José Pedro L. Nunes

Systematic review and meta‐analysis of clinical trials of the effects of low carbohydrate diets on cardiovascular risk factors

A systematic review and meta‐analysis were carried out to study the effects of low‐carbohydrate diet (LCD) on weight loss and cardiovascular risk factors (search performed on PubMed, Cochrane Central Register of Controlled Trials and Scopus databases). A total of 23 reports, corresponding to 17 clinical investigations, were identified as meeting the pre‐specified criteria. Meta‐analysis carried out on data obtained in 1,141 obese patients, showed the LCD to be associated with significant decreases in body weight (−7.04 kg [95% CI −7.20/−6.88]), body mass index (−2.09 kg m−2[95% CI −2.15/−2.04]), abdominal circumference (−5.74 cm [95% CI −6.07/−5.41]), systolic blood pressure (−4.81 mm Hg [95% CI −5.33/−4.29]), diastolic blood pressure (−3.10 mm Hg [95% CI −3.45/−2.74]), plasma triglycerides (−29.71 mg dL−1[95% CI −31.99/−27.44]), fasting plasma glucose (−1.05 mg dL−1[95% CI −1.67/−0.44]), glycated haemoglobin (−0.21% [95% CI −0.24/−0.18]), plasma insulin (−2.24 micro IU mL−1[95% CI −2.65/−1.82]) and plasma C‐reactive protein, as well as an increase in high‐density lipoprotein cholesterol (1.73 mg dL−1[95%CI 1.44/2.01]). Low‐density lipoprotein cholesterol and creatinine did not change significantly, whereas limited data exist concerning plasma uric acid.

Influence of non-steroidal anti-inflammatory drugs on renal function and 24h ambulatory blood pressure-reducing effects of enalapril and nifedipine gastrointestinal therapeutic system in hypertensive patients.

Objective: To evaluate the influence of non-steroidal anti-inflammatory drugs (NSAIDs; aspirin and indomethacin) on the renal and antihypertensive effects of enalapril and nifedipine gastrointestinal therapeutic system (GITS) in patients with essential hypertension. Design and methods: In a crossover study, 18 patients on an unrestricted-salt diet were randomly assigned to receive either enalapril (20-40 mg/day) or nifedipine-GITS (30-60mg/day) for 4-8 weeks, followed by aspirin (100 mg/day for 2 weeks) and then indomethacin (75 mg/day for 1 week). Blood pressure was measured by 24 h ambulatory monitoring. Results: Enalapril and nifedipine-GITS significantly reduced blood pressure compared with placebo. Aspirin did not alter the antihypertensive effect of either drug. Indomethacin attenuated (by 45%) the antihypertensive effect of enalapril throughout the 24 h period of evaluation, but did not interfere with the effect of nifedipine. Furthermore, indomethacin significantly reduced the fractional excretion of sodium and plasma levels of prostaglandins in a similar way when added to either the enalapril or the nifedipine regimen. Conclusions: Vasodilatory prostaglandins are probably involved in the antihypertensive effects of enalapril but not of nifedipine, and this interaction seems to be independent of any indomethacin-induced decrease in renal sodium excretion. Nifedipine may be an appropriate drug to treat hypertensive patients requiring concomitant therapy with NSAID.

Cardiac troponin I in aortic valve disease

BACKGROUND Plasma cardiac troponin I levels may be higher than normal in conditions other than ischemic heart disease. We aimed at measuring troponin I levels in aortic valve patients, in which increased values for left ventricular dimensions and pressure are frequently found. METHODS Plasma levels of troponin I, creatine kinase (CK) and the MB fraction of the same enzyme were measured in a group of 25 clinically stable aortic valve patients. Echocardiographic study was performed in all patients; hemodynamic and coronary angiographic study was performed in 19 patients. Troponin I was also measured in a control population (n=305). RESULTS The mean value for troponin I was found to be higher in aortic valve patients (0.07+/-0.02 ng/ml), when compared to controls (0.01+/-0.02 ng/ml; P<0.05). Significant correlations were found between troponin I and both creatine kinase and its MB fraction. When the 25 patients were divided into two groups, with lower (up to 0.04 ng/ml; 12 patients) and higher (0.05 ng/ml or greater; 13 patients) values for troponin I, patients with higher values were found to have greater mean left ventricular wall thickness (9.9+/-0.3 mm, n=11, vs. 12.1+/-0.3 mm, n=13) and pulmonary artery systolic pressures (36.6+/-2.5 mmHg, n=7, vs. 53.7+/-3.4 mmHg, n=9). CONCLUSIONS We conclude that slightly raised plasma levels of cardiac troponin I are relatively common in aortic valve patients with no evidence of ischemia. Higher left ventricular wall thickness and pulmonary artery systolic pressure may be related to slightly raised troponin I plasma levels.

Chloroethylclonidine irreversibly activates postjunctional alpha2-adrenoceptors in the dog saphenous vein

SummaryThis study was aimed at analysing the contractile response of the dog saphenous vein to chloroethylclonidine. At 37°C, chloroethylclonidine (0.1–100 μmol·1−1) caused along-lasting contraction in both proximal and distal segments of the dog saphenous vein, reaching 77.6 and 52.6% of the maximal response to phenylephrine, respectively. At 18°C, and in both segments, the maximal response to chloroethylclonidine was markedly reduced, whereas that to phenylephrine was not changed and that to UK-14,304 was enhanced. The response to chloroethylclonidine was unaffected by pretreatment with cocaine. Warming to 37°C caused contraction of strips which at 18°C had remained unresponsive to chloroethylclonidine, even if these strips were repeatedly washed before warming. At 18°C, chloroethylclonidine (100 μmol·1−1) did not alter the responses to UK-14,304 and phenylephrine.At 37°C, the contractile response to chloroethylclonidine was antagonized by yohimbine, rauwolscine and prazosin, with the potency rank yohimbine = rauwolscine > prazosin. Phenoxybenzamine (30 nmol · 1−1) displaced the concentration-response curve to chloroethylclonidine to the right and depressed its maximum. After phenoxybenzamine, yohimbine continued to be more effective than prazosin, which remained very potent.We concluded that: 1) the contractile response of the canine saphenous vein to chloroethylclonidine (both in the absence and in the presence of phenoxybenzamine) is predominantly alpha2-adrenoceptor-mediated since it is larger at the proximal than at the distal level of the vein and since it is more sensitive to yohimbine and rauwolscine than to prazosin; 2) the response to chloroethylclonidine and UK-14,304 are apparently due to activation of different alpha2-adrenoceptor subtypes, since prazosin was much more effective against chloroethylclonidine than against UK-14,304, and since at 18°C chloroethylclonidine “occupies” receptors without changing the response to UK-14,304; 3) there is a component of alphal-adrenoceptor stimulation in the response to chloroethylclonidine, since 30 nmol·1−1 phenoxybenzamine partly antagonized the effect of chloroethylclonidine; 4) since the responses to UK-14,304 and chloroethylclonidine are differently affected by cooling, there is some step (or steps) in the chain of events between the receptor and the final response, which is different in the two pathways.

The effectiveness of α2-adrenoceptor activation increases from the distal to the proximal part of the veins of canine limbs

1 The effectiveness of α1‐ and α2‐adrenoceptor activation was compared at different levels of the saphenous and cephalic vein of the dog in vitro. 2 Helically cut strips were used to determine concentration‐response curves to phenylephrine, noradrenaline, UK‐14, 304 (5‐bromo‐6‐(imidazoline‐2‐ylamino)‐quinoxaline) and B‐HT 920 (2‐amino‐6‐allyl‐5,6,7,8‐tetra‐hydro‐4H‐(thiazo)‐4,5‐d‐azepine). The effect of prazosin and yohimbine on these curves was also studied. 3 At the distal level, the maximum response to UK‐14,304 amounted to 33 and 50% of those to noradrenaline in the saphenous and cephalic vein, respectively, while at the proximal level the maximum response to UK‐14,304 amounted to 72 and 78% of those to noradrenaline, in the saphenous and cephalic vein, respectively. 4 In both vessels, the results obtained with B‐HT 920 were very similar to those for UK‐14,304. 5 The pD2 values for UK‐14,304 — which were identical at the three levels of both vessels — and the pA2 values for the antagonism exerted by either prazosin or yohimbine against the responses to UK‐14,304 indicate that the α2‐adrenoceptors are identical at the different levels of both vessels. 6 These results show that the effectiveness of α2‐adrenoceptor stimulation increases from the distal to the proximal regions of canine limb veins. Apparently, this is due to a greater density of α2‐adrenoceptors in the proximal regions. 7 Yohimbine is much more potent against phenylephrine distally than proximally in both vessels. However, after 30 nm phenoxybenzamine — a concentration which eliminates the vast majority of α1‐adrenoceptors without affecting α2‐adrenoceptors — yohimbine became equally potent at both levels, suggesting that the difference existing before phenoxybenzamine depended on α1‐adrenoceptors. Hence it is concluded that α1‐adrenoceptors in distal and proximal portions may differ.

Nicotine Nasal Inhalation, Atrial Fibrillation and Seizures

Accessible online at: www.karger.com/journals/crd Dear Sir, Nicotine is currently used in therapeutics as a means of promoting smoking cessation. Buccal administration, transdermal administration and oral and nasal inhalation have been used. The possibility exists, not only of the transference of nicotine dependence, but also of the abuse of nicotine, especially for preparations with a more rapid onset of effects. The abuse of nicotine may lead to the development of serious clinical effects. A 45-year-old male Caucasian patient was admitted to the emergency service unit after having developed syncope and generalized seizures. The patient was found to have tachycardia (heart rate 170/min), which was shown to correspond to atrial fibrillation, and was initially treated with intravenous amiodarone (300 mg) and digoxin (0.5 mg). He was in a state of agitation. Blood pressure was 153/67 mm Hg. Bilateral mydriasis was noted with a slow pupillary light reflex. Heart and pulmonary sounds were normal, and so was the remaining neurological examination. A cerebral computed tomography scan was normal. Normal values for blood gases, hemoglobin, leukocytes, platelets, plasma sodium, potassium and urea with a slight elevation of plasma glucose (the patient was receiving a glucose-containing serum) were found. The following values for plasma enzymes were measured: creatine kinase 234 units/l, creatine kinase MB fraction 5 units/l, lactate dehydrogenase 251 units/l, myoglobin 445 ng/ml, and troponin I 0.07 ng/ml. The patient had a history of heavy tobacco smoking, but no other diseases were known to exist. For some months, he had been on a program to stop smoking with the substitution of tobacco by inhaled nicotine. The patient had developed a syndrome of nicotine abuse, and in the emergency room he used his personal inhaler several times before being convinced to stop. He confirmed that he had used the inhaler prior to the syncope for an undetermined number of times. The patient refused electrical cardioversion, and was continued to be treated with intravenous amiodarone, returning to sinus rhythm after some hours of therapy. A week later, he was examined once again. The physical examination was normal, and so was a transthoracic echocardiogram. The diagnosis of inhaled nicotine abuse associated with atrial fibrillation and seizures was established. The association between atrial fibrillation and the administration of nicotine has previously been described [1–3]. As far as we are aware of, this is the first report of an association between inhaled nicotine abuse and atrial fibrillation. It may be concluded that the nasal administration of nicotine has the potential for drug abuse, which may be dangerous given the fact that nicotine can produce relatively serious clinical effects.

Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

Recent data have shown that lyso-Gb3, the deacylated derivative of globotriaosylceramide (Gb3), is possibly involved in the pathogenesis of Fabry disease (FD) and might be a clinically useful biomarker of its metabolic load. To test this hypothesis, we assayed Gb3 and lyso-Gb3 and related analogs in plasma and/or urine samples of 12 clinically well-characterized subjects carrying several different GLA variant alleles associated with a wide range of residual α-galactosidase A activities. Urinary Gb3 was measured by HPLC-MS/MS; plasma and urinary lyso-Gb3 and related analogs were measured by UPLC-MS/MS. Individual profiles of Gb3 and lyso-Gb3 and related analogs closely correlated with the phenotypic data for each subject, discerning the classical FD patient from the two patients carrying cardiac variants as well as those from all the others without FD. The lyso-Gb3 analog at m/z 836 was found at increased levels only in patients manifesting clinically severe heart disease, irrespective of the pathogenicity of the GLA variant they carried. This finding suggests that this lyso-Gb3 analog might be an earlier biomarker of progressive heart disease, non-specific of the FD cardiomyopathy. The possibility that urinary Gb3 is a specific marker of kidney involvement in FD deserves further study.

Troponin I in atrial fibrillation with no coronary atherosclerosis.

A number of reports have raised the possibility that myocardial strain could be associated to increased plasma levels of troponin I. A 69-year-old, male, Caucasian, patient was admitted with prolonged chest pain and dyspnoea.The electrocardiogram showed atrial fibrillation with a ventricular rate of about 120 to 150/minute. After treatment with digoxin and amiodarone, the patient returned to sinus rhythm. An elevation in the plasma levels of troponin I was noted, with a maximum value of 0.66 ng/ml. Coronary angiography showed absence of coronary artery atherosclerotic lesions. Atrial fibrillation of recent onset and with a relatively high heart rate may be yet another situation in which acute myocardial strain could be the cause of the abnormal release of cardiac troponin I.

Comparative analysis and meta-analysis of major clinical trials with oral factor Xa inhibitors versus warfarin in atrial fibrillation

Objectives A comparative analysis of three major clinical trials with factor Xa inhibitor oral anticoagulant (XOAC) drugs versus warfarin in atrial fibrillation—Rocket-AF (rivaroxaban), Aristotle (apixaban) and Engage AF Timi 48 (edoxaban; two different doses and sets of data)—was carried out. Methods Data were extracted from the original reports (study level) and a meta-analysis was carried out. Results When compared with warfarin, XOAC therapy was associated with a decrease in haemorrhagic stroke, with a similar pattern for all regimens and meta-analysis showing a risk ratio of 0.488 (95% CI 0.396 to 0.601). Regarding total mortality, a favourable pattern was seen for all four regimens and meta-analysis showed a risk ratio of 0.892 (95% CI 0.840 to 0.947). Major bleeding and gastrointestinal bleeding provided two examples regarding which heterogeneity would seem to exist, when XOAC drugs are compared with warfarin. In what concerns the incidence of myocardial infarction, the primary end point (stroke plus systemic embolism) and ischaemic stroke, the situation is less clear. These results are inconsistent with a putative ‘group effect’ for all the seven parameters under study, and for some of them it would probably be best to look at each of the individual trial data rather than at the meta-analysis data (which seem to lack a clear biological meaning). Conclusions Apixaban, rivaroxaban and edoxaban have shown interesting effects, when compared with warfarin in clinical trials, in patients with atrial fibrillation, particularly with regard to haemorrhagic stroke and to the mortality rate. No other consistent conclusions concerning a putative ‘group effect’ can be reached at the present stage. Concerns regarding adherence to therapy, possible drug interactions, cost and current absence of antidotes may be taken into consideration when choosing an anticoagulant drug.

Anti-troponin I antibodies in renal transplant patients

OBJECTIVE To characterize the prevalence and clinical correlates of anti-troponin I antibodies in renal transplant patients. METHODS A group of 48 consecutive renal transplant patients under immunosuppressive therapy were studied. Anti-troponin I antibodies were measured and clinical data were retrieved. RESULTS An anti-troponin I antibody titer <1:40 was seen in most patients (30). IgG antibody titers ≥1:80 were seen in eight patients, with a single value of 1:160. Regarding IgM antibodies, in six cases titers ≥1:80 were seen, with one value of 1:320. In only one patient were both anti-troponin I antibody IgG and IgM titers 1:80 or higher. Clinical cardiac disease was seen in nine patients. The presence of an anti-troponin I antibody titer ≥1:80 was not associated with the presence of clinical cardiac disease (p=0.232), but was associated with statin therapy status (p=0.008), being less frequent in patients under statin therapy. CONCLUSIONS Anti-troponin I antibodies are seen in a minority of renal transplant patients, and are not associated with the presence of clinical heart disease, but are associated with lack of statin therapy.