean arterial pressure, r = 0.55, P = 0.05). CONCLUSION Antihypertensive therapy with ramipril and felodipine causes regression of IMT in hypertensive patients, probably chiefly through blood pressure reduction. Large prospective studies are required to assess whether a reduction in IMT results in a reduction in morbidity and mortality.

Improvement in Midwall Myocardial Shortening With Regression of Left Ventricular Hypertrophy

Despite normal indices of left ventricular (LV) chamber function, patients with LV hypertrophy (LVH) due to hypertension are thought to have depressed midwall systolic shortening compared with normotensives. The aims of the present study were (1) to confirm this observation and (2) to assess the effects of antihypertensive therapy that cause regression of LVH on LV systolic function assessed at both the midwall and endocardium. Thirty-eight previously untreated hypertensive subjects with LVH underwent echocardiography and were compared with 38 normotensive control subjects. Comparisons between the group with LVH and the control group revealed no significant differences in cardiac output (4.32±0.23 versus 4.55±0.21 L/min), ejection fraction (62.5±2% versus 66.4±1.07%), or endocardial fractional shortening (34.5±1.45% versus 37.0±0.82%), but shortening assessed at the midwall was significantly less in the group with LVH (17.9±1.11% versus 21.6±0.63%, P <0.01). Subsequently, 32 patients with uncontrolled hypertension (24 previously untreated and 8 on existing antihypertensive therapy) underwent treatment with ramipril, with the addition of felodipine and bendrofluazide if required, to reduce blood pressure to <140/90 mm Hg. These 32 patients underwent echocardiography at baseline, after blood pressure control, and after an additional 6 months of tight blood pressure control. Good blood pressure control was achieved after 6 months compared with baseline (143/86±2.8/1.4 versus 174/103±4.1/1.9 mm Hg;P <0.01) with significant regression of LV mass index (124±3.4 versus 145±3.8 g/m2, P <0.01). LV fractional shortening assessed at the midwall improved with regression of LVH (21.9±0.84 and 18.7±1.19%, P <0.05), with posttreatment midwall shortening being similar to that of the normal control subjects evaluated in the first study. Hypertensive patients with LVH have depressed midwall systolic shortening despite normal indices of LV chamber function. Regression of LVH after good blood pressure control improved midwall shortening to normal levels.

QT dispersion in athletic left ventricular hypertrophy.

OBJECTIVE To assess whether physiologic left ventricular hypertrophy as a result of physical training is associated with an increased QT length or dispersion. METHODS Thirty-three subjects were assessed. These consisted of a group of international endurance athletes (including 8 rowers, 2 cyclists, and 1 triathlete), a group of 12 professional soccer players, and a further group of 10 control subjects. Each underwent 2-dimensional echocardiography and 12-lead electrocardiographic examination. RESULTS Left ventricular mass index was considerably greater in both the endurance athlete (163.3 +/- 14.4 g/m2; P <.01) and soccer player groups (144.2 +/- 5.5 g/m 2; P <.05) compared with the controls (109.2 +/- 6.3 g/m2). In spite of these large differences in cardiac structure there were no significant differences in QT parameters between the groups (QT dispersion 56.9 +/- 5.5, 68.5 +/- 9.5, and 67.2 +/- 12.6 ms; QTc dispersion 61.4 +/- 9.2, 69.4 +/- 13.3, and 54.2 +/- 6.5 ms; maximum QT 402 +/- 10.3, 404 +/- 9.6, and 392 +/- 14.0 ms; and maximum QTc 404 +/- 7.0, 413 +/- 9.3, and 399 +/- 9.9 ms among endurance athletes, soccer players, and controls, respectively). CONCLUSION Left ventricular hypertrophy occurring as a consequence of athletic training does not appear to be associated with a major increase in QT length or QT dispersion.

Left ventricular diastolic function in hypertension: a 4 year follow-up study☆

In order to assess the long term effects of antihypertensive treatment on left ventricular diastolic function, 26 hypertensive patients were followed up for a mean of 4.25 years with two-dimensional and Doppler echocardiography. A significant reduction in left ventricular mass index was first apparent after 9 months of therapy (mean (S.D.) 124 (22) vs. 114 (18) g/m2, P < 0.01), and this was maintained over the 4.25 year period (124 (22) vs. 117 (17) g/m2, p < 0.05). At 9 months there was no change in either isovolumic relaxation time (108 (26) vs. 108 (17) ms, P = N.S.) or left ventricular filling as assessed by peak flow velocity E/A ratio (0.94 (0.22) vs. 0.95 (0.27), P = N.S.). However, after 4.25 years there was a significant improvement in IVRT (108 (26) vs. 83 (11) ms, P < 0.01) with a trend towards an improved peak flow velocity E/A ratio, although this did not reach statistical significance (0.95 (0.27) vs. 1.02 (0.26), P = N.S.). Of the 14 patients who had an abnormal isovolumic relaxation time at baseline, 12 normalised and 2 improved. These findings suggest that left ventricular diastolic dysfunction in hypertension may be reversed by prolonged antihypertensive treatment.

Ventricular arrhythmias in hypertension: in which patients do they occur?

Objective It has been suggested that the increased incidence of sudden death in hypertensive patients, particularly those with left ventricular hypertrophy, may be causally related to the increased number and complexity of ventricular arrhythmias that have been demonstrated in these patients. The objective of the present study was to assess some of the factors which might be responsible for these arrhythmias. Subjects and methods One hundred and three untreated subjects were divided into four groups on the basis of blood pressure and echocardiographic measurements: hypertensive patients with left ventricular hypertrophy (n = 38), hypertensive patients without left ventricular hypertrophy (n = 16), patients with borderline or white-coat hypertension (n = 26) and normotensive subjects (n = 23). Each subject underwent two-dimensional and Doppler echocardiography, 12-lead electrocardiogram examination, 12-lead electrocardiogram exercise stress testing, 24-h ambulatory blood pressure monitoring and 24-h Holter monitoring. A further 17 hypertensive patients with left ventricular hypertrophy who were on long-term antihypertensive therapy were also investigated in the same manner and compared with untreated hypertensive patients with left ventricular hypertrophy who were matched for age, sex and race. Results Untreated hypertensive patients, even with left ventricular hypertrophy, had a low prevalence of frequent or complex arrhythmias (seven out of 80 patients with town score 2+). In contrast, hypertensive patients with left ventricular hypertrophy on long-term antihypertensive therapy had a significantly greater prevalence of complex arrhythmias than untreated patients with left ventricular hypertrophy (eight out of 17 treated patients compared with two out of 17 untreated patients with Lown score 2+). Conclusions Hypertensive patients with left ventricular hypertrophy who had received long-term antihypertensive therapy were found to have a high prevalence of complex ventricular arrhythmias, which was in contrast to untreated hypertensive patients, even those with left ventricular hypertrophy. This may reflect the consequences on the left ventricle of long-term antihypertensive treatment. If complex ventricular arrhythmias are implicated in the excess of sudden deaths in hypertensive patients, this might be an important factor.

Plasma mediated neutrophil stimulation during coronary angioplasty: autocrine effect of platelet activating factor.

BACKGROUND--Polymorphonuclear neutrophils are involved in the development of myocardial injury during ischaemia and reperfusion. Coronary angioplasty has been shown to result in neutrophil activation. This may be a result of contact with ligands expressed by endothelial cells or response to soluble stimuli released from ischaemic tissue into the plasma or both. OBJECTIVE--To investigate plasma mediated neutrophil activation during angioplasty. METHODS AND RESULTS--Plasma samples were collected from the coronary sinus, femoral artery, and femoral vein of 14 patients undergoing angioplasty, before and after the first balloon inflation and at the end of the procedure. Plasma samples were incubated with washed neutrophils isolated from healthy donors. Expression of the adhesion molecules CD18 integrin and L-selectin (Leu-8) was measured by flow cytometry, and superoxide anion production was measured by chemiluminescence. Plasma samples from the coronary sinus and femoral artery but not from the peripheral vein induced increased expression of neutrophil CD18 after balloon deflation. Modification of the expression of L-selectin was not noted. Production of superoxide anion by neutrophils was stimulated by plasma samples from the coronary sinus, but not by those from the femoral artery or vein. This plasma mediated neutrophil stimulation was prevented when the neutrophils were pretreated with platelet activating factor receptor antagonists BN52021 or BN50739. The platelet activating factor concentration detected in the coronary sinus was not higher than in control plasma. CONCLUSION--Brief ischaemia during coronary angioplasty leads to the release of soluble stimuli capable of inducing neutrophil integrin expression and free oxygen radical production. Platelet activating factor may act as an autocrine neutrophil stimulus under these conditions.

Left ventricular structure and function in previously untreated hypertensive patients: the importance of blood pressure, the nocturnal blood pressure dip and heart rate.

Background: Cardiac assessment is an important part of risk stratification in hypertensive patients. Left ventricular hypertrophy in particular is a powerful predictor of subsequent cardiovascular morbidity and mortality. Previous studies assessing haemodynamic factors that may be responsible for cardiac changes in hypertensive patients have been performed in those previously treated for hypertension. To investigate more fully these haemodynamic relationships, a large group of previously untreated patients were studied. Methods: Ninety-eight previously untreated hypertensive patients underwent electrocardiography, two-dimensional and Doppler echocardiography, 24 h ambulatory blood pressure monitoring and exercise stress testing. Results: The left ventricular mass index (LVMI) was more closely related to mean 24 h than to clinic blood pressures (24 h systolic r = 0.48, P < 0.01; 24 h diastolic r = 0.49, P < 0.01; clinic systolic r = 0.28, P < 0.01; clinic diastolic r = 0.31, P < 0.01). In addition, the systolic nocturnal blood pressure dip was found to be inversely related to LVMI in men (r = −0.32, P < 0.01). Of the indices of left ventricular diastolic function, age (r = −0.64, P < 0.01), heart rate (r = −0.25, P = 0.02) and LVMI (r = −0.22, P = 0.02) were independently related to the E-A ratio. Age (r = 0.40, P < 0.01), blood pressure (systolic r = 0.39, P < 0.01; diastolic r = 0.43, P < 0.01), the nocturnal blood pressure dip (systolic r = −0.38, P < 0.01, diastolic r = −0.31, P < 0.01) and LVMI (r = 0.37, P < 0.01) were independently related to the isovolumic relaxation time. Conclusions: Blood pressure was the only independent determinant of LVMI; nocturnal blood pressure may be particularly important in men. Age and both haemodynamic and structural factors are independent determinants of parameters of left ventricular diastolic function in hypertensive patients.

Metabolic Changes and Vascular Risk Factors in Hypopituitarism

Adults with hypopituitarism die prematurely, and the excess mortality is from vascular disease. On echocardiography we have demonstrated abnormalities of myocardial diastolic function in hypopituitary adults, indicating possible early ischaemic change. Peripheral arterial disease is evident on ultrasonography. Vascular risk factors have also been examined. Impaired glucose tolerance and unrecognized diabetes are common in hypopituitary adults. Total cholesterol levels are elevated, particularly in hypopituitary women. The role of growth hormone (GH) deficiency in the vascular disease and in the vascular-risk-factor abnormalities is unknown at present. Prolonged GH therapy causes a decrease in the levels of fasting total cholesterol, without any adverse effects on glucose homeostasis. GH therapy trials in adults will clarify the role of GH in the excess vascular risk of hypopituitarism. Prolonged GH therapy will be necessary for the vascular effects to be defined.

Left ventricular hypertrophy, blood pressure and ACE genotype in untreated hypertension

It has been suggested that the deletion polymorphism of the angiotensin-converting enzyme (ACE) genotype may be important in the development of left ventricular hypertrophy (LVH). In order to test this hypothesis we investigated the interaction between blood pressure (BP), LVH and ACE genotype in 86 previously untreated hypertensive patients. Each underwent two-dimensional and Doppler echocardiography and ACE genotyping. There were no significant differences in BP, the parameters of left ventricular structure (including left ventricular mass index) or diastolic function between the three genotype groups. Additionally, there were no significant differences in the relationship between systolic BP and left ventricular mass index among the three genotype groups (II genotype, r = 0.46, P = 0.02; ID genotype, r = 0.42, P = 0.01; DD genotype, r = 0.34, P = 0.10; F = 0.38). In contrast to some previous studies, we have found in this group of previously untreated hypertensive subjects no evidence to suggest that the deletion polymorphism of the ACE genotype is important in the development of LVH.