Cardiac performance: growth hormone enters the race.
It is possible that growth hormone can offer therapeutic benefits for treating some forms of heart failure.
Animals↗
Biomedical subjects
S Fazio
Publications and source records attributed to S Fazio.
Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation.
Apolipoprotein E (apoE) deficiency causes severe hyperlipidemia and atherosclerosis in humans and in gene-targeted mice. Although the majority of apoE in plasma is of hepatic origin, apoE is synthesized by a variety of cell types, including macrophages. Because macrophages derive from hematopoietic cells, bone marrow transplantation was used to examine the potential of apoE synthesized by bone marrow-derived cells to correct the hyperlipidemia and atherosclerosis caused by apoE deficiency. After transplantation of bone marrow from mice with the normal apoE gene into apoE-deficient mice, apoE was detected in serum and promoted clearance of lipoproteins and normalization of serum cholesterol levels. ApoE-deficient mice given transplants of normal bone marrow showed virtually complete protection from diet-induced atherosclerosis.
Animals↗
Optimal determination of right ventricular filling dynamics in systemic hypertension.
To determine the optimal method of normalizing peak filling rate (PFR) determinations and apply it to the assessment of right ventricular (RV) and left ventricular (LV) filling characteristics and their interactions, 41 subjects with hypertension and 40 matched normals underwent echo-Doppler and nuclear study. Conventional normalization of PFR to end-diastolic volume (EDV) yielded poor correlations between nuclear- and echo-derived PFR (RV, r = 0.34; LV, r = 0.42), whereas nuclear and echo PFR normalized to stroke volume (SV) were closely correlated (RV, r = 0.87; LV, r = 0.92). Further, use of PFR normalized to SV revealed to close relation between RV and LV filling characteristics. Multivariate analysis confirmed that, in contrast to normalization to EDV or early to late filling-velocity ratios (E/A), peak filling rate normalized to SV was independent of ejection fraction and heart rate. In addition, RV filling impairment was related to LV filling impairment, and the effects of hypertension eliminated the independent influence of age on both LV and RV filling. In conclusion, normalization of PFR to SV may be preferable to use of EDV or E/A in evaluating RV and LV filling dynamics.
Adult↗
DNA repair synthesis and DNA fragmentation in primary cultures of human and rat hepatocytes exposed to cyproterone acetate.
Cyproterone acetate (CPA), a synthetic steroid used in human therapy, has recently been shown to cause DNA damage in cultured rat hepatocytes and in rat liver. In the present study we have investigated whether CPA also induces genotoxic effects in human hepatocytes. Genotoxicity of CPA was determined by measuring the capability of the compound for inducing DNA repair synthesis and for causing the formation of DNA single-strand breaks. Autoradiography and alkaline elution were used to quantitate DNA repair and DNA fragmentation, respectively. Exposure of hepatocytes to CPA for 20 h induced DNA repair synthesis in two hepatocyte preparations derived from males and in four of the five preparations derived from females. In cultures from some donors, induction of repair was detected at 1 microM CPA, the lowest concentration tested. The maximum effect generally occurred at 10-20 microM. Only a very slight increase in the frequency of DNA single-strand breaks was found following exposure of the hepatocytes to 50 microM CPA for 20 h. For comparative purposes, the effects of CPA on DNA repair and DNA fragmentation were also determined in cultured rat hepatocytes. A strong induction of DNA repair synthesis, but only a slight enhancement in DNA fragmentation was observed in CPA-treated hepatocytes derived from female rats. These results indicate that the measurement of repair is a more sensitive indicator for the genotoxicity of CPA than the measurement of DNA fragmentation. No genotoxic effects of CPA were detectable in hepatocyte cultures derived from male rats. The present findings show that CPA is genotoxic in human hepatocytes and that the striking sex difference in the genotoxicity of CPA in rat cells is not observed with human cells.
Aged↗
The enhanced association of apolipoprotein E with apolipoprotein B-containing lipoproteins in serum-stimulated hepatocytes occurs intracellularly.
Synthesis and secretion of VLDL in HepG2 cells are stimulated by several lipogenic factors, including serum. We previously found that the amount of apolipoprotein (apo) E associated with large lipoproteins such as VLDL increased under conditions of stimulated lipogenesis. The present study was designed to determine if the increased apoE association with VLDL occurs intracellularly or after secretion. In addition to HepG2, we studied rat hepatoma McA-RH7777 cells for production of endogenous rat apoE and transfected human apoE3. In both hepatoma cell lines stimulation of lipogenesis and production of large apoB-containing lipoproteins by serum resulted in increased apoE association with these particles and in decreased apoE association with HDL without affecting the total apoE output. Although evidence of apoE redistribution was seen among lipoproteins in the media, the apoE newly secreted under conditions of stimulated lipogenesis mainly associated with apoB-containing lipoproteins at the expense of its association with HDL. However, this effect was not attributable to reduced HDL lipid and apoA-I mass. Finally, redistribution of apoE from HDL to apoB-containing lipoproteins was also observed intracellularly in both HepG2 and transfected McA-RH7777 cells expressing human apoE3. These data suggest that the redistribution of apoE from HDL to apoB-containing lipoproteins upon activated lipogenesis in hepatoma cells occurs intracellularly and is not attributable to a decrease in HDL production.
Animals↗
Diastolic dysfunction in patients on thyroid-stimulating hormone suppressive therapy with levothyroxine: beneficial effect of beta-blockade.
Thyroid-stimulating hormone (TSH) suppressive therapy with levothyroxine (L-T4) may cause adverse cardiac effects such as rhythm disturbances and ventricular hypertrophy. The latter is a predisposing condition to diastolic dysfunction. Thus, this study was designed to assess the effect of long-term TSH suppressive therapy on cardiac diastolic function. Because beta-blockade is known to reduce ventricular hypertrophy in patients on L-T4 therapy, we also tried to determine whether the addition of a beta-blocker to L-T4 improved diastolic function. Twenty-five patients (21 female and 4 male; mean age 41 +/- 10 yr) on TSH suppressive therapy for 3-9 yr (9 for differentiated carcinoma and 16 for nontoxic goiter) and 20 control subjects were studied. A subgroup of 10 patients, selected for the presence of symptoms and signs of adrenergic overactivity, was treated for 4 months with the beta-blocker bisoprolol (4.25 +/- 1.2 mg/day), and their maintaining L-T4 therapy was unchanged. In the patient group, left ventricular mass was significantly increased (P < 0.001), isovolumic relaxation time was prolonged (P < 0.001), and early diastolic filling velocity was markedly reduced (P < 0.001), whereas late diastolic filling was increased (P < 0.005). Consequently, the early-to-late diastolic flow velocity ratio was markedly decreased (P < 0.001). These alterations were more pronounced in the subgroup of patients with evidence of adrenergic overactivity. In these patients, beta-blockade induced a significant regression of cardiac hypertrophy and improved diastolic dysfunction. In particular, isovolumic relaxation time decreased (P < 0.01) and the early-to-late flow velocity ratio increased significantly (P < 0.01). Both indices reached values after beta-blockade that were no longer different from those of asymptomatic patients. It is concluded that long-term L-T4 therapy increases myocardial mass and causes relevant diastolic dysfunction, particularly in those patients with evidence of mild hyperthyroidism and adrenergic overactivity. Both myocardial hypertrophy and diastolic dysfunction are significantly improved by adrenergic beta-blockade.
Adult↗
Impairment of lung volumes and respiratory muscle strength in adult patients with growth hormone deficiency.
Little is known of the respiratory function in patients with growth hormone (GH) deficiency. The aim of the present study was to evaluate lung volumes and respiratory muscle strength in patients diagnosed as GH deficient in childhood. Ten patients diagnosed as GH deficient in childhood and ten healthy subjects entered the study. For each subject the evaluation of respiratory function followed the same standard approach, consisting of respiratory muscle strength assessment, recording of flow-volume curves, measurement of static lung volumes and lung diffusing capacity. Both maximal inspiratory and expiratory mouth pressures were decreased in GH deficiency. Vital capacity, N2 functional residual capacity and total lung capacity were significantly reduced when compared to healthy subjects. Conversely, the residual volume and diffusing lung capacity to CO did not show any significant change. No significant change of percentage forced expiratory volume in 1 s/forced vital capacity ratio was observed. The decrease of respiratory mouth pressures was not correlated to the decrease of lung volumes. In conclusion, the results of this study show that adult patients affected with childhood onset GH deficiency suffer from impairment of ventilatory function and a decrease of respiratory muscle pressures, probably due to reduction of respiratory muscle strength.
Adult↗
Multiparametric evaluation of functional outcome after pylorus-preserving duodenopancreatectomy.
The aim of the present study was to evaluate the clinical, morphological and functional results obtained in a group of patients previously submitted to Traverso-Longmire pylorus-preserving duodeno-pancreatectomy (PPDP). The study was performed as a clinical, endoscopic, radioisotopic and electro-manometric evaluation. An analysis of the results allowed us to conclude that: 1) most patients show good clinical features, and this becomes more evident as post-operative time progresses; 2) bile reflux gastritis is an infrequent event; 3) gastric emptying times in patients overlap those seen in control subjects, and progressive normalization occurs postoperatively. The best clinical results coexist with normal gastric emptying times; 4) gastrojejunal interdigestive motor activity shows a reduction in phase 3 and a relative increase in phase 2. We argue that the motor activity of the upper gastrointestinal tract can restore, from a functional point of view, the new anatomical situation. On the basis of the good clinical and functional results, pyloric preservation seems to be the most physiological procedure for the restoration of alimentary continuity following duodenopancreatic resection.
Bile Reflux↗
Impaired left ventricular diastolic filling in patients with acromegaly: assessment with radionuclide angiography.
UNLABELLED: Acromegaly is associated with increased cardiac morbidity and mortality, but it is not clear whether this is the result of a specific disease of heart muscle or of increased incidence of hypertension. METHODS: Twenty-six patients with acromegaly (11 male and 15 female, mean age 45 +/- 13 yr) and 15 and 12 age- and sex-matched normal controls underwent high temporal resolution radionuclide angiography and two-dimensional echocardiography at rest. RESULTS: Normal controls and patients with acromegaly did not differ with respect to heart rate, ejection fraction, time to end systole, peak ejection rate (PER) and time to PER. In contrast, peak filling rate (PFR), normalized to end diastolic volume (EDV), or stroke volume (SV), or expressed as the ratio of PFR-to-PER was reduced (p < 0.01), time to PFR (TPFR) was prolonged (p < 0.01), and echocardiographic left ventricular mass index was higher (p < 0.001) in patients with acromegaly compared to normals. Patients with acromegaly were divided in normotensives (group 1, n = 17) and hypertensives (group 2, n = 9). Although left ventricular mass index was significantly (p < 0.01) higher in group 2 compared to group 1, PFR and time to PFR were not different between the two groups of acromegalic patients. In the entire group of patients with acromegaly significant relationships between left ventricular mass index and EDV/s (r = -0.56, p < 0.01), SV/s (r = -0.73, p < 0.001), and PFR/PER (r = -0.61, p < 0.001) were observed. CONCLUSION: Patients with acromegaly have impaired left ventricular diastolic filling at rest related to greater left ventricular mass index even in the absence of systemic hypertension.
Acromegaly↗
Co-expression of cholesteryl ester transfer protein and defective apolipoprotein E in transgenic mice alters plasma cholesterol distribution. Implications for the pathogenesis of type III hyperlipoproteinemia.
Despite the definite etiologic link between apolipoprotein (apo) E mutations and type III hyperlipoproteinemia (HLP), it is not clear what additional factors are involved in the development of florid hyperlipidemia and how to explain the wide variability in the expression of the hyperlipidemic phenotype in carriers of receptor binding-defective apoE variants. The present study was designed to determine whether the overexpression of cholesteryl ester transfer protein (CETP), a plasma protein that transfers cholesteryl esters from the high density lipoproteins (HDL) to the very low density lipoproteins (VLDL) and whose activity is increased in hyperlipidemic states, plays a role in the development of hyperlipidemia and beta-VLDL accumulation in type III HLP. We produced double-transgenic mice that co-expressed high levels of simian CETP and either high or low levels of a human receptor binding-defective apoE variant, apoE(Cys-142). We previously reported that apoE(Cys-142) high-expresser mice showed spontaneous hyperlipidemia and accumulation of beta-VLDL, whereas the low-expresser mice showed only a modest increase in VLDL cholesterol. Co-expression of CETP induced a massive transfer of cholesteryl esters from the HDL to the VLDL in both lines of double-transgenic mice. As a result, HDL cholesterol and apoA-I levels were reduced to about 50% of normal, VLDL cholesterol increased 2.5-fold, and the cholesteryl ester content of VLDL reached values similar to those observed in human beta-VLDL. The ratio of defective to normal apoE in VLDL was unaffected by CETP co-expression and was higher in animals expressing high apoE levels. Finally, in spite of an increased accumulation of beta-VLDL in the high-expresser mice, the VLDL of the low-expresser mice maintained pre-beta mobility upon co-expression of CETP. The results of this study demonstrate that the ratio of defective to normal apoE on the VLDL, rather than the cholesteryl ester content of VLDL, is the major factor determining the development of severe hyperlipidemia and the formation and accumulation of beta-VLDL in type III HLP.
Animals↗
Variable heparan sulfate proteoglycan binding of apolipoprotein E variants may modulate the expression of type III hyperlipoproteinemia.
The initial step in the clearance of apolipoprotein (apo) E-enriched remnant lipoproteins from the plasma appears to be sequestration within the liver mediated by their binding to heparan sulfate proteoglycans (HSPG). The surface-bound remnants are believed to be internalized by their interaction with the low density lipoprotein (LDL) receptor-related protein or by the LDL receptor. Cholesterol-induced rabbit beta-very low density lipoproteins (beta-VLDL) enriched in human apoE3 display 4-5-fold enhanced binding to cultured cells. The present study attempts to determine whether recessive versus dominant type III hyperlipoproteinemia might be explained, at least in part, by a variable interaction of the mutant forms of apoE with the HSPG and impaired uptake. The beta-VLDL+apoE2(Arg158-->Cys), which is associated with recessive type III hyperlipoproteinemia, bound more poorly than beta-VLDL+apoE3 but still possessed significant enhanced binding (approximately 2-2.5-fold compared with beta-VLDL without added apoE) to HepG2 and McA-RH7777 cells. In comparison, beta-VLDL+apoE(Arg142-->Cys), beta-VLDL+apoE(Arg145-->Cys), and beta-VLDL+apoE-Leiden, which are associated with dominant type III hyperlipoproteinemia, bound more poorly. This same hierarchy of binding and uptake was determined by [14C]oleate incorporation into cholesteryl esters in LDL receptor-negative cells and by secretion of apoE3 and the variant apoE forms from McA-RH7777 cells. Furthermore, the enhanced binding of the apoE-enriched beta-VLDL was almost totally inhibited by heparinase treatment of the cells, and the basal binding activity was inhibited by 80-90% following addition of an LDL receptor antibody capable of blocking receptor-ligand interaction. The beta-VLDL enriched in apoE or apoE-dimyristoylphosphatidylcholine complexes bound to isolated HSPG from McA-RH7777 cells or the rat liver to a very similar degree. Likewise, the binding of beta-VLDL plus the various forms of apoE to the LDL receptor-related protein on ligand blots paralleled the results of other studies. In conclusion, all of the type III hyperlipoproteinemic apoE variants are defective in displaying enhanced binding to HSPG and in the cellular uptake initiated by HSPG. However, apoE2(Arg158-->Cys) displayed more activity than the variants associated with the dominant forms of type III hyperlipoproteinemia. The hierarchy of binding and uptake was as follows: apoE3 > apoE2(Arg158-->Cys) > apoE(Arg145-->Cys) > apoE(Arg142-->Cys) approximately apoE-Leiden (the latter two usually displaying very little, if any, enhanced binding and uptake). Thus, a correlation exists between the mode of expression of type III hyperlipoproteinemia and the binding and uptake of the specific apoE mutation.
Animals↗
Enhanced binding and uptake of remnant lipoproteins by hepatic lipase-secreting hepatoma cells in culture.
Rat hepatoma McA-RH7777 cells transfected with a human hepatic lipase (HL) cDNA synthesized and secreted 50-80 ng of human HL/mg of cell protein at 4 h, approximately 50% of which was bound to cell-surface heparan sulfate proteoglycans (HSPG). The newly synthesized HL possessed enzymatic activity. When rabbit beta-very low density lipoproteins (beta-VLDL) and canine chylomicrons or chylomicron remnants were incubated with HL-secreting cells, remnant binding and uptake were enhanced 3-fold compared with nontransfected cells. Furthermore, fluorescence microscopy showed enhanced uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled beta-VLDL by the HL-transfected cells. When 125I-beta-VLDL were added to conditioned medium from HL-secreting cells, the HL in the media enhanced the binding and uptake of the remnant lipoproteins by nontransfected cells about 3-fold. Likewise, surface-bound HL (without HL in the medium) also was able to mediate the enhanced binding of the remnants. This HL-enhanced binding was shown to be mediated by an interaction with cell-surface HSPG. Heparinase treatment to remove cell-surface HSPG or chlorate treatment to prevent HSPG sulfation of the HL-secreting cells abolished all the HL-mediated enhanced binding and uptake. Furthermore, heparinase pretreatment of nontransfected cells prevented the enhanced binding and uptake of beta-VLDL incubated with conditioned medium from HL-secreting cells. As binding was not enhanced in the absence of HSPG, an HL-HSPG initial interaction appears essential. Addition of apolipoprotein (apo) E to the beta-VLDL did not facilitate HL-mediated binding and uptake; in fact, beta-VLDL from apoE-null mice demonstrated a similar degree of enhanced binding as did rabbit beta-VLDL with or without added apoE. On the other hand, beta-VLDL from transgenic mice overexpressing binding-defective apoE(Arg142-->Cys) did not display any enhanced binding and uptake by the HL-secreting cells, and it appears that the apoE(Arg142-->Cys) actually inhibited the HL-mediated interaction. This mutant form of apoE is associated with a dominant mode of expression of type III hyperlipoproteinemia in contrast to the more commonly occurring recessive disorder. Impaired HL interaction with the apoE(Arg142-->Cys) beta-VLDL may contribute to remnant lipoprotein accumulation in the plasma of patients with this mutant form of apoE. Thus, HL contributes to the enhanced cell association of specific types of remnant lipoproteins by initiating their binding to cell-surface HSPG.
Animals↗
Accumulation of human apolipoprotein-E in rat plasma after in vivo intramuscular injection of naked DNA.
Naked DNA was found to be incorporated and consistently expressed after in vivo direct injection into striated muscle. In addition to the local expression of muscle-related or exogenous proteins, intramuscular direct gene transfer may be a useful tool to deliver recombinant proteins into the blood stream. However, no direct demonstration of recombinant protein secretion from muscle to the circulation has been reported thus far. We have injected a naked plasmid DNA containing the human receptor-binding defective apo-E2 cDNA, under the control of CMV promoter, into the quadriceps of Yoshida rats, affected by hereditary hypercholesterolemia and altered LDL-receptor activity. Plasma accumulation of human apo-E2 was demonstrated for at least 45 days after injection. On the contrary, the expression of the normal human apo-E3, injected into the muscle of normal Wistar rats, was demonstrated only in the area of muscular injection and not in the blood plasma. Endogenous rat apo-E expression was not affected by the exogenous human apo-E2 production. Our results demonstrate the availability of intramuscular direct gene transfer as a safe and simple method for the chronic systemic delivery of recombinant proteins to the circulation, although further improvements are needed in order to enhance the efficiency and stability of expression.
Animals↗
Secretion-capture role for apolipoprotein E in remnant lipoprotein metabolism involving cell surface heparan sulfate proteoglycans.
To determine the impact of enhanced apolipoprotein (apo) E secretion on the mechanism of remnant lipoprotein uptake, rat hepatoma cells (McA-RH7777) were stably transfected with normal human apoE3 or receptor binding-defective apoE-Leiden. After a 2-h incubation, the human apoE secreted from the transfected hepatocytes was 10-12 times greater than the endogenous rat apoE. The apoE3-transfected cells bound and internalized rabbit beta-very low density lipoproteins (beta-VLDL) to a much greater degree than did apoE-Leiden-transfected cells and nontransfected cells. The apoE3-secreting cells displayed a 2-3.5-fold enhancement of cell-associated beta-VLDL compared to either the apoE-Leiden-transfected or nontransfected cells. Fluorescently labeled beta-VLDL were observed to concentrate within intracellular granules of the apoE3-transfected cells, presumably within endosomes and lysosomes. Furthermore, electron microscopy revealed that the apoE3-secreting cells displayed abundant beta-VLDL and chylomicron remnants on their cell surfaces and microvilli, in contrast to non-transfected or apoE-Leiden-secreting cells. Electron microscopy also revealed an abundance of chylomicron remnants within intracellular vesicles and multivesicular bodies of apoE3-transfected hepatocytes. Heparinase treatment (3 units/ml) completely abolished the increased association of beta-VLDL with apoE3-transfected cells but did not affect the limited association of beta-VLDL with apoE-Leiden-transfected or nontransfected cells. We established that the apoE3-enriched beta-VLDL were bound to cell surface heparan sulfate proteoglycans, as was the newly synthesized and secreted apoE3 (approximately 12% of the total secreted apoE3 was released by heparinase and suramin; 4% by heparin). In addition, reisolation of beta-VLDL by fast performance liquid chromatography after their incubation with exogenous apoE3, with medium from apoE3-secreting cells, or with the apoE3-secreting cells themselves revealed that the particles were enriched in apoE3 and displayed enhanced binding. These results suggest a secretion-capture role for apoE and indicate an important role for heparan sulfate proteoglycans on the cell surface for remnant lipoprotein metabolism.
Animals↗
Impaired cardiac performance in GH-deficient adults and its improvement after GH replacement.
Cardiac performance was investigated by radionuclide angiography in 11 patients with childhood-onset growth hormone (GH) deficiency and in 12 control subjects. Both at rest and during maximal physical exercise, systolic function was markedly depressed in GH-deficient patients. Ejection fraction rose from 66 +/- 6 to 76 +/- 7% during exercise in control subjects, whereas in GH-deficient patients it remained unchanged or even decreased (55 +/- 6 and 54 +/- 9% at rest and after exercise, respectively; P < 0.01 vs. controls). Cardiac index was significantly lower in GH-deficient patients than in controls, both at rest (2.7 +/- 0.6 vs. 3.7 +/- 0.5 l.min-1.m-2; P < 0.001) and during exercise (8 +/- 1.2 vs. 10 +/- 1.5 l.min-1.m-2; P < 0.01). Five GH-deficient patients were treated with recombinant human (rh) GH for 6 mo at a dose of 0.05 IU.kg-1.day-1. Cardiac index at rest improved from 2.8 +/- 0.6 to 3.3 +/- 0.8 l.min-1.m-2 (P < 0.01) after rhGH. Also, cardiac index response to exercise improved markedly and became similar to that of controls (7.5 +/- 1.2 and 10.1 +/- 1.1 l.min-1.m-2 before and after rhGH, respectively; P < 0.005). Exercise tolerance was impaired in GH-deficient patients and was restored by rhGH treatment. The data support the hypothesis that GH plays an important role in the maintenance of a normal cardiac performance in humans.
Adult↗
Susceptibility to diet-induced atherosclerosis in transgenic mice expressing a dysfunctional human apolipoprotein E(Arg 112,Cys142).
Transgenic mice expressing apolipoprotein (apo) E(Cys 142), a human defective variant of apo E, have elevated levels of plasma cholesterol, triglycerides, and very-low-density lipoproteins (VLDL); beta-VLDL, the biochemical hallmark of the human genetic disease type III hyperlipoproteinemia (HLP), is also present in these mice. This study was designed to determine whether these type III HLP mice have an increased susceptibility to spontaneous or diet-induced atherosclerosis. Three 4-month-old male transgenic mice and three male nontransgenic littermates were assessed for the presence of atherosclerotic lesions in the proximal aorta. No lipid-stained microscopic lesions were visible in the aortas of nontransgenic mice, whereas minimal lesions were observed on the aortic valve stumps of transgenic mice. To magnify the effect of the mutant apo E on the susceptibility of the transgenic animals to atherosclerosis, 8 transgenic and 8 nontransgenic mice were fed a synthetic diet containing 1% cholesterol, 16% fat, and 0.5% cholic acid for 3 months. The diet induced an increase in plasma cholesterol level in both transgenic and nontransgenic mice. However, the increase in plasma cholesterol level in the transgenic mice was all in the VLDL fraction, whereas in nontransgenic mice it was due to increases in both VLDL and high-density lipoprotein (HDL) fractions. Plasma triglyceride levels fell in both groups of mice. After 3 months on the diet, there were compositional changes in the VLDL of both groups, characterized mainly by higher cholesteryl ester content, that resulted in beta-migration on agarose gel electrophoresis. Despite similar VLDL lipid compositions, the extent of atherosclerosis differed markedly in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Growth hormone and the heart.
GH exerts direct effects on myocardial growth and function. Evidence from laboratory models shows that GH (or IGF-I) induces mRNA expression for specific contractile proteins and myocyte hypertrophy. Furthermore, GH increases the force of contraction and determines myosin phenoconversion toward the low ATPase activity V3 isoform. These data provide plausible explanations for the cardiac abnormalities observed in clinical settings of excessive or defective GH production. In acromegaly, the functional consequences of GH excess initially prevail (hyperkinetic syndrome), followed by alterations of cardiac function when myocardial hypertrophy develops. This involves both ventricles and is purposeless because it occurs without increased wall stress. Hypertrophy also entails proliferation of the myocardial fibrous tissue that leads to interstitial remodeling. The functional consequence is an impaired ventricular relaxation that causes a diastolic dysfunction, followed by impairment of systolic function. In untreated disease, cardiac performance slowly but inexorably deteriorates and heart failure eventually develops. Several lines of evidence support the specificity of heart disease in acromegaly. Particularly demonstrative are the recent studies in which GH production was suppressed by octreotide, with a consequent significant regression of hypertrophy and improvement of cardiac dysfunction. It is not yet established whether full recovery of normal cardiac morphology and function is possible after correction of GH excess. The point is not a minor one since the possibility to revert, albeit partially, myocardial fibrosis is of great relevance to the control of cardiac hypertrophy in general. GHD leads to a reduced mass of both ventricles and to impaired cardiac performance with low heart rate (hypokinetic syndrome). These alterations are particularly evident during physical exercise and might provide an important contribution to the reduced exercise capacity of GHD patients, in addition to the reduced muscle mass and strength. The data also support a role of GH in the maintenance of a normal cardiac structure and performance. The hypokinetic syndrome is well documented in young patients in whom GHD began very early in their childhood. In contrast, the data in adult-onset GHD are less consistent. This suggests that the consequences of GHD are more relevant if the disorder starts during early heart development. As observed with other abnormalities associated with GHD, cardiac dysfunction is also susceptible to marked improvement by hrGH. This observation lends further support to the proposal to treat these patients with replacement therapy.
Acromegaly↗
Control of adrenergic overactivity by beta-blockade improves the quality of life in patients receiving long term suppressive therapy with levothyroxine.
Several symptoms and signs of hyperthyroidism are frequently shared by patients receiving L-T4 suppressive therapy. The aim of this study was to evaluate whether a beta-adrenergic blocking drug could reduce the severity of these symptoms and signs in these patients, as previously reported in patients with hyperthyroidism. Eleven patients (mean age, 42 +/- 11 yr; 10 females and one male) affected with differentiated thyroid carcinoma or nontoxic goiter were selected from a more numerous group of patients receiving suppressive therapy based on the presence of palpitations, increased heart rate, left ventricular systolic function, and other symptoms mimicking exaggerated beta-adrenergic activity. In these patients the cardioselective beta-blocking drug bisoprolol was added to the L-T4 suppressive therapy at a dose of 2.5-5 mg/day. Blood samples were collected for the determination of thyroid hormones and TSH concentration during L-T4 therapy and after 3 and 6 months of associated L-T4 plus bisoprolol therapy. Cardiac function was assessed by clinical evaluation, standard and Holter electrocardiogram, as well as one- and two-dimensional echocardiography. Furthermore, we applied the symptom-rating scale previously used by Klein et al. in hyperthyroid patients to assess the quality of life in our group of patients. Our findings show that the addition of bisoprolol to L-T4 suppressive therapy produces a normalization of heart rate, which was significantly increased during TSH suppressive therapy, and the disappearance of atrial arrhythmias with considerable reduction of palpitations. Furthermore, bisoprolol produced an effective improvement in measures of the hyperthyroid symptom scale, with significant reduction of the mean score. The echocardiographic data showed an increased left ventricular mass index with significantly enhanced systolic function at the basal evaluation. After 6 months of combined L-T4 plus bisoprolol therapy, left ventricular mass index normalized, and the indices of left ventricular systolic function were reduced, with a tendency to normalize. Further studies conducted on a larger series of patients are required to verify the long term implications of cardiac parameter variations on cardiovascular morbidity and mortality. Our results, however, show that the addition of bisoprolol to L-T4 suppressive therapy improves the quality of life in those patients with clinical features of enhanced adrenergic activity.
Adult↗