Therapy of dilated cardiomyopathy with recombinant human growth hormone

Dilated cardiomyopathy is a disease of the myocardium which is characterized by predominant enlargement of the left ventricle, decreased systolic function, and reduced myocardial wall thickness. The reduction in the number and function of myocardial fibers induces hypertrophy and leads to interstitial fibrosis. Ventricular dilatation and reduced wall thickness contributes to a further increase of the already elevated myocardial wall stress and triggers the continuous decrease of myocardial function. The initial myocyte injury by different and mostly unknown causes leads to progressive myocyte damage resulting in a similar uniform clinical picture independent from the initial myocellular derangement. One of the common pathways may be an inadequate response of the heart to human growth hormone (GH). Several studies support this hypothesis: GH deficiency results in a significant reduction of ventricular wall thickness and myocardial function, and GH-substitution is able to normalize the depressed left ventricular function. In addition, Sacca et al. reported in an uncontrolled study that GH-therapy reduced left ventricular wall stress by 40% in 7 patients with dilated cardiomyopathy. There was a parallel increase of the ejection fraction from 34% to 47%. This improvement was accompanied by a decrease of the functional classification of heart failure from NYHA 2.7 to 1.6. This therapeutic approach to alter the myocyte function directly by growth factors may open a new therapeutic concept in dilated cardiomyopathy. If double blind, randomized studies confirm the results of Sacca's study, a new era of therapeutic options may be available for the treatment of dilated cardiomyopathy.     

Appearance of the interventricular septum in obstructive lesions of the left ventricular outflow tract

Measurements of the thickness of the septum were made in 26 cardiac specimens and in 13 patients. There were 10 normal specimens, five with aortic stenosis, two with asymmetric septal hypertrophy, four with hypertensive cardiovascular disease, and five with idiopathic cardiomyopathy. Patient measurements were obtained by visualizing the septum during simultaneous left and right ventriculography on angiograms obtained in the left anterior oblique projection. Four patients were normal, five had aortic stenosis, and four had a symmetric septal hypertrophy. Measurements derived from normal cardiac specimens and angiographic appearance suggested that the normal septum is a smooth-walled structure with right and left ventricular surfaces parallel, diverging only slightly at the apex of the ventricle. In aortic stenosis and idiopathic cardiomyopathy, the septum tends to be biconvex with maximal thickening in its middle third. Hypertensive cardiovascular disease produces uniform septal thickening, resembling an exaggeration of normal. However, in asymmetric septal hypertrophy no consistent patterns of hypertrophy or septal thickening are evident; bulging can be present at any point along the left ventricular surface of the septum.     

Nonmetastatic accumulations in bone radionuclide scans in a patient with breast neoplasm

Left ventricular dilation and systolic dysfunction develop in 14-16% of patients with hypertrophic cardiomyopathy. Such findings may easily be misdiagnosed as dilated cardiomyopathy. It is unknown whether left ventricular dilatation and systolic dysfunction in patients with hypertrophic cardiomyopathy are reversible. A 35-year-old man had been a heavy drinker for 13 years and was abstinent for 1 year. Five years previously he suffered cardiac arrest and, based on echocardiographic, radionuclide, and cardiac catheterization findings, the diagnosis of alcohol-induced dilated cardiomyopathy was established. At presentation the heart was of normal size, with concentric left ventricular hypertrophy and only slightly reduced systolic function. Hypertrophic cardiomyopathy was diagnosed since no other cause for left ventricular hypertrophy could be detected. In hypertrophic cardiomyopathy, alcohol may induce reversible systolic dysfunction and left ventricular dilatation.     

Hypertensive cardiac hypertrophy--is genetic variance the missing link?

1. Hypertensive cardiac hypertrophy is a major independent predictor of adverse cardiovascular events. In man the cardiac response to increased afterload is very variable, even when ambulatory blood pressure monitoring is used. Analysis of breeding experiments using normotensive and hypertensive rat strains, human twin studies and other data indicate that genetic factors play a significant role in regulating cardiac mass; in other words, a large component of total variability is accounted for by genetic variance. 2. The observation that some patients with only mild-to-moderate hypertension exhibit gross left ventricular hypertrophy (LVH) similar to the inherited hypertrophic cardiomyopathies such as familial hypertrophic cardiomyopathy (FHC) and Friedreich's ataxia (FA) has prompted us to investigate the hypothesis that genetic factors associated with excessive myocardial hypertrophy, viz. mutations in FHC and FA genes alter the hypertrophic response of the heart to pressure overload. Here we review briefly three lines of study: (i) association analysis to test whether the allele frequencies differ in hypertensive patients with or without left ventricular hypertrophy; (ii) characterization of the cardiac manifestations of FA to understand the mechanism by which the heart is affected in a disease associated with pathology in a subgroup of neurons, and (iii) creation of transgenic models to facilitate the investigation of the interaction between hypertrophic stimuli and underlying genetic predisposition. 3. Information on the nature of the cardiac-mass-modifying genes involved may be useful not only for selecting high risk patients in strategies aimed at preventing the development of LVH, but also in opening new avenues of research on the reprogramming of cardiac myocytes to encourage them to hypertrophy in situations where cardiac muscle has been damaged or is hypoplastic.     

Clinical significance of magnetic resonance and echocardiographic correlations in the evaluation of hypertrophic cardiomyopathy

Relatively few clinical studies have investigated the role of MRI in the patients with hypertrophic cardiomyopathy. To assess MR capabilities in defining the presence, distribution and severity of left ventricular hypertrophy, the prevalence and clinical correlations of right ventricular hypertrophy and the prevalence and clinical implications of structural myocardial abnormalities, MRI and echocardiography were performed on 37 unselected patients with hypertrophic cardiomyopathy. The two methods were in agreement in 100% of cases in diagnosing the disease and classifying left ventricular hypertrophy as asymmetric, concentric or apical, and in 92% of cases in assessing the topographic distribution of hypertrophy of ventricular segments. A statistically significant linear correlation was found between echocardiographic and MR measurements of interventricular septum (r = 0.69, p < 0.0001, SEE = 4) and left posterior wall of the left ventricle (r = 0.67, p < 0.0001, SEE = 2.4). Right ventricular hypertrophy (right anterior wall diastolic thickness > 5 mm) was demonstrated by MRI in 23 of 33 patients (70%). In this group, left posterior wall thickness and left atrial diameter were higher (15 +/- 4 vs 11 +/- 2, p < 0.01 and 45 +/- 9 vs 38 +/- 5 mm, p < 0.05, respectively). On T2-weighted sequences, areas of reduced signal intensity, probably due to myocardial fibrosis, were detected in 16 cases (43%). This group was characterized by higher max. septal thickness (25 +/- 7 vs 21 +/- 6 mm, p < 0.05) and max. left posterior wall thickness (15 +/- 9 vs 7 +/- 8 mm, p < 0.05). All the three cases with dilated and hypokinetic left ventricle showed this kind of tissue abnormality. In conclusion, MRI provided clear, accurate and exhaustive data on the presence and distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy. Right ventricular hypertrophy and structural abnormalities of ventricular myocardium can also be detected and quantified. Right ventricular involvement is associated with more severe hypertrophy of left ventricular posterior wall. Structural myocardial abnormalities, probably due to fibrosis, are related to the extent of left ventricular hypertrophy.     

Recombinant growth hormone: a new cardiovascular drug therapy

GH has an important role in normal cardiovascular physiologic functioning, working indirectly through effects on IGF-1. An excess or deficiency of GH causes an increased rate of cardiovascular disease, including cardiomyopathy. A relative GH deficiency in older subjects may also increase cardiovascular morbidity and mortality risk. In replacement doses, GH can enhance myocardial contractility; can decrease peripheral vascular resistance; and can reduce total cholesterol and LDL-cholesterol values and fibrinogen and PAI levels. These effects of GH, coupled with the ability to improve skeletal muscle function and reduce adiposity, make it an attractive treatment for patients with CHF and a potential maintenance drug for elderly people. Clinical trials, including studies with GHRH that may reduce the adverse effects of GH therapy, such as hyperglycemia and hypertension, are now in progress.     

Promotion of tyrosinase folding in COS 7 cells by calnexin

To evaluate the role of serum free or unbound insulin-like growth factor I (IGF-I) on bone growth, we measured serum free IGF-I levels in 354 healthy children and adults (193 males and 161 females, aged 0-40 yr) and in 21 prepubertal GH-deficient (GHD) children (complete GHD, n = 5; partial GHD, n = 16) using a recently developed immunoradiometric assay. We obtained the following results. 1) In the normal children, the serum free IGF-I levels were low in infancy (<1 yr of age; males, 0.71 +/- 0.26 microg/L, mean +/- SD; females, 1.05 +/- 0.49 microg/L), increased during puberty (males, 5.84 +/- 2.18 microg/L; females, 5.80 +/- 1.49 microg/L), and declined thereafter. 2) Free IGF-I in the serum occupied about 0.95-2.02% of the total IGF-I values, with the highest ratio occurring in infancy (males, 1.77 +/- 0.60%; females, 2.02 +/- 0.87%). 3) The SD scores of serum free IGF-I in the 21 GHD children ranged from -3.30 to 0.30, and the 5 complete GHD children had free IGF-I values more than -2 SD below those of age-matched normal subjects. 4) There was a significant correlation between the SD scores of free IGF-I and those of total IGF-I (r = 0.715; P < 0.0005) in the GHD children. 5) In the 16 partial GHD children receiving GH treatment, the serum free IGF-I levels were elevated to 209% of pretreatment levels after 1 month of GH treatment and remained high during GH therapy. The GH-induced increase in the serum free IGF-I levels was significantly higher than those of the total IGF-I and IGF binding protein-3 levels. 6) The percent increase in the serum free IGF-I level after 1 month of GH treatment showed a significant positive correlation with that of the GH-induced improvement in the percent increase in the height velocity during 1 yr of GH therapy (r = 0.526; P < 0.05). These results show that free IGF-I in the serum has an essential role in bone formation because the higher free IGF-I levels were observed when the growth rate accelerated. The measurement of serum free IGF-I may become a useful tool for both diagnosing GH deficiency and predicting growth responses to long term GH therapy.     

Growth hormone and bone

It is well known that GH is important in the regulation of longitudinal bone growth. Its role in the regulation of bone metabolism in man has not been understood until recently. Several in vivo and in vitro studies have demonstrated that GH is important in the regulation of both bone formation and bone resorption. In Figure 9 a simplified model for the cellular effects of GH in the regulation of bone remodeling is presented (Fig. 9). GH increases bone formation in two ways: via a direct interaction with GHRs on osteoblasts and via an induction of endocrine and autocrine/paracrine IGF-I. It is difficult to say how much of the GH effect is mediated by IGFs and how much is IGF-independent. GH treatment also results in increased bone resorption. It is still unknown whether osteoclasts express functional GHRs, but recent in vitro studies indicate that GH regulates osteoclast formation in bone marrow cultures. Possible modulations of the GH/IGF axis by glucocorticoids and estrogens are also included in Fig. 9. GH deficiency results in a decreased bone mass in both man and experimental animals. Long-term treatment (> 18 months) of GHD patients with GH results in an increased bone mass. GH treatment also increases bone mass and the total mechanical strength of bones in rats with a normal GH secretion. Recent clinical studies demonstrate that GH treatment of patients with normal GH secretion increases biochemical markers for both bone formation and bone resorption. Because of the short duration of GH treatment in man with normal GH secretion, the effect on bone mass is still inconclusive. Interestingly, GH treatment to GHD adults initially results in increased bone resorption with an increased number of bone-remodeling units and more newly produced unmineralized bone, resulting in an apparent low or unchanged bone mass. However, GH treatment for more than 18 months gives increased bone formation and bone mineralization of newly produced bone and a concomitant increase in bone mass as determined with DEXA. Thus, the action of GH on bone metabolism in GHD adults is 2-fold: it stimulates both bone resorption and bone formation. We therefore propose "the biphasic model" of GH action in bone remodeling (Fig. 10). According to this model, GH initially increases bone resorption with a concomitant bone loss that is followed by a phase of increased bone formation. After the moment when bone formation is stimulated more than bone resorption (transition point), bone mass is increased. However, a net gain of bone mass caused by GH may take some time as the initial decrease in bone mass must first be replaced (Fig. 10). When all clinical studies of GH treatment of GHD adults are taken into account, it appears that the "transition point" occurs after approximately 6 months and that a net increase of bone mass will be seen after 12-18 months of GH treatment. It should be emphasized that the biphasic model of GH action in bone remodeling is based on findings in GHD adults. It remains to be clarified whether or not it is valid for subjects with normal GH secretion. A treatment intended to increase the effects of GH/IGF-I axis on bone metabolism might include: 1) GH, 2) IGF, 3) other hormones/factors increasing the local IGF-I production in bone, and 4) GH-releasing factors. Other hormones/growth factors increasing local IGF may be important but are not discussed in this article. IGF-I has been shown to increase bone mass in animal models and biochemical markers in humans. However, no effect on bone mass has yet been presented in humans. Because the financial cost for GH treatment is high it has been suggested that GH-releasing factors might be used to stimulate the GH/IGF-I axis. The advantage of GH-releasing factors over GH is that some of them can be administered orally and that they may induce a more physiological GH secretion. (ABSTRACT TRUNCATED)     

Silent myocardial ischaemia and left ventricle hypertrophy in diabetic patients

The purpose of this study was to evaluate the ability of three noninvasive techniques to detect silent myocardial ischaemia and analyse the factors associated with this condition, particularly left ventricular hypertrophy, in diabetic patients. An ECG stress test, a thallium-201 myocardial scintigraphy with dipyridamole intravenous infusion, ambulatory 48 h ECG monitoring and an echocardiographic study were performed in 92 diabetic patients without cardiac symptoms but with > or = 2 additional cardiovascular risk factors. At least one of these tests was positive in 28 patients (30.4%), suggesting silent myocardial ischaemia. Twenty-four of these patients had a coronary angiography which showed significant coronary stenosis in only 9 cases. An accurate echocardiographic tracing was obtained in 79 patients, particularly in 7 of the 9 with coronary stenosis. Left ventricular hypertrophy was detected in 34 patients, 6 of whom had coronary stenosis. In patients with left ventricular hypertrophy, the positive predictive values of myocardial scintigraphy and the ECG stress test were respectively 50% and 100%, as compared to only 33% and 11% in those without hypertrophy. In summary, coronary stenoses were found in < 10% of asymptomatic diabetic patients with > or = 2 cardiovascular risk factors, but more frequently in individuals with left ventricular hypertrophy. Thus, silent myocardial ischaemia should be searched for first in diabetic patients with hypertrophy, for which the stress test was the most accurate detection method in this study.     

Left ventricular diastolic function: physiology, methods of assessment, and clinical significance

Diastole, that portion of the cardiac cycle that begins with isovolumic relaxation and ends with mitral valve closure, results in ventricular filling and involves both active (energy-dependent) and passive processes. The interactions between active processes (myocardial relaxation) that primarily influence early ventricular filling and passive processes, such as loading conditions, myocardial compliance, and valvular disease, are complex. Clinical methods to assess ventricular filling include cardiac catheterization, radionuclide angiography, and echocardiography. Any measurements of diastolic function must be made with an understanding of the determinants of ventricular filling and the limitations of the diagnostic test. Many cardiac disorders are characterized by elevated pulmonary venous pressures in the face of normal systolic ventricular function, which suggests a primary abnormality of diastolic function. Abnormalities in diastolic function have been observed in coronary artery disease, congestive heart failure (with and without systolic dysfunction), hypertrophic cardiomyopathy, hypertension, and in healthy elderly subjects. Identification of these abnormalities may be useful clinically, particularly in patients with symptoms of heart failure and normal systolic function. Data are not available to determine the optimal therapy for such patients, although evidence suggests that calcium channel blockers, beta blockers, and agents that reverse myocardial hypertrophy may be useful. This review briefly summarizes the physiology of diastole, the methods of clinical assessment of diastolic function, and the role of diastolic function in cardiovascular disease.     

Sudden death as a presenting symptom of hypertrophic cardiomyopathy: treatment with an implantable cardioverter defibrillator

Aborted sudden death as the presenting manifestation of hypertrophic cardiomyopathy in a 14-year-old child is reported. Documented ventricular fibrillation was the cause of cardiac arrest. No ventricular arrhythmia was induced during programmed electrical stimulation. An implantable cardioverter-defibrillator was indicated. As the patient had a family history of myocardial disease, he had undergone a cardiovascular evaluation 4 years before the major event, and was found normal. It is suggested that normal physical examination, ECG, echocardiogram should not rule out the diagnosis of hypertrophic cardiomyopathy when a family history is present. Left ventricular hypertrophy may develop during childhood in patients with hypertrophic cardiomyopathy.     

'Isolated' pulmonary valve stenosis as part of more widespread cardiovascular disease

In 25 patients aged 6 days to 9 years presenting as 'isolated' pulmonary valve stenosis, histology of the myocardium of right and left ventricles, coronary arteries, and ascending aorta has shown abnormality in one or all these areas. Myocardial necrosis, old and recent, unrelated to coronary occlusion was frequent. Myocardial 'dysplasia' involving both ventricles, and resembling hypertrophic cardiomyopathy (HOCM, ASH) was found in 10 and a relation of this to myocardial injury in the fetus is postulated. Varying degrees of coronary occlusion were frequently seen in both right and left coronary arteries. The histology of the ascending aorta was abnormal showing 'higgledy-piggledy' disorder of smooth muscle components in 12 (48%). In a different series of 53 patients who had pulmonary valvotomy for apparent 'isolated' pulmonary valve stenosis there were 14 with clinical evidence of left ventricular abnormality consistent with the pathological changes described, 2 with the same aortic histological changes, and 2 with macroscopical left ventricular hypertrophy. Two of them developed classical hypertrophic cardiomyopathy years later. It is suggested that when pulmonary valve stenosis presents with a thick tricuspid poorly mobile valve, particularly in infants or in patients with evidence of other congenital stigmata, it may be part of a more widespread cardiovascular abnormality. This should be recognized and considered in the evaluation of surgical patients and late survivors who may show unexpected clinical features.     

The importance of left ventricular hypertrophy in human hypertension

Hemodynamic and non-hemodynamic factors contribute to the development of left ventricular hypertrophy (LVH). The presence of LVH is an important independent risk factor for total mortality and for cardiovascular morbidity and mortality. Direct cardiac effects of LVH include an increased risk of developing of congestive heart failure, an increased risk of arrhythmic events, and a reduced coronary flow reserve, promoting myocardial ischemic episodes. In addition, hypertension may promote the development of coronary artery atherosclerosis. The prognostic implications of LVH underscore the importance of diagnostic procedures. The electrocardiogram has a high specificity to identify patients with LVH but the sensitivity is fairly low. Echocardiography provides higher sensitivity and also gives important information, such as the pattern of left ventricular geometry, which is of prognostic importance, and the presence of diastolic dysfunction, which is an early abnormality in the evolution of hypertensive LVH. Reversal of LVH appears to improve prognosis. Reduction of blood pressure is one important component in the regression of LVH. Important quantitative differences exist between drug classes in the reversal of cardiac hypertrophy despite similar antihypertensive effects, suggesting other factors to be of importance in the regression of left ventricular mass. LVH is reduced more by angiotensin-converting enzyme inhibitors than by other antihypertensive drug classes, suggesting an effect on structural myocardial changes beyond that provided by the reduction of blood pressure. Recent data suggest that angiotensin II receptor antagonists (AIIRAs) have quantitatively similar effects on left ventricular mass as do angiotensin-converting enzyme inhibitors. A comparative trial of the AIIRA irbesartan and the beta-blocker atenolol demonstrated that despite similar reductions in blood pressure, the reductions attained in left ventricular mass with irbesartan were progressive and numerically greater than those attained with atenolol. Taken together, these findings provide circumstantial evidence for an important role of angiotensin II acting on angiotensin type 1 (AT1) receptors in the development or maintenance of cardiac hypertrophy. Confirmation of the favorable effects of angiotensin-converting enzyme inhibitors and AIIRAs on left ventricular mass in larger trials, including those assessing cardiovascular morbidity and mortality, will be of major importance in the future treatment of hypertension.     

Cardiomyopathy induced by tachycardia: description of a typical clinical case

Different chronic tachyarrhythmias may cause a form of reversible myocardial dysfunction and left ventricular enlargement known as tachycardia-induced cardiomyopathy. Many authors in recent years observed that the control of heart rate or interruption of the arrhythmia were frequently associated with a significant improvement in ventricular function and a reduction of cardiac dimensions. We report a case of tachycardia-induced cardiomyopathy secondary to atrial fibrillation of unknown duration which occurred in a young patient with structurally normal heart. The regression of left ventricular enlargement and the recovery of left ventricular systolic function were complete few months after the restoration of sinus rhythm.     

The cellular basis of dilated cardiomyopathy in humans

The present investigation was designed to evaluate whether end-stage cardiac failure in patients affected by dilated cardiomyopathy (DC) was dependent upon extensive myocyte cell death with reduction in muscle mass or was the consequence of collagen accumulation in the myocardium independently from myocyte cell loss. In addition, the mechanisms of ventricular dilation were analysed in order to determine whether the changes in cardiac anatomy were important variables in the development of intractable congestive heart failure. DC is characterized by chamber dilation, myocardial scarring and myocyte hypertrophy in the absence of significant coronary atherosclerosis. However, the relative contribution of each of these factors to the remodeling of the ventricle is currently unknown. Moreover, no information is available concerning the potential etiology of collagen deposition in the myocardium and the changes in number and size of ventricular myocytes with this disease. Morphometric methodologies were applied to the analysis of 10 DC hearts obtained from patients undergoing cardiac transplantation. An identical number of control hearts was collected from individuals who died from causes other than cardiovascular diseases. DC produced a 2.2-fold and 4.2-fold increase in left ventricular weight and chamber volume resulting in a 48% reduction in mass-to-volume ratio. In the right ventricle, tissue weight and chamber size were both nearly doubled. Left ventricular dilation was the result of a 59% lengthening of myocytes and a 20% increase in the transverse circumference due to slippage of myocytes within the wall. Myocardial scarring represented by segmental, replacement and interstitial fibrosis occupied approximately 20% of each ventricle, and was indicative of extensive myocyte cell loss. However, myocyte number was not reduced and average cell volume increased 2-fold in both ventricles. In conclusion, reactive growth processes in myocytes and architectural rearrangement of the muscle compartment of the myocardium appear to be the major determinants of ventricular remodeling and the occurrence of cardiac failure in DC.     

The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency

Total body water (TBW) is reduced in adult GH deficiency (GHD) largely due to a reduction of extracellular water. It is unknown whether total blood volume (TBV) contributes to the reduced extracellular water in GHD. GH and insulin-like growth factor I (IGF-I) have been demonstrated to stimulate erythropoiesis in vitro, in animal models, and in growing children. Whether GH has a regulatory effect on red cell mass (RCM) in adults is not known. We analyzed body composition by bioelectrical impedance and used standard radionuclide dilution methods to measure RCM and plasma volume (PV) along with measuring full blood count, ferritin, vitamin B12, red cell folate, IGF-I, IGF-binding protein-3, and erythropoietin in 13 adult patients with GHD as part of a 3-month, double blind, placebo-controlled trial of GH (0.036 U/kg.day). TBW and lean body mass significantly increased by 2.5 +/- 0.53 kg (mean +/- SEM; P < 0.004) and 3.4 +/- 0.73 kg (P < 0.004), respectively, and fat mass significantly decreased by 2.4 +/- 0.32 kg (P < 0.001) in the GH-treated group. The baseline RCM of all patients with GHD was lower than the predicted normal values (1635 +/- 108 vs. 1850 +/- 104 mL; P < 0.002). GH significantly increased RCM, PV, and TBV by 183 +/- 43 (P < 0.006), 350 +/- 117 (P < 0.03), and 515 +/- 109 (P < 0.004) mL, respectively. The red cell count increased by 0.36 +/- 0.116 x 10(12)/L (P < 0.03) with a decrease in ferritin levels by 39.1 +/- 4.84 micrograms/L (P < 0.001) after GH treatment. Serum IGF-I and IGF-binding protein-3 concentrations increased by 3.0 +/- 0.43 (P < 0.001) and 1.3 +/- 0.15 (P < 0.001) SD, respectively, but the erythropoietin concentration was unchanged after GH treatment. No significant changes in body composition or blood volume were recorded in the placebo group. Significant positive correlations could be established between changes in TBW and TBV, lean body mass and TBV (r = 0.78; P < 0.04 and r = 0.77; P < 0.04, respectively), and a significant negative correlation existed between changes in fat mass and changes in TBV in the GH-treated group (r = -0.95; P < 0.02). We conclude that 1) erythropoiesis is impaired in GHD; 2) GH stimulates erythropoiesis in adult GHD; and 3) GH increases PV and TBV, which may contribute to the increased exercise performance seen in these patients.     

Altered myocardial phenotype after mechanical support in human beings with advanced cardiomyopathy

BACKGROUND: Left ventricular assist devices (LVAD) provide lifesaving circulatory support to patients awaiting heart transplantation. To date, the extent to which sustained mechanical unloading alters the phenotype of pathologic myocardial hypertrophy in dilated cardiomyopathy is unknown. METHODS: We examined left ventricular size, myocyte and myocardial immunoreactivity for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in eight patients with advanced dilated cardiomyopathy before and after LVAD support. The mean duration of congestive heart failure was 18 +/- 5 months, and LVAD support averaged 42 +/- 4 days before heart transplantation. RESULTS: Echocardiographically determined left ventricular mass decreased from 505 +/- 83 to 297 +/- 52 gm (p < 0.05) during LVAD support, whereas minimum myocyte diameter decreased from 28.1 +/- 0.9 to 21.7 +/- 0.6 microns (p < 0.01) in transmural myocardial tissue specimens. Overall left ventricular ANP immunopositivity decreased from 48% at LVAD placement to 12% at transplantation (p < 0.05), whereas BNP immunopositivity decreased from 28% to 4% after LVAD support. Moreover, a gradient of ANP and BNP immunostaining from subendocardium to epicardium observed before mechanical unloading diminished after LVAD support. Analysis of the relationship between left ventricular mass and ANP immunopositivity revealed a close and highly significant correlation between these variables. CONCLUSIONS: These studies demonstrate remarkable left ventricular plasticity even in the presence of advanced cardiomyopathy. Parallel reductions in myocardial mass and myocyte size with reductions in ventricular ANP and BNP immunostaining indicate a novel regression of the phenotype of pathologic hypertrophy within the human myocardium after LVAD support.     

Cerebral cysticercosis in Campina Grande, Paraíba--northern Brazil. Computerized tomography diagnosis importance

A woman with Noonan syndrome had clinical and haemodynamic features of restrictive cardiomyopathy. There was no ventricular hypertrophy on echocardiography but myocardial biopsies showed myocyte hypertrophy without pathological disarray. This case illustrates the overlap of the cardiac phenotypes of Noonan syndrome, restrictive cardiomyopathy, and hypertrophic cardiomyopathy.     

Insulin-like growth factor-I in growth hormone-deficient adults: relationship to population-based normal values, body composition and insulin tolerance test

BACKGROUND: Although an insulin tolerance test (ITT) is the most commonly used method for detecting growth hormone (GH) deficiency (GHD) in adults, measurements of serum insulin-like growth factor-I (IGF-I) may also be of value. OBJECTIVE: To validate the use of serum IGF-I concentration in the diagnosis of GHD in adults. DESIGN: A cross-sectional study. PATIENTS: One hundred and four patients, 60 men and 44 women, with known pituitary disease and verified GHD based on ITT. MEASUREMENTS: Serum IGF-I was determined by radioimmunoassay after acid-ethanol extraction. Body composition was estimated with total body potassium combined with total body water assessments. RESULTS: According to age- and sex-adjusted population-based references values, 51 patients had serum IGF-I concentrations below -2 SD of the predicted values and 53 had concentrations within 2 SD. Fifty-seven per cent of the patients aged 41 years (25th percentile) or below and 39% of the patients aged 57 years (75th percentile) or above had serum IGF-I concentrations below -2 SD. Women had lower mean IGF-I SD scores than men (P < 0.01). Serum IGF-I was correlated with peak GH response during ITT (r = 0.40; P < 0.001), age (r = -0.27; P < 0.01), duration of hypopituitarism (r = -0.52; P < 0.001), number of pituitary hormonal deficiencies (r = -0.35; P < 0.001), body cell mass (r = 0.30; P < 0.01) and serum insulin (r = 0.21; P < 0.05). The peak GH response during ITT correlated with spontaneous GH secretion, duration (P = -0.48; P < 0.001) and number of deficiencies (r = -0.50; P 0.001). CONCLUSION: The measurement of serum IGF-I concentrations is not suitable as a single diagnostic test for growth hormone deficiency in adults. Even as a screening test, its use appears to be limited, especially in elderly subjects. The serum level of IGF-I was influenced by several factors in addition to GH, such as age, gender, anthropodometry and serum insulin level. The peak GH response during the insulin tolerance test appears to be influenced to a lesser degree by these factors.     

Chain elongation in the isoprenoid biosynthetic pathway

PURPOSE: To investigate the associations between specific preoperative 12-lead electrocardiogram (ECG) abnormalities, perioperative ischemia, and postoperative myocardial infarction or cardiac death in major vascular surgery. METHODS: Two prospective studies on perioperative myocardial ischemia performed in two tertiary university hospitals were combined to include 405 patients. All preoperative ECGs were analyzed according to the Sokolow-Lyon criteria for left ventricular hypertrophy by investigators who were blinded to the patients' perioperative clinical course. Perioperative myocardial ischemia was detected by continuous ECG recording, and postoperative cardiac complications included myocardial infarction and cardiac death. RESULTS: A total of 19 postoperative cardiac complications occurred (two cardiac deaths and 17 myocardial infarctions). Voltage criteria for left ventricular hypertrophy (78 patients, 19%) and ST segment depression greater than 0.5 mm (98 patients, 24.2%) on preoperative ECGs were both significantly associated with postoperative myocardial infarction or cardiac death (odds ratio, 4.2 and 4.7; p = 0.001 and 0.0005, respectively) and with longer intraoperative and postoperative myocardial ischemia. In each of the two study groups, a preoperative ECG abnormality that involved voltage criteria, ST segment depression, or both (134 patients, 33.1%) was more predictive of postoperative cardiac complications than any other preoperative clinical variable, including a history of myocardial infarction or angina pectoris, diabetes mellitus, pathologic Q-wave by ECG, or preoperative myocardial ischemia. The combined duration of intraoperative and postoperative ischemia and the preoperative ECG with either voltage criteria or ST segment depression were the only independent factors associated with adverse cardiac events by multivariate analysis (p < or = 0.0001 and p = 0.02, respectively). CONCLUSION: Left ventricular hypertrophy and ST segment depression on preoperative 12-lead ECGs are important markers of increased risk for myocardial infarction or cardiac death after major vascular surgery.