Carnitine therapy for the treatment of metabolic syndrome and cardiovascular disease: evidence and controversies.

As the incidence of metabolic syndrome increases, there is also a growing interest in finding safe and inexpensive treatments to help lower associated risk factors. L-carntine, a natural dietary supplement with the potential to ameliorate atherosclerosis, has been the subject of recent investigation and controversy. A majority of studies have shown benefit of L-C supplementation in the metabolic syndrome or cardiovascular risk factors. However, recent work has suggested that dietary L-C may accelerate atherosclerosis via gut microbiota metabolites, complicating the role of L-C supplementation in health.

Roadmap Consensus on Carotid Artery Plaque Imaging and Impact on Therapy Strategies and Guidelines: An International, Multispecialty, Expert Review and Position Statement.

Current guidelines for primary and secondary prevention of stroke in patients with carotid atherosclerosis are based on the quantification of the degree of stenosis and symptom status. Recent publications have demonstrated that plaque morphology and composition, independent of the degree of stenosis, are important in the risk stratification of carotid atherosclerotic disease. This finding raises the question as to whether current guidelines are adequate or if they should be updated with new evidence, including imaging for plaque phenotyping, risk stratification, and clinical decision-making in addition to the degree of stenosis. To further this discussion, this roadmap consensus article defines the limits of luminal imaging and highlights the current evidence supporting the role of plaque imaging. Furthermore, we identify gaps in current knowledge and suggest steps to generate high-quality evidence, to add relevant information to guidelines currently based on the quantification of stenosis.

Carotid atherosclerosis and a reduced likelihood for lowered cognitive performance in a Canadian First Nations population.

BACKGROUND: We investigated the associations among cardiovascular risk factors, carotid atherosclerosis and cognitive function in a Canadian First Nations population. METHODS: Individuals aged > or = 18 years, without stroke, nonpregnant and with First Nations status were assessed by the Trail Making Test Parts A and B. Results were combined into a Trail Making Test executive function score (TMT-exec). Doppler ultrasonography assessed carotid stenosis and plaque volume. Anthropometric, vascular and metabolic risk factors were assessed by interview, clinical examinations and blood tests. RESULTS: For 190 individuals with TMT-exec scores, the median age of the population was 39 years. Compared to the reference group, individuals with elevated levels of left carotid stenosis (LCS) and total carotid stenosis (TCS) were less likely to demonstrate lowered cognitive performance [LCS, odds ratio (OR): 0.47, 95% confidence interval (CI): 0.24-0.96; TCS, OR: 0.40, 95% CI: 0.20-0.80]. No effect was shown for plaque volume. In structural equation modeling, we found that for every 1-unit change in the anthropometric factor in kg/m(2), there was a 0.86-fold decrease in the percent of TCS (p < 0.05). CONCLUSIONS: Individuals with elevated levels of LCS and TCS were less likely to demonstrate lowered performance. There was some suggestion that TCS mediates the effect of anthropometric risk factors on cognitive function.

Registration of amiloride in South Africa: Cutting the Gordian knot.

Amiloride is an antagonist of the renal tubular epithelial sodium channel (ENaC). As such, it is a diuretic that is both potassium and magnesium sparing. It is used for the treatment of potassium depletion and hypertension, and is the specific therapy for hypertension due to overactivity of the ENaC (Liddle syndrome and several additional genetic causes of the Liddle phenotype - low renin and low aldosterone). It is listed as a World Health Organization essential drug, but has never been registered in South Africa (SA) and can therefore only be prescribed under a Section 21 application to the SA Health Products Regulatory Authority (SAHPRA) on a case-by-case basis. In SA, >50% of patients treated for hypertension are not controlled. In the USA, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study reported that African Americans are more likely to be diagnosed with hypertension, more likely to be treated, more likely to be treated intensively, and less likely to achieve blood pressure (BP) control. Although the reasons are complex, studies show that 10 - 20% of blacks may carry the Liddle phenotype. Observational data and a controlled clinical trial done in three African countries have shown that these patients respond to amiloride and not to conventional guideline-based antihypertensive treatment. The former is likely to result in a significant reduction in cardiovascular, stroke and kidney morbidity and mortality, because of improved BP control. Amiloride is very unlikely to ever be registered in SA, as it was first developed >50 years ago, and SAHPRA regulations prevent widespread prescription of this essential drug. This is a classic Gordian knot that requires a novel approach from authorities to sever the knot and improve the health of many South Africans.

High Frequency of Variants of Candidate Genes in Black Africans with Low Renin-Resistant Hypertension.

OBJECTIVES: Black subjects tend to retain salt and water, be more sensitive to aldosterone, and have suppression of plasma renin activity. Variants of the renal sodium channel (ENaC, SCNN1B) account for approximately 6% of resistant hypertension (RHT) in Blacks; other candidate genes may be important. METHODS: Six candidate genes associated with low renin-resistant hypertension were sequenced in Black Africans from clinics in Kenya and South Africa. CYP11B2 was sequenced if the aldosterone level was high (primary aldosteronism phenotype); SCNN1B, NEDD4L, GRK4, UMOD, and NPPA genes were sequenced if the aldosterone level was low (Liddle phenotype). RESULTS: There were 14 nonsynonymous variants (NSVs) of CYP11B2: 3 previously described and associated with alterations in aldosterone synthase production (R87G, V386A, and G435S). Out of 14, 9 variants were found in all 9 patients sequenced. There were 4 NSV of GRK4 (R65L, A116T, A142V, V486A): at least one was found in all 9 patients; 3 were previously described and associated with hypertension. There were 3 NSV of SCNN1B (R206Q, G442V, and R563Q); 2 previously described and 1 associated with hypertension. NPPA was found to have 1 NSV (V32M), not previously described and NEDD4L did not have any variants. UMOD had 3 NSV: D25G, L180V, and T585I. CONCLUSIONS: A phenotypic approach to investigating the genetic architecture of RHT uncovered a surprisingly high yield of variants in candidate genes. These preliminary findings suggest that this novel approach may assist in understanding the genetic architecture of RHT in Blacks and explain their two fold risk of stroke.

Relationship between blood pressure and stroke risk in patients with symptomatic carotid occlusive disease.

BACKGROUND AND PURPOSE: Blood pressure lowering in patients with a previous transient ischemic attack (TIA) or stroke reduces the risk of recurrent stroke and coronary vascular events. However, there is uncertainty about the risks and benefits in patients with severe carotid occlusive disease, particularly those with a carotid occlusion or bilateral > or =70% carotid stenosis in whom cerebral perfusion is often impaired and may depend directly on systemic blood pressure. Therefore, we studied the effect of carotid artery disease on the relationship between blood pressure and stroke risk in patients with recent TIA or stroke. METHODS: We compared the relationship between blood pressure (systolic and diastolic blood pressures, pulse pressure) and stroke risk in TIA and stroke patients with documented stenosis of at least 1 carotid artery [European Carotid Surgery Trial (ECST) and North American Symptomatic Carotid Endarterectomy Trial (NASCET)] with that in TIA and stroke patients with a low prevalence of carotid disease [United Kingdom Transient Ischaemic Attack (UK-TIA) Aspirin Trial]. In ECST and NASCET, we also determined the relationship between blood pressure and stroke risk in patients with unilateral carotid occlusion and patients with bilateral > or =70% carotid stenosis. RESULTS: Stroke risk on medical treatment increased with blood pressure in ECST and NASCET, but the relationships were less steep than in the UK-TIA trial. The relationship between blood pressure and stroke risk was not affected by the presence of a unilateral carotid occlusion but was significantly affected by the presence of bilateral carotid stenosis > or =70% (interaction: systolic blood pressure, P=0.002; diastolic blood pressure, P=0.03; pulse pressure, P=0.003). In this group, the relationship was inverted because of the high stroke risks at lower blood pressures. This interaction was not present after carotid endarterectomy and was not present for the risk of myocardial infarction. CONCLUSIONS: The risk of stroke increases with blood pressure in the great majority of patients with symptomatic carotid artery disease, but the relationship is less steep than in other patients with TIA or stroke. The relationship is unaffected by unilateral carotid occlusion alone but is inverted in patients with bilateral > or =70% carotid stenosis, suggesting that aggressive blood pressure lowering may not be advisable in this group. These patients represent only a few percent of all patients with TIA or stroke but have a high risk of recurrent stroke.

Hemodynamic effects of antihypertensive drugs. Possible implications for the prevention of atherosclerosis.

By lowering blood pressure, a number of hypertensive complications can be prevented, including congestive heart failure and such consequences of hypertensive arteriolar disease as nephropathy, intracerebral hemorrhage, and lacunar stroke. Whether atherosclerotic complications such as myocardial infarction can be prevented is more problematic and may depend on effects of the antihypertensive drugs other than the reduction of blood pressure, such as effects on plasma lipids and possibly hemodynamic effects. The following discussion summarizes a series of studies that suggest that the hemodynamic effects of antihypertensive drugs may be an important aspect of this problem. In studies in rhesus monkeys and hypertensive patients, antihypertensive drugs were shown to have differing effects on blood velocity and heart rate, important parameters in the genesis of arterial flow disturbances. In patients with carotid stenosis, hydralazine increased, whereas propranolol reduced, the occurrence of abnormal high-velocity flow patterns associated with turbulence and vortex formation. In a hypertensive (one kidney, one-clip) cholesterol-fed rabbit model, propranolol was significantly more effective than hydralazine in preventing the occurrence of aortic atherosclerosis. These observations suggest that the cardioprotective effect of beta blockers may extend to an antiatherosclerotic effect by hemodynamic mechanisms. This hypothesis is being further tested in patients with carotid stenosis.

Tolerance to nicotinic acid flushing.

The mechanism of tolerance to nicotinic acid flushing was determined in subjects during a 5-day course of treatment. Objective measures of skin blood flow were used to confirm the development of tolerance. Plasma levels of nicotinic acid showed marked intraindividual variability but were not decreased with the development of tolerance. However plasma levels of 9-alpha 11-beta prostaglandin F2, a stable metabolite of prostaglandin D2, became undetectable in most subjects with the development of tolerance. Thus tolerance is not associated with decreased levels of nicotinic acid or development of tolerance to the prostaglandin mediator, but with decreased levels of the mediator.

Grapefruit juice--felodipine interaction: mechanism, predictability, and effect of naringin.

Grapefruit juice produces a marked and variable increase in felodipine bioavailability. The pharmacokinetics of felodipine and its single primary oxidative metabolite, dehydrofelodipine, were studied after drug administration with 200 ml water, grapefruit juice, or naringin in water at the same concentration as the juice in a randomized crossover trial of nine healthy men. With grapefruit juice, mean +/- SEM felodipine area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) were 206% +/- 23% (range, 123% to 330%, p < 0.01) and 170% +/- 24% (range, 127% to 310%, p < 0.02), respectively, compared with water. Dehydrofelodipine/felodipine ratios for AUC (1.5 +/- 0.2 versus 2.2 +/- 0.2, p < 0.001) and felodipine Cmax (1.5 +/- 0.2 versus 2.2 +/- 0.2, p < 0.001) were reduced, consistent with inhibition of presystemic felodipine metabolism. Intersubject changes in felodipine and dehydrofelodipine AUC supported inhibition of both primary and secondary metabolic steps as a mechanism. The interaction could not be predicted from baseline pharmacokinetics with water and did not result in more consistent bioavailability among individuals. Naringin solution produced much less of an interaction, showing that other factors were important.

Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics.

The bioavailability of some dihydropyridine calcium antagonists can be markedly augmented by grapefruit juice and may involve the bioflavonoid naringin. The pharmacokinetics of nisoldipine coat-core tablet were studied in a Latin square-designed trial in which 12 healthy men were administered the drug with water, grapefruit juice, or encapsulated naringin powder at the same amount as that assayed in the juice. Compared with water, grapefruit juice increased the maximum concentration of nisoldipine to 406% +/- 73% (mean +/- SEM; range, 107% to 836%; p < 0.001), increased the area under the plasma concentration-time curve to 198% +/- 46% (range, 81% to 682%; p < 0.001), and reduced time to reach maximum nisoldipine concentration to 58% +/- 9% (range, 13% to 100%; p < 0.01), probably by inhibition of presystemic metabolism and possibly by enhancement of drug dissolution. The interaction could not be predicted from baseline pharmacokinetics with water and resulted in greater interindividual variability. The naringin capsule did not change nisoldipine pharmacokinetics. All treatments produced minor effects on supine blood pressure and heart rate, probably because subjects were normotensive. Current information supports the cautioning of patients about concomitant ingestion of grapefruit juice and nisoldipine.

Erythromycin-felodipine interaction: magnitude, mechanism, and comparison with grapefruit juice.

OBJECTIVE: To investigate a potentially marked effect by erythromycin on felodipine pharmacokinetics, to characterize the mechanism, and to compare the interaction with that between grapefruit juice and felodipine. METHODS: Felodipine, 10 mg extended release, was administered with 250 ml water, 250 mg erythromycin, or 250 ml grapefruit juice in a randomized crossover study of 12 healthy men. Erythromycin base, 250 mg four times a day, was started the day before and continued on that study day. Pharmacokinetic values of felodipine, the primary metabolite dehydrofelodipine, and the major secondary derivative M3 metabolite were studied. RESULTS: Compared with water, erythromycin produced severalfold higher felodipine area under the plasma drug concentration-time profile (AUC), plasma peak drug concentration (Cmax), and apparent elimination half-life (t1/2); however, the effect was variable among individuals. Erythromycin augmented dehydrofelodipine AUC, Cmax, and t1/2 but decreased dehydrofelodipine/felodipine ratios. The AUC of the M3 metabolite and the M3 metabolite/dehydrofelodipine ratios were reduced. These findings support inhibition of both metabolic pathways likely mediated by CYP3A4. Grapefruit juice produced similar mean effects but did not prolong felodipine or dehydrofelodipine t1/2. Individually, felodipine AUC with erythromycin was greater than or similar to that with grapefruit juice. Relative felodipine AUC (erythromycin compared with grapefruit juice) correlated with relative felodipine Cmax but not with relative felodipine t1/2, suggesting felodipine AUC differed between these treatments, mainly from factors affecting presystemic drug elimination. CONCLUSIONS: Erythromycin produced an important pharmacokinetic interaction with felodipine by inhibition of drug metabolism. Although erythromycin and grapefruit juice shared a common mechanism, erythromycin likely reduced felodipine biotransformation at the gut wall and liver, whereas single-dose grapefruit juice had an effect mainly at the gut wall.

Grapefruit juice-terfenadine single-dose interaction: magnitude, mechanism, and relevance.

OBJECTIVE: To investigate the single dose-response effects of grapefruit juice on terfenadine disposition and electrocardiographic measurements. METHODS: Twelve healthy males received 250 ml water or regular- or double-strength grapefruit juice with 60 mg terfenadine in a randomized crossover trial. Plasma concentrations of the cardiotoxic agent terfenadine and the active antihistaminic metabolite terfenadine carboxylate were determined over 8 hours. The QTc interval was monitored. RESULTS: Terfenadine concentrations were measurable (> 1 ng/ml) in 27 (20%; p < 0.001) and 39 (30%; p < 0.001) samples from individuals treated with regular- and double-strength grapefruit juice, respectively, compared to only four (3%) samples with water. Terfenadine plasma peak drug concentration (Cmax) was also higher. Terfenadine carboxylate area under the plasma drug concentration-time curve (AUC), Cmax, and time to reach Cmax (tmax) were increased by both strengths of juice. However, terfenadine carboxylate apparent elimination half-life (t1/2) was not altered. The magnitude of the interaction of terfenadine carboxylate AUC and Cmax ranged severalfold and correlated among individuals for regular-strength (r2 = 0.87; p < 0.0001) and double-strength (r2 = 0.78; p < 0.0001) grapefruit juice. No differences in the pharmacokinetics of terfenadine and terfenadine carboxylate were observed between the two strengths of grapefruit juice. QTc interval was not altered. CONCLUSIONS: A normal amount of regular-strength grapefruit juice produced maximum single-dose effects on terfenadine and carboxylic acid metabolite pharmacokinetics. The mechanism likely involved reduced presystemic drug elimination by inhibition of more than one metabolic pathway. The extent of the interaction was not sufficient to produce electrocardiographic changes. However, the pharmacokinetic effects were highly variable among individuals. This study further enhances the awareness of the potential for a serious interaction between grapefruit juice and terfenadine.

HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia.

BACKGROUND: Orange juice-a rich source of vitamin C, folate, and flavonoids such as hesperidin-induces hypocholesterolemic responses in animals. OBJECTIVE: We determined whether orange juice beneficially altered blood lipids in subjects with moderate hypercholesterolemia. DESIGN: The sample consisted of 16 healthy men and 9 healthy women with elevated plasma total and LDL-cholesterol and normal plasma triacylglycerol concentrations. Participants incorporated 1, 2, or 3 cups (250 mL each) of orange juice sequentially into their diets, each dose over a period of 4 wk. This was followed by a 5-wk washout period. Plasma lipid, folate, homocyst(e)ine, and vitamin C (a compliance marker) concentrations were measured at baseline, after each treatment, and after the washout period. RESULTS: Consumption of 750 mL but not of 250 or 500 mL orange juice daily increased HDL-cholesterol concentrations by 21% (P: < 0.001), triacylglycerol concentrations by 30% (from 1.56 +/- 0.72 to 2.03 +/- 0.91 mmol/L; P: < 0.02), and folate concentrations by 18% (P: < 0.01); decreased the LDL-HDL cholesterol ratio by 16% (P: < 0.005); and did not affect homocyst(e)ine concentrations. Plasma vitamin C concentrations increased significantly during each dietary period (2.1, 3.1, and 3.8 times, respectively). CONCLUSIONS: Orange juice (750 mL/d) improved blood lipid profiles in hypercholesterolemic subjects, confirming recommendations to consume >/=5-10 servings of fruit and vegetables daily.

Lipids and stroke: a paradox resolved.

BACKGROUND: Although dyslipidemia is a well established risk factor for coronary artery disease, its relationship to ischemic cerebrovascular disease has remained unclear, perhaps because of the heterogeneous nature of strokes. METHODS: In a case-control study, we measured the serum concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, serum triglycerides, and lipoprotein(a) levels and determined the apolipoprotein E phenotype and serum ferritin level in 90 consecutive systematically investigated patients with stroke or transient ischemic attack of atherothrombotic origin. Ninety age-, sex-, and community-matched subjects served as controls. RESULTS: Plasma total cholesterol (5.99 vs 5.45 mmol/L [232 vs 211 mg/dL], P=.003), low-density lipoprotein cholesterol (3.96 vs 3.45 mmol/L [153 vs 133 mg/dL], P=.004), and serum triglyceride (2.09 vs 1.82 mmol/L [8] vs 70 mg/dL], P=.03) levels were significantly higher among the patients with atherothrombotic strokes and transient ischemic attacks than among the control subjects. The inverse was true for high-density lipoprotein cholesterol (1.07 vs 1.18 mmol/L [41 vs 46 mg/dL], P=.02) levels. No significant differences were found in lipoprotein(a) levels or in the distribution of apolipoprotein E phenotypes or allele frequency. Serum ferritin levels did not differ significantly between patients and control subjects. CONCLUSIONS: Elevated low-density lipoprotein cholesterol and triglyceride levels are significant independent risk factors in patients with proven atherothrombotic cerebrovascular disease manifesting as stroke or transient ischemic attack. The level of stored serum iron, as reflected by serum ferritin levels, does not correlate with the presence of atherothrombotic cerebrovascular or coronary disease.

Prognosis for patients following a transient ischemic attack with and without a cerebral infarction on brain CT. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group.

BACKGROUND: Although cerebral infarctions are commonly observed on brain CTs of patients with TIAs, their prognostic importance is unknown. METHOD: The association between appropriately sited brain infarctions (ie, lesions located in the anterior circulation of the brain and ipsilateral to the symptomatic stenosed carotid artery) visualized on CT and the risk of subsequent stroke was assessed by Cox proportional hazards regression in 164 patients presenting with TIA (and no history of previous stroke) and severe angiographically defined carotid stenosis (70 to 99%) from the North American Symptomatic Carotid Endarterectomy Trial. RESULTS: Patients with a TIA and CT-verified brain lesions were older and were more likely to have higher degrees of carotid stenosis and carotid plaque ulceration, a longer duration of symptoms, and a history of hypertension. With regard to prognosis, after adjusting for all known risk factors (patient characteristics) in a regression analysis, the presence of ischemic lesions observed on CT was not associated with an increased risk of ipsilateral stroke at 2 years (adjusted hazard ratio = 1.00; 95% CI: 0.39 to 2.58; p value = 0.99). CONCLUSION: Considered in combination with other patient characteristics, the mere presence of an appropriately sited cerebral infarction on CT does not alter the prognosis (risk of ipsilateral strokes) of severely stenosed patients with TIA. Therefore, there is no clinical rationale in differentiating patients with TIA on the basis of CT findings alone.

An approach to ascertain probands with a non-traditional risk factor for carotid atherosclerosis.

In our previous studies of the determinants of carotid plaque area (CPA), we used a linear multiple regression model, which permitted us to control for the presence of known risk factors in order to reveal the contribution of putative new risk factors. We recognized that this approach could identify patients whose observed CPA was excessive when considering traditional risk factors. Subjects whose observed CPA markedly exceeded the expected CPA were easily identified because of their deviation from the regression line that was derived using all members of the study sample. We classified such subjects as having 'unexplained atherosclerosis' relative to the overall study sample when traditional risk factors were included as independent variables. We then examined the plasma homocyst(e)ine concentration in members of the subgroup with 'unexplained atherosclerosis'. We found a significantly higher mean plasma concentration of homocyst(e)ine in the subgroup with 'unexplained atherosclerosis', compared to rest of the study sample (20.4 +/- 4.3 vs. 13.2 +/- 3.2 mumol/l, P < 0.005). We also found that significantly more subjects with 'unexplained atherosclerosis' had plasma homocyst(e)ine concentrations in excess of 14 mumol/l compared to the rest of the study sample (52 vs. 33%, P < 0.002). We thus propose that systematic identification of subjects with 'unexplained atherosclerosis' relative to the rest of a well-characterized study sample might be a useful approach to identify subjects in whom there are newer, non-traditional determinants of predisposition to atherosclerosis.