Framingham Heart Study Identifying major CVD risk factors

Over the years, careful monitoring of the Framingham Study population has led to the identification of the major CVD risk factors –
high blood pressure,
high blood cholesterol,
smoking,
obesity,
diabetes, and
physical inactivity

Hypertension
Each 20-mm Hg increase in systolic blood pressure or 10-mm Hg increase in diastolic blood pressure doubles coronary heart disease mortality and stroke mortality. Proposed mechanisms by which hypertension promotes atherosclerosis include damage to endothelial cells, promoting activation and incorporation of lipids into subintima, and stimulation of subintimal smooth muscle cell proliferation.

 

 

 

 

For prevention of CAD, the NCEP has determined that an LDL-C level of less than 100 mg/dL is optimal for CAD prevention, and a level of 70 mg/dL or less is now recommended for persons with existing CAD plus other risk factors. Ideal blood pressure was set at 120/80 mm Hg or less by

 

low-dose aspirin, and fish oil—may be considered, depending on the age and estimated CV risk of the patient.

Each 20–mm Hg increase in systolic blood pressure or 10–mm Hg increase in diastolic blood pressure doubles coronary artery disease mortality and stroke mortality.

It is instructive to note that although human LDL-C concentrations tend to cluster from 120 to 200 mg/dL and atherosclerotic disease is the main cause of death in humans, typical nonhuman mammalian LDL-C levels are 10 to 60 mg/dL, and atherosclerosis does not occur unless animals are fed high-fat food.

 

The risk of a coronary event is thought to increase by 2%for every 1%decrease in plasma HDL

 

 

Framingham Heart Study Identifying major CVD risk factors

Over the years, careful monitoring of the Framingham Study population has led to the identification of the major CVD risk factors –
high blood pressure,
high blood cholesterol,
smoking,
obesity,
diabetes, and
physical inactivity

Hypertension
Each 20-mm Hg increase in systolic blood pressure or 10-mm Hg increase in diastolic blood pressure doubles coronary heart disease mortality and stroke mortality. Proposed mechanisms by which hypertension promotes atherosclerosis include damage to endothelial cells, promoting activation and incorporation of lipids into subintima, and stimulation of subintimal smooth muscle cell proliferation.

 

 

 

 

For prevention of CAD, the NCEP has determined that an LDL-C level of less than 100 mg/dL is optimal for CAD prevention, and a level of 70 mg/dL or less is now recommended for persons with existing CAD plus other risk factors. Ideal blood pressure was set at 120/80 mm Hg or less by

 

low-dose aspirin, and fish oil—may be considered, depending on the age and estimated CV risk of the patient.

Each 20–mm Hg increase in systolic blood pressure or 10–mm Hg increase in diastolic blood pressure doubles coronary artery disease mortality and stroke mortality.

It is instructive to note that although human LDL-C concentrations tend to cluster from 120 to 200 mg/dL and atherosclerotic disease is the main cause of death in humans, typical nonhuman mammalian LDL-C levels are 10 to 60 mg/dL, and atherosclerosis does not occur unless animals are fed high-fat food.

 

The risk of a coronary event is thought to increase by 2%for every 1%decrease in plasma HDL

 

 

Diet and exercise

Certain changes in diet and exercise may have a positive impact on raising HDL levels:^[29]

• Decreased intake of simple carbohydrates.^{[30][31][32][33]}
• Aerobic exercise^[34]
• Weight loss^[35]
• Magnesium supplements raise HDL-C.^[36]
• Addition of soluble fiber to diet^[37]
• Consumption of omega-3 fatty acids such as fish oil^[38] or flax oil^[39]
• Increased intake of cis-unsaturated fats^[40]
• Consumption of medium-chain triglycerides (MCTs) such as caproic acid, caprylic acid, capric acid, and lauric acid.
• Removal of trans fatty acids from the diet^[41]

Most saturated fats increase HDL cholesterol to varying degrees and also raise total and LDL cholesterol.^[42] A high-fat, adequate-protein, low-carbohydrate ketogenic diet may have similar response to taking niacin (vitamin B3) as described below (lowered LDL and increased HDL) through beta-hydroxybutyrate coupling the Niacin receptor 1.^[43]

HDL levels can be increased by smoking cessation,^[35] or mild to moderate alcohol intake.^{[44][45][46][47][48][49]}

Pharmacologic (1- to 3-gram/day) niacin doses increase HDL levels by 10–30%,^[53] making it the most powerful agent to increase HDL-cholesterol.^[54][55] A randomized clinical trial demonstrated that treatment with niacin can significantly reduce atherosclerosis progression and cardiovascular events.^[56] However, niacin products sold as “no-flush”, i.e. not having side-effects such as “niacin flush“, do not contain free nicotinic acid and are therefore ineffective at raising HDL, while products sold as “sustained-release” may contain free nicotinic acid, but “some brands are hepatotoxic”; therefore the recommended form of niacin for raising HDL is the cheapest, immediate-release preparation.^[57]

AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides

As above, but instead of a placebo, patients were given 1,500 to 2,000 mg/day of extended-release niacin.

After two years the niacin group, as expected, had experienced a significant increase in plasma HDL-C (along with some other benefits like a greater reduction in plasma triglycerides).  However, there was no improvement in patient survival.  The trial was futile and the data and safety board halted the trial.  In other words, for patients with cardiac risk and LDL-C levels at goal with medication niacin, despite raising HDL-C and lowering TG, did nothing to improve survival. This was another strike against the HDL hypothesis.

 

CETP. – Dalcetrapib

By 2008, as the AIM-HIGH trial was well under way, another pharma giant, Roche, was well into clinical trials with another drug that blocked CETP.  This drug, a cousin of torcetrapib called dalcetrapib, albeit a weaker CETP-inhibitor, appeared to do all the “right” stuff (i.e., it increased HDL-C) without the “wrong” stuff (i.e., it did not appear to adversely affect blood pressure). It did nothing to LDL-C or apoB.  This study, called dal-OUTCOMES, was similar to the other trials in that patients were randomized to either standard of care plus placebo or standard of care plus escalating doses of dalcetrapib.   A report of smaller safety studies (called dal-Vessel and Dal-Plaque) was published a few months ago in the American Heart Journal, and shortly after Roche halted the phase 3 clinical trial.  Once again, patients on the treatment arm did experience a significant increase in HDL-C, but failed to appreciate any clinical benefit.  Another futile trial.

 

Mendelian randomization

On May 17 of this year a large group in Europe (hence the spelling of randomization) published a paper in The Lancet, titled, “Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.”  Mendelian randomization, as its name sort of suggests, is a method of using known genetic differences in large populations to try to “sort out” large pools of epidemiologic data.

In the case of this study, pooled data from tens of studies where patients were known to have myocardial infarction (heart attacks) were mapped against known genetic alterations called SNPs (single nucleotide polymorphisms, pronounced “snips”).  I’m not going to go into detail about the methodology because it would take 3 more blog posts., But, the reason for doing this analysis was to ferret out if having a high HDL-C was (only) correlated with better cardiovascular outcome, which has been the classic teaching, or if there was any causal relationship.  In other words, does having a high HDL-C cause you to have a lower risk of heart disease or is it a marker for something else?

This study found, consistent with the trials I’ve discussed above, that any genetic polymorphism that seems to raise HDL-C does not seem to protect from heart disease.  That is, patients with higher HDL-C due to a known genetic alteration did not seem to have protection from heart disease as a result of that gene. This suggests that people with high or low HDL-C who get coronary artery disease may well have something else at play.

 

Comments are closed