José R. Berrazueta

Contribution of nitric oxide to exercise‐induced changes in healthy volunteers: effects of acute exercise and long‐term physical training

Endothelium plays a central role in the regulation of regional blood flow through the release of certain vasoactive substances. We conducted this study to test whether an increase in the production of nitric oxide (NO) metabolites, atrial natriuretic peptide (ANP) and plasma and intraplatelet cyclic guanosine 3′:5′ monophosphate (cGMP) is involved in the adaptation to chronic exercise in physically trained people and in the vasodilatation induced by acute physical exercise. We studied one group of 10 trained athletes and another group of 10 untrained people. We measured plasma levels of nitrites, nitrates and cGMP and intraplatelet levels of cGMP, as an indicator of intracellular guanylate cyclase activity, and ANP before and after a maximal treadmill test. Resting cardiac rate (CR) and systolic blood pressure (SBP) were lower in the athlete group than in the control group (73.8 ± 3.6 vs. 92 ± 5.9; P < 0.02 and 110 ± 2.58 vs. 118 ± 3.27; P < 0.02 respectively). SBP did not show differences between groups after the exercise test. Diastolic blood pressure (DBP) at rest was lower in the athlete group (71 ± 1.79 vs. 80.5 ± 3.53; P < 0.03) and the decrease after maximal exercise was more pronounced in this group (64 ± 2.67 vs. 74.5 ± 3.2; P < 0.02). Basal plasma nitrites were 4.9 ± 0.8 in the athlete group and 1.9 ± 0.3 in the control group (P < 0.05). After exercise, test differences between groups remained (P < 0.05). Nitrates were significantly higher in the group of athletes and did not show exercise‐related changes. Plasma levels of cGMP and ANP increased in both groups after the treadmill test, with no differences between groups. Among the athletes, cGMP increased from 1.11 ± 0.1 to 2.6 ± 0.4 (P < 0.001), whereas in the untrained group plasma cGMP rose from 1.14 ± 0.09 to 1.86 ± 0.2 (P < 0.01). There was a significant correlation between the increases in plasma cGMP and the atrial natriuretic peptide in both groups (r = 0.91, P < 0.0002, for athletes; and r = 0.68, P < 0.04, for control group). The intraplatelet concentration of cGMP did not show differences between groups and did not change after exercise. In conclusion, we have found increased basal levels of plasma nitrite and nitrate in trained subjects. Exercise does not produce differences in the increments of these metabolites. Therefore, we speculate the release of nitric oxide is not augmented by exercise in trained athletes.

Successful treatment of shoulder pain syndrome due to supraspinatus tendinitis with transdermal nitroglycerin. A double blind study

&NA; We have conducted a prospective double blind randomized and placebo controlled clinical study in 20 patients with shoulder pain syndrome caused by supraspinatus tendinitis to determine whether transdermal nitroglycerin (NTG) has analgesic action in this condition. In a randomized manner we used a 5‐mg NTG (Nitroplast®) patch per day over 3 days or similar placebo patches applied in the most painful area. Patients were evaluated before treatment was initiated and after 24 and 48 h. The assessment was made blindly by the same clinical investigator. The follow‐up showed a significant decrease in intensity of pain at 24 h (7.05 ± 0.4 to 4.5 ± 0.5) and 48 h (2 ± 0.3) in the NTG group (P < 0.003). No changes were observed in the placebo group. The mean pain duration, activity of the extremity and hours of sleep also improved in the NTG group, with no significant modification in the placebo group. Two patients experienced headache as a side effect 24 h after treatment was started. Patients in the NTG group remained free of symptoms when they were assessed 15 days later. We conclude that NTG is useful in the treatment of shoulder pain syndrome caused by supraspinatus tendinitis and that this treatment could be a useful approach to the management of this common disturbance and probably also in other tendon musculoskeletal disorders.

Plasma Adrenomedullin Levels in Type 1 Diabetes: Relationship with clinical parameters

OBJECTIVE To assess the relationship between plasma adrenomedullin (AM) levels and the presence of microvascular complications in type 1 diabetic patients. RESEARCH DESIGN AND METHODS We measured plasma AM and cAMP levels in 103 type 1 diabetic patients (46 without complications, 24 with retinopathy only, 14 with microalbuminuria but normal kidney function, and 19 with renal insufficiency) and 41 matched healthy control subjects. RESULTS Patients with renal insufficiency had higher levels of AM and cAMP than all other groups. Patients with only retinopathy showed a trend to have higher levels than patients without complications. There were no differences among all other groups. There was a significant correlation between AM and cAMP in the total diabetic group (rs = 0.36, P < 0.001) but not in the control group. In multiple regression analysis, plasma AM demonstrated significant relationships with creatinine clearance (β = −0.31, P = 0.004) and duration of the disease (β = 0.28, P = 0.008). CONCLUSIONS Plasma AM and cAMP are increased in type 1 diabetic patients with renal insufficiency. Creatinine clearance (CrClc) and duration of the disease are related to plasma AM levels in these patients.

Espectro mutacional de los genes sarcoméricos MYH7, MYBPC3, TNNT2, TNNI3 y TPM1 en pacientes con miocardiopatía hipertrófica ☆

Introduccion y objetivos Las mutaciones en los genes sarcomericos son la causa mas frecuente de miocardiopatia hipertrofica. Para cada gen, la frecuencia de mutaciones varia entre los estudios, y las manifestaciones clinicas son muy heterogeneas, lo que dificulta el empleo de la informacion genetica en la practica clinica. Nuestro objetivo es determinar la frecuencia de mutaciones en los genes sarcomericos MYH7, MYBPC3, TNNT2, TNNI3 y TPM1 en una serie de pacientes con miocardiopatia hipertrofica. Metodos Se analizaron las regiones codificantes de estos cinco genes mediante secuenciacion en 120 pacientes (el 29% con antecedentes familiares), comparando el fenotipo segun el gen mutado. Resultados Se hallaron mutaciones en 32 pacientes; 10 y 20 tenian mutaciones en MYH7 (8%) y MYBPC3 (16%). Se hallaron mutaciones de TNNT2 y TPM1 en 2 y 1 pacientes, y ninguna de TNNI3. Dos pacientes tenian dos mutaciones (dobles mutantes). El 61% de las mutaciones no habian sido descritas previamente. No hallamos diferencias en la media de edad al diagnostico o el tamano de la hipertrofia entre los portadores de mutaciones en MYH7 y los de MYBPC3. Conclusiones El 26% de los pacientes tenian mutaciones en alguno de los cinco genes estudiados. Mas de la mitad de las mutaciones no habian sido descritas. El gen MYBPC3 fue el mas mutado, seguido de MYH7. No se hallaron diferencias fenotipicas entre los pacientes segun el gen mutado, lo que dificultaria el empleo de la informacion genetica para estratificar el riesgo en estos pacientes.

Mutations in Sarcomeric Genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in Patients With Hypertrophic Cardiomyopathy

INTRODUCTION AND OBJECTIVES Mutation of a sarcomeric gene is the most frequent cause of hypertrophic cardiomyopathy. For each such gene, however, previous studies have reported a range of different mutation frequencies, and clinical manifestations have been highly heterogeneous, both of which limit the use of genetic information in clinical practice. Our aim was to determine the frequency of mutations in the sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in a cohort of Spanish patients with hypertrophic cardiomyopathy. METHODS We used sequencing to analyze the coding regions of these five genes in 120 patients (29% with a family history) and investigated how the patient phenotype varied with the gene mutated. RESULTS In total, 32 patients were found to have mutations: 10 in MYH7 (8%), 20 in MYBPC3 (16%), 2 in TNNT2, 1 in TPM1 and none in TNNI3. Overall, 61% of mutations had not been described before. Two patients had two mutations (i.e., double mutants). There was no difference in the mean age at diagnosis or the extent of the hypertrophy between those with MYH7 mutations and those with MYBPC3 mutations. CONCLUSIONS Some 26% of patients had a mutation in one of the five sarcomeric genes investigated. More than half of the mutations had not been described before. The MYBPC3 gene was the most frequently mutated, followed by MYH7. No phenotypic differences were observed between carriers of the various mutations, which makes it difficult to use genetic information to stratify risk in these patients.

Endothelial dysfunction, measured by reactive hyperaemia using strain-gauge plethysmography, is an independent predictor of adverse outcome in heart failure.

In congestive heart failure (CHF), arterial response is regulated by endothelial molecules. The aim of this study was to evaluate whether endothelial dysfunction (ED) was a predictor of outcome in a cohort of patients with heart failure.

Soluble Fas ligand plasma levels are associated with forearm reactive hyperemia in subjects with coronary artery disease: a novel biomarker of endothelial function?

OBJECTIVES Fas ligand expression by endothelial cells is downregulated under proinflammatory conditions, facilitating the vascular infiltration by circulating cells. We have analyzed whether the forearm vasodilatory response to reactive hyperemia is associated with soluble Fas ligand (sFasL) plasma concentrations in subjects with coronary artery disease (CAD). METHODS Forearm blood flow to reactive hyperemia, an indicator of endothelial function, and forearm blood flow to nitroglycerin (endothelial-independent) were measured in 110 subjects with stable CAD. sFasL and C-reactive protein (CRP) concentrations were also determined. RESULTS There was a linear trend for the increase of sFasL and forearm reactive hyperemia (p<0.001). In contrast, no association was observed between sFasL and forearm blood flow to nitroglycerine. sFasL was not related with the presence of cardiovascular risk factors. Partial correlation coefficient adjusted by age and gender remained significant between sFasL and forearm blood flow to reactive hyperemia (r=0.35; p<0.001). No association between CRP concentrations and forearm reactive hyperemia, forearm blood flow to nitroglycerin or sFasL plasma concentrations was noted. CONCLUSIONS Our results are consistent with the hypothesis that sFasL levels could reflect endothelial function in subjects with CAD and suggest that sFasL plasma concentrations could be a potential biomarker of endothelial function.

Repeat Mitral Valve Replacement: 30-Years Experience

Prosthetic heart valve dysfunction is an acquired condition that carries a significant risk of emergency surgery. However, the long-term natural history of the condition is not well understood. Between 1974 and 2006, 1535 isolated mitral valve replacements were performed at our hospital (in-hospital mortality 5%). In total, 369 patients needed a second operation (in-hospital mortality 8.1%), while 80 (age 59.8+/-11.4 years) needed a third. The reasons for the third intervention were structural deterioration (67.5%), paravalvular leak (20%) and endocarditis (6.3%). Some 15 patients died in hospital (18.8%). After a mean follow-up period of 17.8 years, 21 patients needed another intervention (i.e., a fourth intervention). The actuarial reoperation-free rate at 20 years was 40.1+/-13.8%. The late mortality rate was 58.5% (18-year survival rate 15.4+/-5.4%). Indications for repeat mitral valve replacement must be judged on an individual basis given the high risk associated with surgery.

Low Levels of Intraplatelet cGMP in IDDM

OBJECTIVE To determine the levels of intraplatelet cGMP, an index of activity of the antiaggregatory nitric oxide pathway, in IDDM patients. RESEARCH DESIGN AND METHODS We measured intraplatelet and plasmatic cGMP levels in 22 IDDM patients and 22 age- and sex-matched control subjects. RESULTS Intraplatelet cGMP levels decreased in the IDDM patients (0.32 ±; 0.16 pmol/109 platelets) when compared with the control group (0.52 ±; 0.32 pmol/109 platelets), P = 0.032. Plasmatic cGMP levels were not significantly different between groups. Intraplatelet cGMP levels correlated negatively with the duration of the disease (r = −0.43, P < 0.05). CONCLUSIONS IDDM patients have lower levels of intraplatelet cGMP, which may be responsible in part for their platelet hyperactivity.

Functional polymorphisms in genes of the Angiotensin and Serotonin systems and risk of hypertrophic cardiomyopathy: AT1R as a potential modifier

BackgroundAngiotensin and serotonin have been identified as inducers of cardiac hypertrophy. DNA polymorphisms at the genes encoding components of the angiotensin and serotonin systems have been associated with the risk of developing cardiovascular diseases, including left ventricular hypertrophy (LVH).MethodsWe genotyped five polymorphisms of the AGT, ACE, AT1R, 5-HT2A, and 5-HTT genes in 245 patients with Hypertrophic Cardiomyopathy (HCM; 205 without an identified sarcomeric gene mutation), in 145 patients with LVH secondary to hypertension, and 300 healthy controls.ResultsWe found a significantly higher frequency of AT1R 1166 C carriers (CC+AC) among the HCM patients without sarcomeric mutations compared to controls (p = 0.015; OR = 1.56; 95%CI = 1.09-2.23). The AT1R 1166 C was also more frequent among patients who had at least one affected relative, compared to sporadic cases. This allele was also associated with higher left ventricular wall thickness in both, HCM patients with and without sarcomeric mutations.ConclusionsThe 1166 C AT1R allele could be a risk factor for cardiac hypertrophy in patients without sarcomeric mutations. Other variants at the AGT, ACE, 5-HT2A and 5-HTT did not contribute to the risk of cardiac hypertrophy.