NEWS

NEWS (June 2010)

 

The latest on cholesterol

P.N. Durrington of Manchester writes that while statins inhibit hydroxyl methyl CoA reductase, (the rate limiting enzyme for when the liver manufactures cholesterol), drugs which block enzymes at other stages of the cholesterol this manufacture, particularly the squalene synthase inhibitors, are entering the clinical phase of their development. It is only low density cholesterols in the blood that is harmful. Drugs which interfere with liver production of these in the liver, such as microsomal triglyceride transfer protein inhibitors and apolipoprotein B mRNA antisense oligonucleotides, are currently undergoing evaluation. Cholesteryl ester transfer protein (CETP) inhibitors, which decrease cholesteryl ester heteroexchange within the circulation, have undergone development to the point of clinical evaluation and this will eventually settle the controversy about whether CETP is pro- or anti-atherogenic.  One hopes that statins, which lower the beneficial high density cholesterol, will be replaced by drugs which do not have this harmful effect, and that such drugs do not have the other harmful side effects of statins, e.g., increased risk of diabetes, according to Dr David Preiss of the University of Glasgow.

 

Adiposity Associated With Longer Survival in the over 60s

According to John Batsis, speaking at the American Geriatrics Society 2010 Annual Scientific Meeting, older adults with higher adiposity appear to have longer survival if they do not have other illnesses at 60.   2920 normal subjects older than 60 years of age were characterised for body fat content and followed up.  There were 428 deaths in the cohort. The third of the patients with the highest body mass index survived significantly longer than the third with the lowest index.

adjusted for in the model, the mean hazard ratio (HR) was 0.65 (95% confidence interval [CI] 0.45 - 0.95). Sharon Brangman, incoming president of the  Society said "it (the study) seems to indicate that having a little extra fat tissue is associated with longer survival, even though it is not exactly clear why." We (the CTT) speculate that a little more fat in the brain might account for the result.

 

Anger and Hostility are Associated with Worsened Coronary Heart Disease Outcomes according to Peter Yellowlees writing in the Journal of the American College of Cardiology.  We (the CTT) suggest that the reason for this (and stress is a common history amongst heart attack patients) could be related to high adrenaline levels, which cause (1) increased work for the heart that can be counteracted by ß-adrenergic antagonists and (2) platelet activation which can be counteracted by alpha₂-adrenergic antagonists.

 

Bad News for Obese Mothers

A report from USA and the UK in the journal, "Experimental Physiology" provides evidence and arguments to suggest that obesity in pregnant women causes more cardiovascular disease in the offspring later in their lives.

 

More on Homocysteine, Folic Acid and Vitamin B

A raised blood concentration of the amino acid homocysteine is a common finding in heart attack patients and is associated with poorer long term survival than such patients with normal levels.  Homocysteine is derived from methionine in the diet, which is high in lean red meat (although a recent report found an association between coronary disease and processed meat but not red meat).  In excess, it causes arterial disease and thrombosis.  Its clearance is dependent on the vitamins folic acid and B6.  Trials of folic acid have hitherto been disappointing in not significantly lowering homocysteine levels.  However new reports in which these two vitamins were trialed showed not only a lowering of homocysteine levels, but also a reduced mortality.  In the American Journal of Cardiology and an article in the April issue of the journal, "Stroke".

 

The Mediterranean Diet and Physical Activity Reduce the Risks of both Coronary Disease and Alzheimer's Disease.

That the Mediterranean diet is beneficial for heart disease is shown by the fact that offspring of Mediterranean parents who move to the UK or USA and adopt the Western diet have the same risk as dwellers in those countries, i.e., it is a diet related risk and not a congenital one.  Two new reports in the Journal of the American Medical Association suggest that subjects eating the Mediterranean diet are also less likely to develop Alzheimer's disease.  We (the CTT) speculate that this results from the high content of beneficial oil lipids in the Mediterranean diet, e.g., olive oil, fish oil, compared with the Western low fat diet.  The brain (a fatty organ) and nerve cells depend completely on lipid in the cell membranes to do their work of transmitting electrical signals.  Should we be starving our brains of fat?

 

Growing Worries about Glucose

"Pre-diabetes identifies subjects with impaired fasting glucose and/or impaired glucose tolerance  at high risk for type 2 diabetes; moreover, it is associated to insulin resistance, subclinical inflammation and cardiovascular diseases," writes Gianluca Bardini, in the journal, "Diabetes Care" "Recently, 1-hour hyperglycaemia (1hPG) during glucose tolerance test with a cut point of 155 mg/dl has been indicated as a further risk factor for type 2 diabetes and showed early carotid atherosclerosis."  We (the CTT) already know that heart attack patients with pre-diabetes have a worse outcome then such patients with normal glucose tolerance, and that high glucose content within the artery lumen inhibits production of the anti-atherogenic nitric oxide in response to increase blood flow.

 

In the USA, Stem Cells are Beginning to used to Treat Patients who have had a Heart Attack.

We think that this is premature as the evidence of benefit is not yet convincing.  It does not seem right to start this expensive treatment in the UK.

 

Risk to Cardiac Patients of Non-cardiac Surgery

A prominent surgeon in the UK has pointed out that any surgery, not necessarily cardiac carries a risk of peri-operative myocardial infarction in patients with coronary disease.  The prevention of such an outcome by treating such patients with anti-thrombotic drugs is stymied by the increased operative risk due to bleeding.  A recent report from Dr Nicholas Crude of the University of Edinburgh indicates increased peri-operative risk of death or heart damage in patients with stents in their coronary arteries who undergo non-cardiac surgery.  The only answer to this problem is development of an anti-thrombotic drug that does not cause bleeding.

 

The Pharmaceutical Industry continues to Ignore Zofenopril

Zofenopril is a highly lipophilic ACE inhibitor characterised by long- lasting tissue penetration and sustained cardiac ACE inhibition. As shown in preclinical studies, zofenopril has cardioprotective

properties and attenuates ventricular remodelling in animal models of myocardial injury. Furthermore, zofenopril has antioxidant activity in vitro and in vivo, which may contribute to the anti-ischaemic and antiatherogenic effects observed in experimental models. Orally administered zofenopril is rapidly converted into the active moiety zofenoprilat and is excreted hepatically and renally. The efficacy and tolerability of zofenopril in the treatment of essential hypertension have been evaluated in four well-designed trials. In a dose-finding study (zofenopril 7.5 to 60 mg/day) dosages >7.5 mg/day were significantly more effective than placebo in reducing 24-hour ambulatory blood pressure (BP). In three comparative studies, zofenopril 30 to 60 mg/day once daily was as effective as atenolol 50 to 100 mg/day, amlodipine 5 to 10 mg/day and enalapril 20 to 40 mg/day when assessed by reductions in diastolic BP. In general, adverse effects reported for zofenopril were class specific, mild and transient, and rarely required drug withdrawal. Two major controlled trials evaluated the efficacy and tolerability of zofenopril in the treatment of myocardial infarction (MI). The Survival of Myocardial Infarction Long term Evaluation (SMILE) trial assessed 6 weeks' zofenopril treatment in 1556 patients with anterior acute (<24 hours from symptoms) MI not receiving thrombolytic therapy. Zofenopril significantly reduced the relative risk for the incidence of death or severe congestive heart failure (CHF) at 6 weeks by 32.7% (95% CI = 6.8 to 51.4%) compared with placebo. Mortality at 12 months was also significantly reduced in zofenopril versus placebo recipients, indicating that the benefits of zofenopril therapy extended beyond treatment end. Hypotension was more frequent in zofenopril than in placebo recipients (17.1 vs 8.9%; p < 0.001). In the SMILE-II trial, the tolerability and efficacy of zofenopril versus lisinopril for 6 weeks were compared in patients with MI receiving thrombolytic therapy (n =1024). The incidence of severe hypotension was similar between zofenopril and lisinopril recipients (10.9 vs 11.7%), but this event was considered by the investigators to be related to the study medication in a significantly lower percentage of zofenopril versus lisinopril recipients (6.7 vs 9.8%; p < 0.05).

In conclusion, these findings indicate that zofenopril is at least as effective and well tolerated as many other antihypertensive drugs in the treatment of essential hypertension. On the strength of its anti-ischaemic properties (as shown by its efficacy in acute MI), it should be particularly suitable for the treatment of patients with myocardial ischaemia.  (Review by Claudio Borghi and Ettore Ambrosioni in Clinical Drug Investigation).  This valuable drug is not available.