Simon B. Dimmitt

Influence of pattern of alcohol intake on blood pressure in regular drinkers: a controlled trial

Objective To evaluate the effects of patterns of drinking (weekend versus daily drinking) on the pressor responses to alcohol in 55 male drinkers using clinic and 24 h ambulatory blood pressure monitoring. Design A randomized, controlled cross-over trial. Methods Recruitment required a regular alcohol intake of 210–500 ml absolute alcohol/week, with > 60% consumed as beer. Fourteen subjects were categorized as predominantly weekend drinkers, whereas the remaining 41 subjects regularly drank on a daily basis. After 4 weeks of familiarization, all subjects were randomly allocated to drinking low-alcohol beer (0.9% vol: vol) only or to maintain their usual drinking habits with provision of full-strength beer (5% vol: vol) for 4 weeks. They then switched back to their usual drinking habits or low-alcohol beer, respectively, for a further 4 weeks while maintaining their usual drinking pattern. Results Baseline ambulatory systolic blood pressure in weekend but not in daily drinkers was 2.4 mmHg higher on Monday than it was on Thursday (P = 0.02). This Monday-Thursday difference was lost during intervention. When subjects switched from the high-alcohol to the low-alcohol period the falls in ambulatory systolic blood pressure in weekend (3.1 mmHg, P < 0.001) and daily drinkers (2.2 mmHg, P < 0.001) were similar. Most of the fall was evident during week 1 of the low-alcohol period for weekend drinkers but not until week 4 for daily drinkers. Conclusion The pressor response to alcohol consumption is similar in magnitude in weekend and daily drinkers, present throughout a 24 h period and has a rapid onset/offset in weekend drinkers but is more sustained in daily drinkers.

Low density lipoprotein composition and oxidizability in coronary disease - Apparent favourable effect of beta blockers

The oxidative modification of LDL in vivo may have an important role in atherogenesis. To determine whether LDL fatty acid, anti-oxidant composition and sensitivity to oxidation in vitro is different in subjects with established atherosclerosis we compared 20 men with angiogram proven coronary disease with 25 controls without clinical evidence of arterial disease. LDL-cholesterol, total triglycerides and LDL fatty acid composition did not differ significantly between the groups. LDL oxidation lag time and oxidation rate in coronary patients (132 min, 0.02 absorbance units/min) and controls (140, 0.017) were not significantly different. However coronary disease subjects taking beta-blockers had evidence for reduced LDL oxidizability (lag time 148 +/- 7 min; oxidation rate 0.017 +/- 0.002 abs units/min) compared with those not on beta-blockers (lag time 114 +/- 7 min, rate 0.025 +/- 0.003, P < 0.005). LDL beta-carotene was significantly lower in coronary patients (0.92 mumol/mmol LDL cholesterol; controls 1.58; P = 0.001). LDL alpha-tocopherol appeared lower in coronary patients (2.8 mumol/mmol LDL cholesterol; controls 3.3; P = 0.056) and was significantly lower in smokers (2.56; non-smokers 3.24; P = 0.04). LDL oxidation rate was negatively correlated with LDL alpha-tocopherol (r = -0.51, P = 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated apolipoprotein B‐48 and remnant‐like particle–cholesterol in heterozygous familial hypercholesterolaemia

Apolipoprotein B‐48 (apoB‐48) is a marker of triglyceride‐rich lipoprotein (TRL) remnants of intestinal origin. Chylomicron remnants are causally related to atherosclerosis. We have shown previously that fasting plasma apoB‐48 may predict postprandial lipaemia. Remnant‐like particle–cholesterol (RLP‐C) may also reflect TRL remnants. We aimed to determine whether subjects with heterozygous familial hypercholesterolaemia (FH) had an accumulation of remnants of intestinal origin, as reflected by fasting plasma apoB‐48 and RLP‐C levels.

Chylomicron remnant metabolism in familial hypercholesterolaemia studied with a stable isotope breath test

Chylomicron remnant metabolism was studied using a stable isotope breath test in 25 patients with familial hypercholesterolaemia (FH) (10 homozygotes, 15 heterozygotes), and in 15 normolipidaemic controls. A lipid emulsion mimicking the composition of chylomicron remnants and labelled with cholesteryl (13)C-oleate was injected intravenously; (13)CO(2) was measured subsequently in breath using isotope-ratio mass spectrometry. The fractional catabolic rate (pools/h) of the emulsion, derived from a compartmental model, did not differ significantly among the groups: homozygous FH mean 0.20 (S.E.M. 0.05), heterozygous FH 0.12 (0.02), controls 0.16 (0.03). We suggest that the catabolism of chylomicron remnants from plasma is not impaired in FH and that the hepatic uptake of these particles is not dependent on functional LDL receptors.

RECENT INSIGHTS INTO DIETARY FATS AND CARDIOVASCULAR DISEASE

1. Fat deposition in the arterial intima is fundamental to the atheroma process. Circulating lipoproteins are thought to be the source of much of the deposited fat. The interplay of dietary fat has not been fully clarified.

Gliptins – do they increase cardiovascular risk or benefit?

Introduction: In 2008, the US FDA required all new glucose-lowering therapies to show cardiovascular safety, and this applies to the dipeptidyl peptidase-4 inhibitors (‘gliptins’). Areas covered: The cardiovascular safety trials of saxagliptin and alogliptin have recently been published and are the subject of this evaluation. Expert opinion: The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53 trial and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care were both multicentre, randomised, double-blind, placebo-controlled, Phase IV clinical trials. These trials showed that saxagliptin and alogliptin did not increase the primary end point, which was a composite of cardiovascular outcomes that did not include hospitalisations for heart failure. However, saxagliptin significantly increased hospitalisation for heart failure, which was a component of the secondary end point. The effect of alogliptin on hospitalisations for heart failure has not been reported. Neither agent improved cardiovascular outcomes. As there is no published evidence of improved outcomes with gliptins, it is unclear to us why these agents are so widely available for use. We suggest that the use of gliptins be restricted to Phase IV clinical trials until such time as cardiovascular safety and benefits/superiority are clearly established.

Cholesterol trials and mortality.

An overview of clinical trials can reveal a class effect on mortality that is not apparent from individual trials. Most large trials of lipid pharmacotherapy are not powered to detect differences in mortality and instead assess efficacy with composite cardiovascular endpoints. We illustrate the importance of all-cause mortality data by comparing survival in three different sets of the larger controlled lipid trials that underpin meta-analyses. These trials are for fibrates and statins. Fibrate treatment in five of the six main trials was associated with a decrease in survival, one fibrate trial showed a non-significant reduction in mortality that can be explained by a different target population. In secondary prevention, statin treatment increased survival in all five of the main trials, absolute mean increase ranged from 0.43% to 3.33%, the median change was 1.75%, which occurred in the largest trial. In primary prevention, statin treatment increased survival in six of the seven main trials, absolute mean change in survival ranged from -0.09% to 0.89%, median 0.49%. Composite safety endpoints are rare in these trials. The failure to address composite safety endpoints in most lipid trials precludes a balanced summary of risk-benefit when a composite has been used for efficacy. Class effects on survival provide informative summaries of the risk-benefit of lipid pharmacotherapy. We consider that the presentation of key mortality/survival data adds to existing meta-analyses to aid personal treatment decisions.

Statin Dose Based on Limited Evidence

The review by Smith and Grundy [(1)][1] of the American College of Cardiology/American Heart Association Cholesterol Treatment Guideline is helpful, but recommendations for statin dosing are not supported by robust evidence. Simvastatin is routinely available in a 16-fold range of strengths (5 to 80

Variations in circadian heart rate in psychiatric disorders: theoretical and practical implications

Correspondence: Hans G Stampfer School of Psychiatry and Clinical Neurosciences, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia Tel +618 9346 2140 Email hans.stampfer@uwa.edu.au: Background: Data are presented to demonstrate dimensions of variation in circadian heart rate in patients under treatment for a psychiatric disorder and to comment on their clinical relevance. Method: Serial recordings of 24-hour heart rates were obtained from individuals under treatment for a psychiatric disorder and from healthy volunteers. Results: The mean 24-hour heart rate can vary independently of the circadian rate pattern or “rate architecture.” Sleep and waking heart rate can vary independently. Variations in circadian heart rate are state-dependent: broadly different clinical states are associated with distinctly different patterns of circadian heart rate, particularly during sleep. Conclusion: Different regulatory mechanisms or pathways are involved in mediating different aspects of circadian heart rate. An analysis of circadian heart rate can contribute useful physiological adjunct information to psychiatric assessment and the monitoring of patient response to treatment.

Common statin side effects explain poor compliance

The systematic review by DeVera et al. 1 found that poor adherence to statin pharmacotherapy increases cardiovascular events, but gave no consideration to the possibility that poor compliance may be due to side effects. Statin side effects have been under-estimated in recent studies, which do not include statin intolerant patients. However, more than 50% of patients discontinue statin therapy 1 and side effects are likely to be the main reason for doing so. Independent audit 2 and earlier randomized clinical trials show that side effects are relatively common and include fatigue, myopathy, liver dysfunction, cerebral haemorrhage, subtle cognitive impairment, neuropathy, renal failure, diabetes mellitus and cataracts. Side effects are dose related 2–4, often appear before cardiovascular benefits are obtained 4,5, impair quality of life, but are difficult to model and weigh against the benefits of pharmacotherapy 6. Insofar as side effects impede compliance, cardiovascular events may increase 1. Highly significant reductions in mortality and around 25% reduction in total cardiovascular events were seen with just 20-40 mg of simvastatin in landmark earlier trials (4S 7 and the Heart Protection Study, HPS 8). This is about three-fold the dose required to lower low density lipoprotein (LDL)-cholesterol by 50% of maximum, the ‘effective dose (ED)50’, which in a comprehensive meta-analysis of statins and doses 5 is about 12 mg for simvastatin. By comparison, the mean statin dose prescribed in a recent large Japanese audit 9 was equivalent to about 24 mg simvastatin or 6 mg of atorvastatin daily 5, very similar to the statin doses used in 4S 7 and HPS 8. This may prove to be the effective standard defined daily dose (DDD) for statins, but higher doses may be indicated in high risk patients, lower doses in smaller, elderly patients or those with liver impairment or side effects. Commonly promoted higher doses of the newer more potent statins, such as 80 mg atorvastatin 3 are over 25-fold the ED50, do not reduce mortality 3,4 and side effects can be markedly increased 2–4, liver dysfunction up to six-fold 3. Given the lifelong requirement for therapy, side effects are likely to compromise compliance. Closer attention to smoking, weight and blood pressure reduction is likely to reduce cardiovascular risk more effectively and safely. We suggest that lower statin dosing is very effective and may improve outcomes because reduced side effects will increase statin adherence.