Rafael Alexandre Meneguz-Moreno

Longevity in Untreated Congenital Growth Hormone Deficiency Due to a Homozygous Mutation in the GHRH Receptor Gene

CONTEXT Reduced longevity observed in hypopituitarism has been attributed to GH deficiency (GHD). It is, however, unclear whether GHD or other confounding factors cause this early mortality. OBJECTIVE The aim was to study longevity in subjects from a large kindred with untreated, lifetime isolated GHD (IGHD) due to a homozygous mutation in the GHRH receptor gene and in heterozygous carriers of the mutation. DESIGN, SETTING, AND PARTICIPANTS We carried out a retrospective cohort study on three groups. We first compared mortality risk of 65 IGHD individuals and their 128 unaffected siblings from 34 families. We then compared mean age of death of the IGHD to the general population. A transversal study was carried out to compare the rate of heterozygosity for the mutation in two groups of young (20-40 yr old) and old (60-80 yr old) normal-appearing subjects from the same county. MAIN OUTCOME MEASURE We measured longevity. RESULTS The risk of death of IGHD subjects was not different from their siblings. Life span in IGHD individuals was shorter than the general population. When stratified by sex, this difference persisted only in females, due to a high frequency of IGHD deaths in females aged 4-20. There was no significant difference in life span between IGHD subjects and siblings or the general population when analyzing subjects who reached age 20. The prevalence of heterozygosity did not differ in young and old groups, suggesting no survival advantage or disadvantage. CONCLUSIONS In a selected genetic background, lifelong untreated IGHD does not affect longevity.

Insulin Sensitivity and β-Cell Function in Adults with Lifetime, Untreated Isolated Growth Hormone Deficiency

CONTEXT GH reduces insulin sensitivity (IS), whereas IGF-I increases it. IGF-I seems to be critical for the development of the β-cells, and impaired IS has been reported in GH deficiency (GHD). OBJECTIVE The aim of the study was to assess IS and β-cell function in adult patients with untreated isolated GHD (IGHD) due to a homozygous mutation in the GHRH receptor gene. DESIGN, SETTING, AND PATIENTS We conducted a cross-sectional study in 24 GH-naive adult IGHD subjects and 25 controls. INTERVENTION We performed an oral glucose tolerance test with glucose and insulin measurements at 0, 30, 60, 90, 120, and 180 min. MAIN OUTCOME MEASURES IS was assessed by homeostasis model assessment index of insulin resistance (IR), quantitative IS check index, oral glucose IS in 2 h (OGIS2) and 3 h (OGIS3). β-Cell function was assayed by homeostasis model assessment index-β, insulinogenic index, and area under the curve of insulin-glucose ratio. RESULTS During the oral glucose tolerance test, glucose levels were higher in IGHD subjects (P<0.0001), whereas insulin response presented a trend toward reduction (P=0.08). The number of individuals with impaired glucose tolerance was higher in the IGHD group (P=0.001), whereas the frequency of diabetes was similar in the two groups. Homeostasis model assessment index of IR was lower (P=0.04), and quantitative IS check index and OGIS2 showed a nonsignificant trend toward elevation (P=0.066 and P=0.09, respectively) in IGHD. OGIS3 showed no difference between the groups. Homeostasis model assessment index-β, insulinogenic index, and ratio of the areas of the insulin and glucose curves were reduced in the IGDH group (P=0.015, P<0.0001, and P=0.02, respectively). CONCLUSIONS Adult subjects with lifetime congenital untreated IGHD present reduced β-cell function, no evidence of IR, and higher frequency of impaired glucose tolerance.

Adipokine Profile and Urinary Albumin Excretion in Isolated Growth Hormone Deficiency

BACKGROUND GH deficiency (GHD) is often associated with cardiovascular risk factors, including abdominal fat accumulation, hypercholesterolemia, and increased C-reactive protein. Despite the presence of these risk factors, adults with congenital lifetime isolated GHD (IGHD) due to an inactivating mutation in the GHRH receptor gene do not have premature atherosclerosis. OBJECTIVE The aim was to study the serum levels of adiponectin and leptin (antiatherogenic and atherogenic adipokine, respectively), and the urinary albumin excretion (UAE) in these IGHD individuals. DESIGN AND PATIENTS We conducted a cross-sectional study of 20 IGHD individuals (seven males; age, 50.8 +/- 14.6 yr) and 22 control subjects (eight males; age, 49.9 +/- 11.5 yr). MAIN OUTCOME MEASURES Anthropometric factors, body composition, blood pressure, serum adiponectin, leptin, and UAE were measured. RESULTS Adiponectin was higher [12.8 (7.1) vs. 9.7 (5) ng/ml; P = 0.041] in IGHD subjects, whereas no difference was observed in leptin [7.3 (6.3) vs. 9.3 (18.7 ng/ml] and UAE [8.6 (13.8) vs. 8.5 (11.1) microg/min]. CONCLUSIONS Subjects with lifetime untreated IGHD have an adipokine profile with high adiponectin and normal leptin levels that may delay vascular damage and lesions of the renal endothelium.

Arrest of atherosclerosis progression after interruption of GH replacement in adults with congenital isolated GH deficiency

OBJECTIVE GH replacement therapy (GHRT) in adult-onset GH deficiency (AOGHD) reduces carotid intima-media thickness (IMT) and increases myocardial mass, with improvement of systolic and diastolic function. These observations have reinforced the use of GHRT on AOGHD. Conversely, we have previously reported that in adults with lifetime congenital and severe isolated GH deficiency (IGHD) due to a mutation in GHRH receptor gene (GHRHR), a 6-month treatment with depot GH increased carotid IMT, caused the development of atherosclerotic plaques, and an increase in left ventricular mass index (LVMI), posterior wall, and septal thickness and ejection fraction. Such effects persisted 12 months after treatment (12-month washout - 12 mo). METHODS We have studied the cardiovascular status (by echocardiography and carotid ultrasonography) of these subjects 60 months after completion of therapy (60-month washout - 60 mo). RESULTS Carotid IMT reduced significantly from 12 to 60 mo, returning to baseline (pre-therapy) value. The number of individuals with plaques was similar at 12 and 60 mo, remaining higher than pre-therapy. LVMI, relative posterior wall thickness, and septum thickness did not change between 12 and 60 mo, but absolute posterior wall increased from 12 to 60 mo. Systolic function, evaluated by ejection fraction and shortening fraction, was reduced at 60 mo in comparison with 12 mo returning to baseline levels. The E/A wave ratio (expression of diastolic function) decreased at 60 mo compared with both 12 mo and baseline. CONCLUSIONS In adults with lifetime congenital IGHD, the increase in carotid IMT elicited by GHRT was transitory and returned to baseline 5 years after therapy discontinuation. Despite this, the number of subjects with plaques remained stable at 60 mo and higher than at baseline.

Emerging role of the GH/IGF-I on cardiometabolic control

Growth hormone (GH), the main regulator for post-natal growth, has important metabolic actions on different tissues, similar or opposite to insulin like growth factor I (IGF-I), mainly produced by the liver after the binding of GH to its receptor. Experiments with animal models indicate an important role of GH on insulin resistance although the IGF-I role is not yet completely established. In humans, GH promotes an increase on lypolisis and lipid oxidation, while IGF-I leads to an increase on lipid oxidation only in a chronic way. While growth actions are time-limited, metabolic and cardiovascular actions of the GH/IGF-I axis are throughout life. GH anabolic effects have been used on chronic and hypercatabolic conditions, although investigations on the clinical outcomes are still scarce. In this paper, we intend to review GH metabolic actions experienced by animal models, studies with normal humans and GH deficient individuals, individuals with diabetes mellitus type 1 and metabolic syndrome individuals, hypercatabolic states and the relationship between GH and adipokines, endothelial disfunction and atherogenesis.O hormonio de crescimento (GH), principal regulador do crescimento pos-natal, tem importantes acoes metabolicas em diferentes tecidos, sinergicas ou ate antagonicas as do fator de crescimento semelhante a insulina tipo I (IGF-I), produzido sobretudo no figado apos ligacao do GH ao seu receptor. Experimentos em modelos animais indicam um papel importante do GH na resistencia a insulina, enquanto o papel do IGF-I nessa condicao ainda nao esta completamente elucidado. Em humanos, o GH promove aumento da lipolise e da oxidacao lipidica, enquanto o IGF-I desencadeia o aumento da oxidacao lipidica apenas cronicamente. Enquanto as acoes sobre o crescimento sao tempo limitado, as acoes metabolicas e cardiovasculares do eixo GH/IGF-I perduram durante toda a vida. Os potenciais efeitos anabolicos do GH tem sido utilizados em condicoes cronicas e hipercatabolicas, embora as investigacoes sobre os desfechos clinicos ainda sejam escassas. Neste artigo, pretendemos revisar as acoes metabolicas do GH oriundas de modelos animais, os estudos em humanos normais e individuos com deficiencia de GH, diabete melito tipo 1, sindrome metabolica, estados hipercatabolicos e a relacao do eixo GH/IGF-I com as adipocinas, disfuncao endotelial e aterogenese

Papel emergente do eixo GH/IGF-I no controle cardiometabólico

Growth hormone (GH), the main regulator for post-natal growth, has important metabolic actions on different tissues, similar or opposite to insulin like growth factor I (IGF-I), mainly produced by the liver after the binding of GH to its receptor. Experiments with animal models indicate an important role of GH on insulin resistance although the IGF-I role is not yet completely established. In humans, GH promotes an increase on lypolisis and lipid oxidation, while IGF-I leads to an increase on lipid oxidation only in a chronic way. While growth actions are time-limited, metabolic and cardiovascular actions of the GH/IGF-I axis are throughout life. GH anabolic effects have been used on chronic and hypercatabolic conditions, although investigations on the clinical outcomes are still scarce. In this paper, we intend to review GH metabolic actions experienced by animal models, studies with normal humans and GH deficient individuals, individuals with diabetes mellitus type 1 and metabolic syndrome individuals, hypercatabolic states and the relationship between GH and adipokines, endothelial disfunction and atherogenesis.O hormonio de crescimento (GH), principal regulador do crescimento pos-natal, tem importantes acoes metabolicas em diferentes tecidos, sinergicas ou ate antagonicas as do fator de crescimento semelhante a insulina tipo I (IGF-I), produzido sobretudo no figado apos ligacao do GH ao seu receptor. Experimentos em modelos animais indicam um papel importante do GH na resistencia a insulina, enquanto o papel do IGF-I nessa condicao ainda nao esta completamente elucidado. Em humanos, o GH promove aumento da lipolise e da oxidacao lipidica, enquanto o IGF-I desencadeia o aumento da oxidacao lipidica apenas cronicamente. Enquanto as acoes sobre o crescimento sao tempo limitado, as acoes metabolicas e cardiovasculares do eixo GH/IGF-I perduram durante toda a vida. Os potenciais efeitos anabolicos do GH tem sido utilizados em condicoes cronicas e hipercatabolicas, embora as investigacoes sobre os desfechos clinicos ainda sejam escassas. Neste artigo, pretendemos revisar as acoes metabolicas do GH oriundas de modelos animais, os estudos em humanos normais e individuos com deficiencia de GH, diabete melito tipo 1, sindrome metabolica, estados hipercatabolicos e a relacao do eixo GH/IGF-I com as adipocinas, disfuncao endotelial e aterogenese

Prognostic value of renal function in patients with aortic stenosis treated with transcatheter aortic valve replacement

The objectives of the present study were to analyze the variation of renal function after transcatheter aortic valve replacement (TAVR) focused on acute kidney injury (AKI) and its impact on short‐ and mid‐term mortality.

Prospective comparison between three TAVR devices: ACURATE neo vs. CoreValve vs. SAPIEN XT. A single heart team experience in patients with severe aortic stenosis.

We sought to compare the new transcatheter aortic valve replacement (TAVR) device ACURATE neo (ACT) with the already established CoreValve (MCV) and SAPIEN XT (SXT) for the treatment of severe aortic stenosis (AS).

Fórmula de CKD‐EPI versus Cockcroft‐Gault na predição de nefropatia induzida por contraste após intervenção coronária percutânea, em pacientes sem disfunção renal significativa

INTRODUCTION Individuals with glomerular filtration rate (GFR) ≥60 ml/min/1.73 m2 estimated by the Cockcroft-Gault formula (CG) who undergo percutaneous coronary intervention (PCI) frequently develop contrast-induced nephropathy (CIN). This study aimed to assess whether individuals with significant renal impairment assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, but not by CG, more often develop CIN following PCI than those without renal impairment by either formula. METHODS In this cross-sectional study analyzing patients with baseline CG GFR ≥60 ml/min/1.73 m2 before PCI, subjects were divided into two groups according to CIN occurrence. Baseline CKD-EPI GFR was calculated for all patients. RESULTS We analyzed 140 patients. Baseline GFR was 87.5±21.3 and 77.1±15.0 ml/min/1.73 m2 for CG and CKD-EPI, respectively. CIN occurred in 84.6% of individuals with baseline CKD-EPI GFR <60 ml/min/1.73 m2 vs. 51.1% of those without. Males and those with higher body mass index were more likely to present baseline CKD-EPI GFR <60 ml/min/1.73 m2 (p=0.021). Non-ionic contrast agent use and baseline CKD-EPI GFR ≥60 ml/min/1.73 m2 were protective factors against CIN. Greater amounts of contrast agent and acute coronary syndrome were associated with higher CIN risk. In subjects with serum creatinine <1.0 mg/dl, GFR was more likely to be overestimated by CG, but not by CKD-EPI (sensitivity 100.0%; specificity 52.0%). CONCLUSION In patients undergoing PCI without renal dysfunction by CG, a finding of CKD-EPI GFR <60 ml/ min/1.73 m2 was associated with a higher probability of CIN, especially among men and those with higher body mass index.

Drug-Coated Balloons: Hope or Hot Air: Update on the Role of Coronary DCB

Purpose of ReviewThe present manuscript reviews the mechanism of action of drug-coated balloons (DCBs), offering a brief summary of the main clinical evidence on these devices.Recent FindingsDCBs are regular semi-compliant balloons coated with antiproliferative agents that are rapidly released on contact with the vessel intima, exerting an anti-restenotic effect. This technology may offer some benefits of drug-eluting stents, in particular for the treatment of restenotic lesions, small vessels, and in patients at high-bleeding risk, when the prolonged dual antiplatelet regimen should be avoided. Most recent data have pointed to a possible benefit of these devices in treating bare metal stents (BMS) or drug-eluting stents in-stent restenosis (DES ISR), effectively reducing the recurrence of restenosis and avoiding additional layers of metal in the same coronary segment. In other clinical scenarios such as bifurcations, small vessels, and de novo lesions, data is more scarce and the benefits are still unclear.SummaryThere are potential benefits related to the use of DCB in selected populations. However, larger clinical trials with longer follow-up are still needed to confirm the enthusiastic initial results.