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I pazienti con malattie cardiometaboliche hanno un percorso diagnostico-terapeutico particolarmente complesso, che coinvolge molteplici figure professionali. Cardiologo e diabetologo, i coordinatori di questo processo, devono reciprocamente contribuire alla realizzazione di un percorso virtuoso comune di cure e di assistenza. Con queste premesse è stato costituito un gruppo di miglioramento formato da cardiologi ARCA (Associazioni Regionali Cardiologi Ambulatoriali) e diabetologi AMD (Associazione Medici Diabetologici) che operano in Campania, per definire le criticità della realtà in cui si opera e realizzare un PDTA dedicato, che consideri i diversi stadi clinici dell’associazione Scompenso Cardiaco (SC) e Diabete e proponga processi diagnostici e terapeutici condivisi. Il documento ripercorre le evidenze disponibili e raccoglie le opinioni del gruppo circa l’individuazione di pazienti a più alto rischio di diabete e/o scompenso e il management del paziente con diagnosi nota di diabete mellito e scompenso cardiaco.

Aims To explore the feasibility of upper limbs cardiopulmonary exercise test (CPET) in Friedreich ataxia (FRDA) patients and to compare the results with sex, age, and body mass index (BMI) matched cohort of healthy controls (HC). Methods and results Cardiopulmonary exercise test was performed using an upper limbs cycle ergometer on fasting subjects. Peak oxygen uptake (peak VO2) was recorded as the mean value of VO2 during a 20 s period at the maximal effort of the test at an appropriate respiratory exchange rate. The ventilatory anaerobic threshold (AT) was detected by the use of the V-slope method. We performed echocardiography with an ultrasound system equipped with a 2.5 MHz multifrequency transducer for complete M-mode, two-dimensional, Doppler, and Tissue Doppler Imaging analyses. We studied 55 FRDA and 54 healthy matched controls (HC). Peak VO2 showed a significant 31% reduction in FRDA patients compared to HC (15.2 ± 5.7 vs. 22.0 ± 6.1 mL/kg/min; P Conclusions Upper limb CPET is useful in the assessment of exercise tolerance and a possible tool to determine the functional severity of the mitochondrial oxidative defect in patients with FRDA. The cardiopulmonary exercise test is an ideal functional endpoint for Phases II and III trials through a simple, non-invasive, and safe exercise test.

The use of technology offers recognized benefits to persons with diabetes. The aim of this study was to evaluate the organization of healthcare facilities, the composition of the diabetes team, and the use of Continuous Subcutaneous Insulin Infusion (CSII) and Continuous Glucose Monitoring (CGM) in Italy.Diabetes care centers were asked to complete a web survey based on information collected in 2018. Sixty-one pediatric and 243 adult centers participated in the survey, accounting for 507,386 patients, mostly with type 2 diabetes (86.4%). Fifty-three percent of pediatric centers and 11% of adult centers reported a team composed of diabetologists, nurses, and psychologists. Overall, 13,204 patients (2.6%) were using CSII (95% with type 1 diabetes), and 28,936 (5.7%), were using CGM (74% with type 1 diabetes). When stratifying for the type of diabetes, 24% and 40.8% of patients with type 1 were using CSII and CGM, respectively, whereas low use of technology was reported for patients with type 2 and women with gestational diabetes. The percentage of adult and pediatric patients with type 1 diabetes on CSII and CGM was respectively 21% and 32%, and 35% and 57%.The spread of CGM and CSII increased in Italy between 2013 and 2018. However, the percentage of users is still lower than what is expected based on clinical indications for use of technology. The inadequate number of professionals in the diabetes care team and insufficient economic resources are relevant barriers to disseminating technology for diabetes management.

Objectives Rhabdomyolysis is a rare syndrome in which a serious muscle damage suddenly appears, with the possible occurrence of severe complications such as kidney failure, electrolyte imbalances and death, and represents the most severe form of statin-induced muscle injury. Case presentation Here we present the case of a 55-year-old woman who started therapy with amoxicillin clavulanic acid on a background of atorvastatin therapy, resulting in rhabdomyolysis. Conclusions This case highlights the importance of evaluating potential drug interactions in patients taking statin and the need of monitoring clinical and laboratory findings suggestive of rhabdomyolysis.

SCODIAC was a pilot study which revealed an increasing use of SGLT2i in 123 outpatients affected with Heart Failure (HF) and Type 2 Diabetes Mellitus. SCODIAC-II study, the second phase of the program, has been carried out to determine diagnostic and therapeutic pathways in a larger group of patients and to verify whether the use of innovative antidiabetic therapies could modify echocardiographic parameters and cardiovascular therapies. 406 HF-diabetic patients, referred to Cardiologists and Diabetologists of pertaining healthcare districts in Campania, were enrolled in this retrospective study and divided in Group A, composed of 136 patients with preserved Ejection Fraction (HF-pEF)( 45%) and Group B, formed of 270 patients with reduced EF (HF-rEF)(≤ 45%). All patients had performed periodic clinical and echocardiographic evaluations. The antidiabetic therapies resulted modified after 1 year with a greater use of GLP1-AR, gliptins and SGLT2i. Cardiovascular therapies resulted also modified with a greater use of sacubitril/valsartan and a reduction of ACEi and ARBs in HF-rEF patients. Echocardiography E velocity, A velocity and E/e' ratio resulted markedly reduced in 25 HF-pEF and in 60 HF-rEF patients treated with SGLT2i, in respect to both the whole sample of subjects at beginning and the other diabetic patients. LAVi resulted reduced only in HF-pEF patients and EF increased only in HF-rEF patients. The approach to the patients with HF and diabetes must necessarily take place in the healthcare districts, be multidisciplinary and integrated. SGLT2i could improve left ventricular function in HF-rEF patients and modify cardiovascular therapies, almost in this setting of patients.Trial registration The protocol was approved by the University of Naples Federico II Ethics Committee and registered at ClinicalTrial.gov (CT04375943). The principles outlined in the Declaration of Helsinki were followed.

Background SCODIAC study revealed an increasing use of SGLT2 inhibitors in 123 patients affected with Heart Failure (HF) and Type 2 Diabetes Mellitus (T2DM), referred to Cardiologists and Diabetologists of the pertaining healthcare districts. SCODIAC Follow Up, the second phase of the program, has been carried out to determine diagnostic and therapeutic pathways in a larger group of HF diabetic patients and to verify whether the use of innovative antidiabetic therapies could modify echocardiographic parameters and influence cardiological therapy. Methods 406 patients affected with HF and T2DM, referred to Cardiologists and Diabetologists of pertaining healthcare districts in Campania, and followed for at least one year between 2018 and 2019, were enrolled in this retrospective study and divided in Group A, composed of 136 HF diabetic patients with preserved Ejection Fraction (HF-pEF) (> 45%) and Group B, formed of 270 HF diabetic patients with reduced EF (HF-rEF) (≤ 45%). All patients had performed periodic clinical evaluations and an echocardiographic exam every 12 months. Anthropometric parameters, HF etiology, co-morbidities, complications and ongoing therapies were collected. Results The clinical and laboratory parameters and the treatments adopted were assessed at beginning and after 12 months of treatment. The antidiabetic therapies resulted modified after one year with a greater use of GLP1 AR, gliptins and SGLT2i. Cardiological therapy resulted also modified with a greater use of ARNI and a reduction of ACE inhibitors and ARBs in HF-rEF patients. At the end of the study echocardiography E velocity, A velocity and E/E’ ratio resulted markedly reduced in 25 HF-pEF patients and in 60 HF-rEF patients treated with SGLT2i, in respect to both the whole sample of subjects at beginning and the other diabetic patients, while LAVi resulted reduced only in HF-pEF patients and EF increased only in HF-rEF patients. Conclusions The approach to the patients with HF and T2DM must necessarily take place in the healthcare districts and be multidisciplinary and integrated in order to tailor therapy to the characteristics of the patient. SGLT2i could improve left ventricular function in HF-rEF patients and modify cardiological therapeutic approach, almost in this setting of patients. Trial registration: The protocol was approved by the University of Naples Federico II Ethics Committee and registered at ClinicalTrial.gov (CT04375943). The principles outlined in the Declaration of Helsinki were followed.

Background and aims: Recently, the albuminocentric view of diabetic kidney disease (DKD) in type 2 diabetes (T2DM) has been changing. Therefore, the relationship between diabetic retinopathy (DR) and chronic kidney disease (CKD) has to be addressed according to this new clinical presentation of DKD. The aim of this study was to evaluate, in a real-world setting, the correlation DR–DKD in T2DM. Methods and results: A total of 2068 type 2 diabetic patients enrolled in a multicenter cross-sectional study were investigated. Albuminuric subjects were largely prevalent among subjects with DR (p = 0.019). In the whole study population, no difference in albumin excretion rate (AER) was observed between presence/absence of DR; instead, AER was significantly higher among patients with glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (CKD) (p = 0.009), above all in those with CKD and AER ≥0.03 g/24 h (p = 0.005). Multivariate analysis confirmed that eGFR (O.R. 0.976; 95% C.I.: 0.960–1.028; p < 0.001) and AER (O.R. 1.249; 95% C.I. 1.001–1.619; p = 0.004) were independently associated with DR and HDL–cholesterol (O.R.: 1.042; 95% C.I.: 1.011–1.120; p = 0.014). Additionally, among patients with eGFR

Background Friedreich ataxia is an autosomal recessive disease with no available therapy. Clinical trials with erythropoietin in Friedreich ataxia patients have yielded conflicting results, and the long-term effect of the drug remains unknown. Methods We designed a double-blind, placebo-controlled, multicenter trial to test the efficacy of epoetin alfa on 56 patients with Friedreich ataxia. The primary endpoint of the study was the effect of epoetin alfa on peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test. Secondary endpoints were frataxin levels in peripheral blood mononuclear cells, improvement in echocardiography findings, vascular reactivity, neurological progression, upper limb dexterity, safety, and quality of life. Epoetin alfa or placebo (1:1 ratio) was administered subcutaneously at a dose of 1200 IU/Kg of body weight every 12 weeks for 48 weeks. Results A total of 56 patients were randomized; 27 completed the study in the active treatment group, and 26 completed the study in the placebo group[KG1]. VO2 max was not modified after treatment (0.01 [−0.04 to 0.05]; P = .749), as well as most of the secondary endpoint measures, including frataxin. The 9-hole peg test showed a significant amelioration in the treatment group (−17.24 sec. [−31.5 to −3.0]; P = .018). The treatment was safe and well tolerated. Conclusions Although results are not in favor of an effect of epoetin alfa in Friedreich ataxia, this is the largest trial testing its effect. It is still possible that epoetin alfa may show some symptomatic effect on upper-limb performance. This study provides class I evidence that erythropoietin does not ameliorate VO2 max in patients with Friedreich ataxia. © 2016 International Parkinson and Movement Disorder Society

Summary Objective Vascular dysfunction and accelerated atherosclerosis are prominent features of hypothyroidism. The relative roles of thyroid hormone (TH) deficiency and the associated vascular risk conditions are still unclear. We studied the impact of acute and chronic hypothyroidism on vascular reactivity. Patients We studied 12 patients with chronic primary hypothyroidism (cHY; TSH: 52 ± 14 mU/l), seven patients with acute hypothyroidism secondary to total thyroidectomy (aHY; TSH: 97 ± 24) and 13 healthy subjects (TSH: 1·2 ± 0·5). Measurements We measured forearm blood flow (FBF) using plethysmography during intra-brachial infusion of: acetylcholine (ACh), sodium nitroprusside (NP) and norepinephrine (NE). We also measured serum C-reactive protein (CRP), TNF-alpha, asymmetric dimethylarginine (ADMA) and the forearm balance of nitric oxide (NO) during ACh infusion. Results As compared with the controls, the vasodilatory response to ACh was reduced in cHY (P = 0·001) and aHY (P = 0·04), as was the forearm release of NO (P

Context: Congenital hypothyroidism (CH) is the most prevalent endocrine disorder in the newborn and is routinely treated with life-long levothyroxine replacement therapy. Although several studies have demonstrated that such therapy may impact on the cardiovascular system, little is known with regard to the effects of long-term levothyroxine administration in patients with CH. Objective: The aim of the current study was to evaluate whether long-term levothyroxine replacement therapy in young adults with CH is associated with cardiovascular abnormalities. Patients and Methods: Thirty young adults with CH aged 18.1 ± 0.2 yr and 30 age- and sex-matched controls underwent cardiac and carotid Doppler ultrasound and symptom-limited cardiopulmonary exercise testing. Hypothyroidism was diagnosed by neonatal screening, and levothyroxine treatment was initiated within the first month of life and carefully adjusted to maintain TSH levels in the normal range and free T4 in the high-normal range. Results: Compared with controls, hypothyroid patients exhibited left ventricular diastolic dysfunction, impaired exercise capacity, and increased intima-media thickness. At multiple regression analysis, the number of episodes of plasma TSH levels less than 0.5 mU/liter and greater than 4.0 mU/liter from the age of 1 yr onward, and mean TSH plasma levels during puberty were independent predictors of diastolic filling and cardiopulmonary performance indexes (multiple r values: 0.61–0.75). Conclusions: Long-term levothyroxine treatment in young adults with congenital hypothyroidism is associated with impaired diastolic function and exercise capacity and increased intima-media thickness.

Experimental hyperglycemia and hyperinsulinemia have been shown to affect vascular reactivity. Chronic red wine consumption is associated with less cardiovascular mortality. Whether ingestion of a natural meal and red wine causes acute changes in vascular homeostasis is poorly understood. The aim of the current study was to clarify whether meal ingestion, with and without red wine, exert acute effects on vascular reactivity in healthy humans. We studied vascular reactivity and forearm nitrite balance in 10 healthy subjects under 3 different circumstances: (1) fasting; (2) after ingestion of a standard natural meal (1,050 kcal); and (3) after the same meal enriched with a glass of red wine. We measured forearm blood flow (FBF) by strain-gauge plethismography during intrabrachial, graded infusion of acetylcholine (ACh), sodium nitroprusside (NP), and norepinephrine (NE). We also measured the forearm balance of nitrite before and during ACh infusion. Despite significant increases in plasma glucose and insulin concentrations, the vasodilatory response to Ach and NP after meal ingestion was not different from the fasting response. Similarly, the vasoconstrictory response to NE was similar postprandially and during fasting. Addition of red wine did not modify the response to any of the vasoactive agents. Finally, the forearm nitrite production during Ach infusion was not different in the 3 experimental settings. Food intake, whether associated or not with red wine, does not affect vascular reactivity in normal human subjects.

GH is involved in the long-term regulation of peripheral vascular resistance and vascular reactivity. We determined whether GH plays a role in the acute regulation of vascular function in humans. The acute vascular effects of GH were studied in eight healthy subjects according to a double-blind, placebo-controlled design. Forearm blood flow (FBF), vascular resistance, and nitric oxide (NO) production were monitored during a 4-h infusion of GH into the brachial artery at a rate chosen to raise local GH to stress levels (approximately 40 ng/ml). During GH infusion, FBF rose 75% (P < 0.05), whereas forearm vascular resistance decreased comparably (P < 0.05). These changes were paralleled by augmented forearm release of NO (P < 0.02). GH heightened the response of FBF to the endothelium-dependent vasodilator acetylcholine (Ach; P < 0.02). With the highest Ach dose, FBF reached 30.4 +/- 4.2 and 16.9 +/- 3.1 ml/dl x min in the GH and placebo studies, respectively (P < 0.005). The slopes of the dose-response curves also differed markedly (0.45 +/- 0.07 and 0.25 +/- 0.05 ml/dl x min/ microg in the GH and placebo studies, respectively; P < 0.01). GH caused an upward shift of the FBF response to the endothelium-independent vasodilator sodium nitroprusside (P < 0.01), but did not affect the slope of the dose-response curve. GH infusion did not cause any appreciable increment in the venous IGF-I concentration in the test arm. In conclusion, GH acutely lowers peripheral vascular resistance and stimulates endothelial function. These effects are mediated by activation of the NO pathway and appear to be independent of IGF-I.

BACKGROUND Serum α-L-fucosidase activity is considered a marker of hepatocellular carcinoma. To the authors' knowledge, its clinical usefulness in the early detection of hepatocellular carcinoma in the follow-up of cirrhotic patients has not been reported previously. METHODS The authors prospectively studied serum α-L-fucosidase activity, in addition to α-fetoprotein and ultrasonography, in a regular screening of 132 cirrhotic patients during an 8-year follow-up. RESULTS At enrollment, 120 patients had low α-L-fucosidase activity (below the cutoff value) and 12 had high activity. All patients had serum α-fetoprotein levels below the cutoff value. During the follow-up, hepatocellular carcinoma was detected in 19 patients, 16 with α-L-fucosidase activity below the cutoff value at enrollment and 3 with activity above it. In 7 of those 16 patients with carcinoma and low enzyme activity, the enzyme activity showed a significant increase 6-9 months before there was ultrasonographic evidence of a focal lesion, and by the time of diagnosis it had risen above the cutoff value in all of them; in only 3 of the 7 patients was the increase in α-L-fucosidase activity associated with an increase in α-fetoprotein. In another 4 of the 19 patients with carcinoma, only α-fetoprotein increased. CONCLUSIONS Serum α-L-fucosidase activity is useful in the early detection of hepatocellular carcinoma. The data from this study suggest that cirrhotic patients who have a marked increase in serum α-L-fucosidase levels during follow-up should be closely monitored for signs of hepatocellular carcinoma development. Cancer 1998;83:2468-2474. © 1998 American Cancer Society.

Pulmonary arterial hypertension has a poor prognosis quoad vitam et valitudinem. Herein, we report on a middle-aged woman affected by idiopathic pulmonary arterial hypertension whose quality of life and exercise tolerance improved remarkably after a six-month course of treatment with the long-acting phosphodiesterase-5 inhibitor tadalafil.

To clarify whether the vasoconstrictory response is impaired and to study vascular function in patients with migraine during the headache attack.We studied vascular reactivity in the resistance arteries by using the forearm perfusion technique associated with plethysmography. We measured forearm blood flow by strain-gauge plethysmography during intra-brachial infusion of acetylcholine, sodium nitroprusside or norepinephrine in 11 controls and 13 patients with migraine, 11 of them (M) in the interval between the migraine attacks and 4 during a headache attack (MH). Written informed consent was obtained from patients and healthy controls, and the study was approved by the Ethics Committee of the University Federico II.Compared to healthy control subjects, in patients with migraine studied during the interictal period, the vasodilating effect of acetylcholine, that acts through the stimulation of endothelial cells and the release of nitric oxide, was markedly reduced, but became normal during the headache attack (P < 0.05 by analysis of variance). The response to nitroprusside, which directly relaxes vascular smooth muscle cells (VSMCs), was depressed in patients with migraine studied during the interictal period, but normal during the headache attack (P < 0.005). During norepinephrine infusion, forearm blood flow decreased in control subjects (-40% ± 5%, P < 0.001). In contrast, in patients with migraine, either when studied during or free of the headache attack forearm blood flow did not change compared to the baseline value (-3% ± 13% and -10.4% ± 15%, P > 0.05).In migrainers, the impaired relaxation of VSMCs is restored during the headache attack. The vasoconstrictory response is impaired and remains unchanged during the migraine attack.

OBJECTIVE: Vascular dysfunction and accelerated atherosclerosis are prominent features of hypothyroidism. The relative roles of thyroid hormone (TH) deficiency and the associated vascular risk conditions are still unclear. We studied the impact of acute and chronic hypothyroidism on vascular reactivity. PATIENTS: We studied 12 patients with chronic primary hypothyroidism (cHY; TSH: 52 +/- 14 mU/l), seven patients with acute hypothyroidism secondary to total thyroidectomy (aHY; TSH: 97 +/- 24) and 13 healthy subjects (TSH: 1.2 +/- 0.5). MEASUREMENTS: We measured forearm blood flow (FBF) using plethysmography during intra-brachial infusion of: acetylcholine (ACh), sodium nitroprusside (NP) and norepinephrine (NE). We also measured serum C-reactive protein (CRP), TNF-alpha, asymmetric dimethylarginine (ADMA) and the forearm balance of nitric oxide (NO) during ACh infusion. RESULTS: As compared with the controls, the vasodilatory response to ACh was reduced in cHY (P = 0.001) and aHY (P = 0.04), as was the forearm release of NO (P < 0.05). During NP infusion, FBF rose to 24 +/- 2 ml/dl/min in the controls and to significantly lower values in cHY (12 +/- 1; P = 0.001) and aHY (15 +/- 2; P = 0.004). NE-induced vasoconstriction was similar in the controls and aHY, but blunted in cHY. Serum CRP, TNF-alpha and ADMA were not different in the three groups. CONCLUSIONS: (i) Hypothyroidism associates with endothelial and nonendothelial mediated vascular dysfunction; (ii) these defects are evident even after short-term hypothyroidism, indicating that TH deficiency per se is sufficient to alter vascular homeostasis; and (iii) chronic, but not acute, hypothyroidism impairs the vasoconstrictory effect of NE in the resistance vessels.

BACKGROUND Recent application of brain natriuretic peptide and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in cardiac valvular disease is very promising. AIMS To test the usefulness of NT-proBNP in the assessment of patients with aortic or mitral regurgitation. PATIENTS AND METHODS Sixty-seven patients - 23 with aortic and 12 with mitral regurgitation vs. 32 controls - were examined by color Doppler echocardiography, cardiopulmonary exercise testing, Minnesota Living with Heart Failure Questionnaire (MLWHFQ) and plasma NT-proBNP assay at rest (T0) and after maximal physical exercise (T1). RESULTS NT-proBNP was significantly higher in patients than in controls, both at T0 (298 +/- 85 vs. 46 +/- 11 pg/ml; P < 0.01) and at T1 (366 +/- 106 vs. 50 +/- 12 pg/ml; P < 0.01). MLWHFQ score was significantly higher in patients (19 +/- 3 vs. 1 +/- 0.6; P < 0.001) with a significant inverse correlation with VO2max (r = -0.538, P < 0.001) and a direct correlation with NT-proBNP (T0: r = 0.415, P < 0.01; T1: r = 0.458, P < 0.01). NT-proBNP was inversely correlated with VO2max (T0: r = -0.444, P < 0.001; T1:r = -0.428, P < 0.001) and directly correlated with left atrial diameter (T0: r = 0.370, P < 0.01; T1: r = 0.409, P = 0.001), and left ventricular mass index (r = 0.279, P < 0.01, and r = 0.272, P < 0.01). No correlations were found between echocardiographic parameters of valvular disease severity and VO2max, NT-proBNP and MLWHFQ. CONCLUSIONS NT-proBNP is useful in the assessment of the cardiac functional damage secondary to mitral and aortic regurgitation.

Background: Migraine is associated with increased risk of cardiovascular disease, but the mechanisms are unclear.Objective: To investigate the activity of endothelial and vascular smooth muscle cells (VSMCs) in patients with migraine.Methods: Case-control study of 12 patients with migraine without aura and 12 matched healthy control subjects. Endothelial and VSMC components of vascular reactivity were explored by plethysmography measurement of forearm blood flow (FBF) during infusions of vasoactive agents into the brachial artery. Forearm production of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) was also quantified.Results: In patients with migraine, the vasodilating effect of acetylcholine (ACh), an endothelium-ependent vasodilator, was markedly reduced (p < 0.001 by analysis of variance). In response to the highest dose of ACh, FBF rose to 8.6 +/- 2.2 in patients with migraine and to 22.7 +/- 3.0 mL x dL(-1) x min(-1) in controls (p = 0.001). The dose-response curve to nitroprusside, a vasodilator directly acting on VSMCs, was depressed in patients with migraine (p < 0.001 by analysis of variance). The maximal response of FBF to nitroprusside was 12.1 +/- 2.0 in patients with migraine and 24.1 +/- 1.8 mL x dl(-1) x min(-1) in controls (p < 0.001). During ACh infusion, NO release from the endothelium was similar in patients and controls. In contrast, there was a marked release of cGMP from VSMCs in controls, but not in patients with migraine (-1.9 +/- 2.2 in patients with migraine and -19.1 +/- 5.4 nmol x dL(-1) x min(-1) in controls; p = 0.03).Conclusions: Patients with migraine are characterized by a distinct vascular smooth muscle cell dysfunction, revealed by impaired cyclic guanosine monophosphate and hemodynamic response to nitric oxide.

The cardiovascular consequences of thyroid diseases are attributed to the altered secretion of thyroid hormones. The possibility that TSH also affects the cardiovascular system has been poorly explored. Endothelial cells and vascular smooth muscle cells possess TSH receptors.The study was designed to determine whether TSH exerts any effect on vascular homeostasis.Two different double-blind, controlled studies were performed, one in eight healthy volunteers and the other in six thyroidectomized patients. Recombinant human (rh) TSH (or saline) was infused intrabrachially (1 mU/min) to raise TSH to severe hypothyroidism levels (approximately 100 microU/ml). Endothelium-dependent and -independent vasodilation was tested by intraarterial infusion of acetylcholine and sodium nitroprusside, respectively, and forearm blood flow was measured by plethysmography.Endothelium-dependent vasodilation was potentiated by rhTSH (P0.05 for the treatment effect; general linear model). The dynamics of the response was also profoundly affected by rhTSH because the dose-response curve was much steeper than in controls (P0.02 for the interaction between TSH and acetylcholine). rhTSH had no effect on endothelium-independent vasodilation (P = NS for both treatment and interaction). During rhTSH infusion, free T(3) levels increased slowly from 2.3 +/- 0.2 to 3.6 +/- 0.2 pg/ml. In thyroidectomized patients, rhTSH potentiated endothelium-mediated vasodilation to an extent similar to that of healthy subjects (P = 0.05 for the treatment effect and P = 0.01 for the interaction), without affecting the response to nitroprusside. In these patients, thyroid hormones remained unchanged during rhTSH infusion.rhTSH exerts marked effects on the resistance vessels by enhancing endothelial-mediated vasodilation, independent of changes in thyroid hormone concentration.

Context: Thyroid hormone regulates several cardiovascular functions, and low T3 levels are frequently associated with cardiovascular diseases. Whether T3 exerts any acute and direct effect on endothelial function in humans is unknown. Objective: Our objective was to clarify whether acute changes in serum T3 concentration affect endothelial function. Design, Setting, and Subjects: Ten healthy subjects (age, 24 ± 1 yr) participated in a double-blind, placebo-controlled trial at a university hospital. Interventions: T3 (or placebo) was infused for 7 h into the brachial artery to raise local T3 to levels observed in moderate hyperthyroidism. Vascular reactivity was tested by intraarterial infusion of vasoactive agents. Main Outcome Measures: We assessed changes in forearm blood flow (FBF) measured by plethysmography. Results: FBF response to the endothelium-dependent vasodilator acetylcholine was enhanced by T3 (P = 0.002 for the interaction between T3 and acetylcholine). The slopes of the dose-response curves were 0.41 ± 0.06 and 0.23 ± 0.04 ml/dl·min/μg in the T3 and placebo study, respectively (P = 0.03). T3 infusion had no effect on the FBF response to sodium nitroprusside. T3 potentiated the vasoconstrictor response to norepinephrine (P = 0.006 for the interaction). Also, the slopes of the dose-response curves were affected by T3 (1.95 ± 0.77 and 3.83 ± 0.35 ml/dl·min/mg in the placebo and T3 study, respectively; P < 0.05). The increase in basal FBF induced by T3 was inhibited by NG-monomethyl-l-arginine. Conclusions: T3 exerts direct and acute effects on the resistance vessels by enhancing endothelial function and norepinephrine-induced vasoconstriction. The data may help clarify the vascular impact of the low T3 syndrome and point to potential therapeutic strategies.

Epidemiological studies have shown that red wine consumption is associated with less cardiovascular mortality in the general population and in the diabetic patients. To determine whether red wine improves insulin resistance in diabetic patients and to explore the relation between insulin sensitivity and endothelial function, we studied vascular reactivity and insulin-mediated glucose uptake in 9 type 2 diabetic patients before and after 2 weeks of red wine consumption (360 mL/d, wine-treated diabetics) and 8 type 2 diabetic patients who did not consume wine (control diabetics). Vascular reactivity was evaluated by plethysmography during intraarterial infusion of acetylcholine (Ach), sodium nitroprusside, and L-N-monomethylarginine. Forearm nitrite balance was measured during Ach infusion. Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp at 1 mU/kg per minute. The basal forearm blood flow and the response to Ach, to sodium nitroprusside, and to L-N -monomethylarginine were unchanged both in the wine-treated and in the control diabetics. In contrast, insulin-mediated whole body glucose disposal improved by 43% after red wine consumption (from 2.79 +/- 0.4 to 4.02 +/- 0.5 mg/kg of lean body mass per minute, P = .02), but did not change in the control group. In conclusion, red wine consumption for 2 weeks markedly attenuates insulin-resistance in type 2 diabetic patients, without affecting vascular reactivity and nitric oxide production.

Insulin-deficient rats are characterized by multiple defects in the pathway of glycogen synthesis and breakdown in both liver and skeletal muscle. The aim of this study was to clarify whether islet transplantation under the kidney capsule, which is associated with delivery of insulin into the peripheral circulation, is able to normalize glycogen metabolism in liver and muscle of streptozotocin-diabetic rats. Three groups of male Lewis rats were studied under fasting condition: controls, untreated diabetics, and islet transplanted diabetics. Glycogen content, glucose-6-phosphate concentration, and glycogen synthase activity were measured in both liver and skeletal muscle. Untreated diabetic rats were characterized by an increase in glycogen content of 178% and a reduction of glucose-6-phosphate level of 50%. Both glycogen and glucose-6-phosphate contents were restored to normal in transplanted diabetic rats. Active glycogen synthase (0.35 ± 0.1 nmol/min/mg) and activity ratio (0.22 ± 0.04) were significantly impaired compared with controls (0.99 ± 0.2 nmol/min/mg and 0.43 ± 0.06, respectively) and were normalized by islet transplantation. In the skeletal muscle, glycogen content was similar in the three groups of animals, whereas muscle glucose-6-phosphate level was reduced by 28% and glycogen synthase was in a less active state in the untreated diabetic rats. Both the glucose-6-phosphate concentration and the kinetic profile of glycogen synthase were normalized by islet transplantation. In conclusion, islet transplantation under the kidney capsule corrects the diabetes-induced abnormalities in glycogen and glucose-6-phosphate content and glycogen synthase activity in both liver and skeletal muscle.

Background —The reason why patients with growth hormone (GH) deficiency (GHD) are at increased risk for premature cardiovascular death is still unclear. Although a variety of vascular risk factors have been identified in GHD, little is known regarding vascular reactivity and its contribution to premature arteriosclerosis. Methods and Results —We assessed vascular function in 7 childhood-onset, GH-deficient nontreated patients (age 22±3 years, body mass index [BMI] 25±1 kg/m 2 ) and 10 healthy subjects (age 24±0.4 years, BMI 22±1 kg/m 2 ) by using strain gauge plethysmography to measure forearm blood flow in response to vasodilatory agents. The increase in forearm blood flow to intrabrachial infusion of the endothelium-dependent vasodilator acetylcholine was significantly lower in GH-deficient nontreated patients than in control subjects ( P P P P 2 ) who were receiving stable GH replacement therapy. In these patients, the response to both endothelium-dependent and -independent vasodilators, as well as forearm nitrite and cGMP, release was not different from that observed in normal subjects. Peak hyperemic response to 5-minute forearm ischemia was significantly reduced in GH-deficient nontreated patients (17.2±2.6 mL · dL −1 · min −1 , P −1 · min −1 ) compared with normal subjects (29.5±3.2 mL · dL −1 · min −1 ). Conclusions —The data support the concept that GH plays an important role in the maintenance of a normal vascular function in humans.

Background — Although thyroid hormone (TH) exerts relevant effects on the cardiovascular system, it is unknown whether TH also regulates vascular reactivity in humans. Methods and Results — We studied 8 patients with hyperthyroidism, basally (H) and 6 months after euthyroidism was restored by methimazole (EU). Thirteen healthy subjects served as control subjects (C). We measured forearm blood flow (FBF) by strain-gauge plethysmography during intrabrachial graded infusion of acetylcholine, sodium nitroprusside (SNP), norepinephrine, and L-NMMA (inhibitor of NO synthesis). Basal FBF (in mL · dL −1 · min −1 ) was markedly higher in H than in C (5.8±1.2 and 1.9±0.1, respectively; P P P P =0.01 versus H and P =NS versus C). In contrast, the response to SNP infusion was comparable in the patients and control subjects. During norepinephrine infusion, the fall in FBF was much more pronounced in H (−6±1) than in C (−0.7±0.3, P P P Conclusions — In hyperthyroidism, (1) the marked basal vasodilation is largely accounted for by excessive endothelial NO production, (2) vascular reactivity is exaggerated because of enhanced sensitivity of the endothelial component, (3) the vasoconstrictory response to norepinephrine is potentiated, and (4) this abnormal vascular profile is corrected when euthyroidism is restored by medical therapy. The data demonstrate that vascular endothelium is a specific target of TH.