Progression of atherosclerosis with carnitine supplementation: a randomized controlled trial in the metabolic syndrome.

BACKGROUND: L-carnitine (L-C), a ubiquitous nutritional supplement, has been investigated as a potential therapy for cardiovascular disease, but its effects on human atherosclerosis are unknown. Clinical studies suggest improvement of some cardiovascular risk factors, whereas others show increased plasma levels of pro-atherogenic trimethylamine N-oxide. The primary aim was to determine whether L-C therapy led to progression or regression of carotid total plaque volume (TPV) in participants with metabolic syndrome (MetS). METHODS: This was a phase 2, prospective, double blinded, randomized, placebo-controlled, two-center trial. MetS was defined as ≥ 3/5 cardiac risk factors: elevated waist circumference; elevated triglycerides; reduced HDL-cholesterol; elevated blood pressure; elevated glucose or HbA1c; or on treatment. Participants with a baseline TPV ≥ 50 mm3 were randomized to placebo or 2 g L-C daily for 6 months. RESULTS: The primary outcome was the percent change in TPV over 6 months. In 157 participants (L-C N = 76, placebo N = 81), no difference in TPV change between arms was found. The L-C group had a greater increase in carotid atherosclerotic stenosis of 9.3% (p = 0.02) than the placebo group. There was a greater increase in total cholesterol and LDL-C levels in the L-C arm. CONCLUSIONS: Though total carotid plaque volume did not change in MetS participants taking L-C over 6-months, there was a concerning progression of carotid plaque stenosis. The potential harm of L-C in MetS and its association with pro-atherogenic metabolites raises concerns for its further use as a potential therapy and its widespread availability as a nutritional supplement. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02117661, Registered April 21, 2014, https://clinicaltrials.gov/ct2/show/NCT02117661 .

Prophylactic warfarin post anterior ST-elevation myocardial infarction: A systematic review and meta-analysis.

OBJECTIVES: To determine the role of warfarin (WF) prophylaxis in the prevention of left ventricular thrombus (LVT) formation and subsequent embolic complications following an anterior ST elevation myocardial infarction (STEMI) complicated by reduced left ventricular ejection fraction (LVEF) and wall motion abnormalities. BACKGROUND: The role of oral anticoagulation prophylaxis, in addition to dual antiplatelet therapy (DAPT), in the current era of percutaneous coronary intervention has not been well studied, despite being a class IIb recommendation in the AHA/ACC STEMI guidelines. METHODS: The Cochrane search strategy was used to search PubMed, Embase and the Cochrane library for relevant results. Four studies, two retrospective, one prospective registry, and a randomized feasibility control trial met criteria for inclusion. Data was pooled using a random effects model and reported as odds ratios (OR) with their 95% confidence intervals (CI). Primary outcomes of interest were rate of stroke, major bleeding and mortality. RESULTS: Pooled analysis included 526 patients in the No WF group and 347 patients in the WF group. No statistical difference in rate of stroke (OR: 2.72 [95% CI: 0.47-15.88; p=0.21]) or mortality (OR: 1.50 [95% CI 0.29-7.71; p=0.63]) was observed. Major bleeding was significantly higher in the WF group (OR: 2.56 [95% CI: 1.34-4.89; p=0.004]). CONCLUSIONS: The routine use of DAPT and WF for prophylaxis against LVT formation following an anterior STEMI with associated decrease in LVEF and wall motion abnormalities, appears to result in no mortality benefit or reduction in stroke rates, but may increase the frequency of major bleeding.

Lack of independent effect of type 2 diabetes beyond characteristic comorbidities and medications on small muscle mass exercising muscle blood flow and exercise tolerance.

Persons with type 2 diabetes (T2D) are believed to have reduced exercise tolerance; this may be partly due to impaired exercising muscle blood flow (MBF). Whether there is an impact of T2D on exercising MBF within the typical constellation of comorbidities (hypertension, dyslipidemia, obesity) and their associated medications has not been investigated. We tested the hypothesis that small muscle mass exercise tolerance is reduced in persons with T2D versus Controls (matched for age, body mass index, fitness, comorbidities, non-T2D medications) and that this is related to blunted MBF. Eight persons with T2D and eight controls completed a forearm critical force (fCFimpulse) test as a measure of exercise tolerance (10-min intermittent maximal effort forearm contractions; the average contraction impulse in the last 30 sec quantified fCFimpulse). Forearm blood flow (FBF; ultrasound) and mean arterial pressure (MAP; finger photoplethysmography) were measured; forearm vascular conductance (FVK) was calculated. Data are means ± SD, T2D versus Control. fCFimpulse was not different between groups (136.9 ± 47.3  N·sec vs. 163.1 ± 49.7 N·sec, P = 0.371) nor was the ∆FBF from rest to during exercise at fCFimpulse (502.9 ± 144.6 vs. 709.1 ± 289.2 mL/min, P = 0.092), or its determinants ∆FVK and ∆MAP (both P > 0.05), although there was considerable interindividual variability. ∆FBF was strongly related to fCFimpulse (r = 0.727, P = 0.002), providing support for the relationship between oxygen delivery and exercise tolerance. We conclude that small muscle mass exercising MBF and exercise tolerance are not impaired in representative persons with T2D versus appropriately matched controls. This suggests that peripheral vascular control impairment does not contribute to reduced exercise tolerance in this population.

Independent effect of type 2 diabetes beyond characteristic comorbidities and medications on immediate but not continued knee extensor exercise hyperemia.

We tested the hypothesis that type 2 diabetes (T2D), when present in the characteristic constellation of comorbidities (obesity, hypertension, dyslipidemia) and medications, slows the dynamic adjustment of exercising muscle perfusion and blunts the steady state relative to that of controls matched for age, body mass index, fitness, comorbidities, and non-T2D medications. Thirteen persons with T2D and 11 who served as controls performed rhythmic single-leg isometric quadriceps exercise (rest-to-6 kg and 6-to-12 kg transitions, 5 min at each intensity). Measurements included leg blood flow (LBF, femoral artery ultrasound), mean arterial pressure (MAP, finger photoplethysmography), and leg vascular conductance (LVK, calculated). Dynamics were quantified using mean response time (MRT). Measures of amplitude were also used to compare response adjustment: the change from baseline to 1) the peak initial response (greatest 1-s average in the first 10 s; ΔLBFPIR, ΔLVKPIR) and 2) the on-transient (average from curve fit at 15, 45, and 75 s; ΔLBFON, ΔLVKON). ΔLBFPIR was significantly blunted in T2D vs. control individuals (P = 0.037); this was due to a tendency for reduced ΔLVKPIR (P = 0.063). In contrast, the overall response speed was not different between groups (MRT P = 0.856, ΔLBFON P = 0.150) nor was the change from baseline to steady state (P = 0.204). ΔLBFPIR, ΔLBFON, and LBF MRT did not differ between rest-to-6 kg and 6-to-12 kg workload transitions (all P > 0.05). Despite a transient amplitude impairment at the onset of exercise, there is no robust or consistent effect of T2D on top of the comorbidities and medications typical of this population on the overall dynamic adjustment of LBF, or the steady-state levels achieved during low- or moderate-intensity exercise.

Performance of the "CCS Algorithm" in real world patients.

BACKGROUND: With the publication of the 2014 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation, the Canadian Cardiovascular Society Atrial Fibrillation Guidelines Committee has introduced a new triage and management algorithm; the so-called "CCS Algorithm". The CCS Algorithm is based upon expert opinion of the best available evidence; however, the CCS Algorithm has not yet been validated. Accordingly, the purpose of this study is to evaluate the performance of the CCS Algorithm in a cohort of real world patients. METHODS: We compared the CCS Algorithm with the European Society of Cardiology (ESC) Algorithm in 172 hospital inpatients who are at risk of stroke due to non-valvular atrial fibrillation in whom anticoagulant therapy was being considered. RESULTS: The CCS Algorithm and the ESC Algorithm were concordant in 170/172 patients (99% of the time). There were two patients (1%) with vascular disease, but no other thromboembolic risk factors, which were classified as requiring oral anticoagulant therapy using the ESC Algorithm, but for whom ASA was recommended by the CCS Algorithm. CONCLUSIONS: The CCS Algorithm appears to be unnecessarily complicated in so far as it does not appear to provide any additional discriminatory value above and beyond the use of the ESC Algorithm, and its use could result in under treatment of patients, specifically female patients with vascular disease, whose real risk of stroke has been understated by the Guidelines.

Identifying patients at low risk for activity-related events: the RARE Score.

PURPOSE: To prospectively assess whether the Risk of Activity Related Events (RARE) Score accurately identifies patients who are at low risk of experiencing an adverse event while exercise training at cardiac rehabilitation. METHODS: Individuals screened for entry into cardiac rehabilitation were classified as high-risk (RARE Score ≥ 4) or low-risk (RARE Score < 4) using the RARE Score. Patients were followed until program completion or withdrawal, and adverse events were documented. RESULTS: Individuals (n = 656) were eligible for analysis (high risk: n = 260; low risk: n = 396). Eleven events (1 major, 10 minor) were recorded during the study, and the overall event rate was low (1 event per 1321 patient hours of exercise training). Individuals triaged as high-risk had significantly more events than the low-risk cohort (high risk: n = 8 vs low risk: n = 3; P = .024) and were 4 times more likely to experience an adverse event (OR: 4.2; 95% CI: 1.0-20.0). More than 99% of low-risk patients were event free (negative predictive value: 99.2%; 95% CI: 98.3-99.8), while participating in exercise at cardiac rehabilitation. CONCLUSION: The RARE Score accurately identifies patients who are at low risk of experiencing adverse events during exercise training at cardiac rehabilitation. The identification of low-risk patients allows for the possibility of reduced on-site supervision and monitoring, or the provision of alternative models of cardiac rehabilitation, including community- or home-based cardiac rehabilitation programs.

High and low contact frequency cardiac rehabilitation programmes elicit similar improvements in cardiorespiratory fitness and cardiovascular risk factors.

AIM: Cardiac rehabilitation (CR) is a proven intervention that substantially improves physical health and decreases death and disability following a cardiovascular event. Traditional CR typically involves 36 on-site exercise sessions spanning a 12-week period. To date, the optimal dose of CR has yet to be determined. This study compared a high contact frequency CR programme (HCF, 34 on-site sessions) with a low contact frequency CR programme (LCF, eight on-site sessions) of equal duration (4 months). METHODS: A total of 961 low-risk cardiac patients (RARE score <4) self-selected either a HCF (n = 469) or LCF (n = 492) CR programme. Cardiorespiratory fitness and cardiovascular risk factors were measured on admission and discharge. RESULTS: Similar proportions of patients completed HCF (n = 346) and LCF (n = 351) (p = 0.398). Patients who were less fit (<8 METs) were more likely to drop out of the LCF group, while younger patients (<60 years) were more likely to drop out of the HCF group. Both groups experienced similar reductions in weight (-2.3 vs. -2.4 kg; p = 0.779) and improvements in cardiorespiratory fitness (+1.5 vs. +1.4 METs; p = 0.418). CONCLUSIONS: Patients in the LCF programme achieved equivalent results to those in the HCF programme. Certain subgroups of patients, however, may benefit from participation in a HCF programme, including those patients who are predisposed to prematurely discontinuing the programme and those patients who would benefit from increased monitoring. The LCF model can be employed as an alternative option to widen access and participation for patients who are unable to attend HCF programmes due to distance or time limitations.

Comparison of the efficacy of administering a combination of ezetimibe plus fenofibrate versus atorvastatin monotherapy in the treatment of dyslipidemia.

BACKGROUND: This trial compares the efficacy of administering a combination of ezetimibe plus fenofibrate as an alternative to statin monotherapy for the treatment of dyslipidemia. In this randomized, unblinded crossover study, 43 patients with documented hypercholesterolemia requiring pharmacotherapy were randomized to receive six weeks of either a combination of 10 mg of ezetimibe plus 160 mg of fenofibrate (combination) or 10 mg of atorvastatin monotherapy (atorvastatin). The primary endpoint was the percentage reduction of low-density lipoprotein cholesterol (LDL-C). RESULTS: LDL-C decreased by 34.6% with the combination therapy versus 36.7% with atorvastatin monotherapy. The difference between the two groups was not statistically significant (p = 0.46). Both study interventions provided similar improvements in total cholesterol (-25.1% with combination versus -24.6% with atorvastatin, p = 0.806) and high-density lipoproteins (+10.0% with combination versus +8.9% with atorvastatin, p = 0.778). Combination therapy showed a trend towards a greater reduction in triglycerides (-25.4% with combination versus -14.5% with atorvastatin, p = 0.079), although there was no significant difference between the two study interventions in terms of the improvement in the TC:HDL ratio (-29.0% with combination versus -28.7% with atorvastatin, p = 0.904). CONCLUSIONS: The combination of ezetimibe plus fenofibrate appeared to produce nearly identical alterations in serum lipoprotein levels when compared to monotherapy with 10 mg of atorvastatin. Daily treatment with the combination of ezetimibe plus fenofibrate is an acceptable alternative to atorvastatin for the treatment of dyslipidemia in patients who are intolerant of statins.

Efficacy of alternate day versus daily dosing of rosuvastatin.

BACKGROUND: Compared with other statins, rosuvastatin has a relatively long half-life, which may allow for the administration of this medication on an alternate day basis. OBJECTIVE: To compare the efficacy of administering rosuvastatin on a daily basis versus on an alternate day basis for the treatment of dyslipidemia. METHODS: In the present crossover study, 45 patients with documented hypercholesterolemia requiring pharmacotherapy were administered either 20 mg of rosuvastatin on alternate days or 10 mg of rosuvastatin daily for six weeks. After a four-week washout period, patients were then switched to the other regimen for another six weeks. The primary end point was the percentage reduction of low-density lipoprotein cholesterol (LDL-C). RESULTS: LDL-C decreased by 48.5% versus 40.9% with daily and alternate day dosing, respectively. This represented an additional absolute reduction of LDL-C of 7.6% (95% CI 1.8% to 13.4%, P=0.012) with the daily dosing regimen. Both dosing regimens provided similar improvements in high-density lipoprotein cholesterol and triglycerides. CONCLUSIONS: Compared with alternate day dosing, daily dosing of rosuvastatin provides a statistically significant advantage in LDL-C reduction. However, the alternate day regimen may be a viable option for those patients in whom cost is a limitation to compliance.

Plasma PCSK9 levels are significantly modified by statins and fibrates in humans.

BACKGROUND: Proprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. It modulates levels of circulating low density lipoprotein cholesterol (LDLC) by negatively regulating low density lipoprotein receptor (LDLR) levels. PCSK9 variants that result in 'gain of function' have been linked to autosomal dominant hypercholesterolemia, while significant protection from coronary artery disease has been documented in individuals who carry 'loss of function' PCSK9 variants. PCSK9 circulates in human plasma, and we previously reported that plasma PCSK9 is positively correlated with total cholesterol and LDLC in men. RESULTS: Herein, we report the effects of two lipid-modulating therapies, namely statins and fibrates, on PCSK9 plasma levels in human subjects. We also document their effects on endogenous PCSK9 and LDLR expression in a human hepatocyte cell line, HepG2, using immunoprecipitation and immunoblot analyses. Changes in plasma PCSK9 following fenofibrate or gemfibrozil treatments (fibric acid derivatives) were inversely correlated with changes in LDLC levels (r = -0.558, p = 0.013). Atorvastatin administration (HMGCoA reductase inhibitor) significantly increased plasma PCSK9 (7.40%, p = 0.033) and these changes were inversely correlated with changes in LDLC levels (r = -0.393, p = 0.012). Immunoblot analyses of endogenous PCSK9 and LDLR expression by HepG2 cells in response to statins and fibrates showed that LDLR is more upregulated than PCSK9 by simvastatin (2.6x vs 1.5x, respectively at 10 muM), while fenofibrate did not induce changes in either. CONCLUSION: These results suggest that in vivo (1) statins directly increase PCSK9 expression while (2) fibrates affect PCSK9 expression indirectly through its modulation of cholesterol levels and (3) that these therapies could be improved by combination with a PCSK9 inhibitor, constituting a novel hypercholesterolemic therapy, since PCSK9 was significantly upregulated by both treatments.

Comparison between a low glycemic load diet and a Canada Food Guide diet in cardiac rehabilitation patients in Ontario.

BACKGROUND: A high dietary glycemic load is associated with an increased risk of noninsulin-dependent diabetes mellitus and coronary artery disease. OBJECTIVE: To evaluate the effect of a low glycemic load diet on cardiac rehabilitation patients. METHODS: One hundred twenty patients who were advised to follow a low glycemic load diet were evaluated and compared with 1434 patients who were advised to follow the principles of Canada's Food Guide to Healthy Eating for People Four Years and Over as part of the Ontario Cardiac Rehabilitation Pilot Project. RESULTS: Patients on the low glycemic load diet lost more weight at six months (2.8 kg loss versus 0.2 kg gain, P < 0.0001), had a greater reduction in abdominal obesity (2.9 cm versus 0.4 cm, P < 0.0001), and had a greater improvement in high density lipoprotein cholesterol (0.14 mmol/L versus 0.02 mmol/L, P < 0.0001), triglycerides (-0.44 mmol/L versus -0.08 mmol/L, P < 0.0001) and glycemic control (fasting glucose -0.94 mmol/L versus 0.91 mmol/L, P = 0.0019). After one year of follow-up, the low glycemic load patients had maintained (weight gain 0.7 kg, triglycerides -0.07 mmol/L, fasting glucose -0.10 mmol/L and glycosylated hemoglobin A1c -0.18%; all not significant) or augmented (waist circumference -1.3 cm, P = 0.038; high density lipoprotein cholesterol 0.08 mmol/L, P < 0.0001) the initial results. CONCLUSIONS: Implementation of a low glycemic load diet was associated with substantial and sustained improvements in abdominal obesity, cholesterol and glycemic control.