High Blood Pressure / Hypertension

Lipid Abnormalities and Hypertension

By Cardiologist on August 13th, 2011

Abnormalities of blood lipids constitute one of the more common risk factors for cardiovascular disease that coexist with systemic arterial hypertension. Hypertension and lipid disturbances may be part of a genetic abnormality, the Familial Dyslipidemic Syndrome, which is found in approx 12% of people with hypertension and in approx 50% of those with early familial hypertension, increased low-density lipoprotein cholesterol, and triglycerides. Thus, it is often necessary to consider the additional cardiovascular risk associated with dyslipidemia when planning a therapeutic strategy for hypertensive patients.

Cholesterol is one of the major factors in the pathogenesis of atherosclerosis. Spontaneous atherosclerosis begins at birth and is associated with lipid accumulation, macrophage and smooth muscle cell proliferation, foam cell formation, and endothelial cell toxicity. Much has been learned concerning the progression from isolated macrophage foam cells and fatty streaks to atheroma and fibroatheroma. Fibroatheromas are the most advanced form of spontaneous atherosclerosis and may produce stenosis of blood vessels. However, the atheroma and fibroatheroma may undergo accelerated change owing to disruption of the fibrous cap.

Table  Epidemioloeical Relation Between blood pressure and Serum Lipids”

Study	Number of subjects	Lipid fraction associated with blood pressure	Correlation coefficient	P
Tecumseh	3064	total serum cholesterol	0.16 systolic blood pressure	<0.001
Community		TG	0.18 systolic blood pressure
Health
Southern	4839	total serum cholesterol	0.28 systolic blood pressure	<0.05
California		TG
Lipid Research	7747	TG + very low-density lipoprotein	Not given	<0.05
Clinics Program		total serum cholesterol
Prevalence
Framingham	5127	total serum cholesterol	0.15 systolic blood pressure 0.20 diastolic blood pressure	Not given
Tromso	16744	total serum cholesterol Non-high-density lipoprotein-C	0.19 systolic blood pressure 0.25 diastolic blood pressure 0.13 systolic blood pressure	<0.001
Zavaroni et al.	64	TG	Not given	<0.05
Williams et al.	6128	low-density lipoprotein-C	Not given	<0.001

Disruption is likely owing to hemodynamic forces. During the early stages of plaque disruption, these fissures probably reseal by incorporating platelets and thrombus and may produce no symptoms or may produce a spectrum of unstable coronary syndromes, e.g., unstable angina and myocardial infarction.

The association between high cholesterol concentrations and atherosclerosis has been known for some time. For clinical purposes, the focus has been on total serum cholesterol, high-density lipoprotein cholesterol (high-density lipoprotein-C), low-density lipoprotein cholesterol (low-density lipoprotein-C) and serum triglyceride concentrations. Although other measurements may have value in some settings, e.g. lipoprotein (a), clinical intervention trials have focused on the aforementioned lipids. The lipoproteins surround the lipid center and serve as transport mechanisms.

low-density lipoprotein-C contains mostly apolipoprotein B-100, which is made in the liver. Most of the cholesteryl ester in the core of low-density lipoprotein is produced from the breakdown of very low-density lipoprotein by the liver. Apolipoprotein B-100 is recognized by low-density lipoprotein receptors on peripheral cells (e.g. endothelial cells of coronary arteries, and the liver). The liver removes approx 75% of low-density lipoprotein from the circulation; the removal rate of low-density lipoprotein from the circulation depends on both the number and availability of low-density lipoprotein receptors.

low-density lipoprotein-C can accumulate in the arterial wall when serum concentrations are high. When low-density lipoprotein-C is trapped in the endothelium, the particles undergo physical and chemical modifications; that is, peroxidation of polyunsaturated fatty acids in low-density lipoprotein-C converts low-density lipoprotein lecithin to low-density lipoprotein lysolecithin. This oxidized low-density lipoprotein is taken up 10 times faster by macro-phages than native low-density lipoprotein, which leads to the formation of foam cells. Oxidized low-density lipoprotein is a potent chemoattractant for circulating macrophages and when ingested by the macrophages inhibits their motility; this leads to sequestration of macrophages in the arterial wall. Oxidized low-density lipoprotein has been reported to be cytotoxic to endothelial cells. Modified low-density lipoprotein is highly immunogenic and low-density lipoprotein-immune complexes are rapidly phago-cytized by macrophages. Glycated low-density lipoprotein is also a potent immunogen.

High-density lipoprotein is secreted into the plasma by the liver and intestines and accepts cholesterol from peripheral cells and other lipoproteins. High-density lipoprotein serves as a reservoir for apolipoproteins and is also the major pathway for cholesterol metabolism by the liver. When high-density lipoprotein interacts with the surface of cells, lecithin cholesterol acyltransferase combines cholesterol and phosphatidyl choline to make cholesteryl ester, which is then transported to the liver. High-density lipoprotein also prevents the oxidation of low-density lipoprotein by binding to transition metal ions in the intima. Thus, in contrast to low-density lipoprotein, high high-density lipoprotein levels help prevent atherosclerosis.

Triglycerides may be an independent risk factor for cardiovascular disease in women but not in men. However, the major value of detection of an elevated plasma triglyceride concentration may be to alert the physician to the presence of insulin resistance.

There are four groups of patients that characterize the vast majority of patients with hypertension and coexistent abnormalities of blood lipids:

1.  Those with no prior history of a cardiovascular event

2.  Those with a history of a prior cardiovascular event

3.  Those with coexisting diabetes mellitus or syndrome X

Lipid abnormalities in hypertension with and without previous cardiovascular disease

All patients with hypertension should have a complete assessment for the common, known risk factors for cardiovascular disease, including a careful history (age, sex, smoking, substance abuse, hormonal status for women, diabetes, family history of cardiovascular disease), physical examination (evidence of vascular disease or diabetes), electrocardiogram (evidence of previous myocardial infarction, ischemia, or left ventricular hypertrophy), and a lipid profile. The presence of hypertension requires that a more detailed evaluation be given to all risk factors than in an otherwise healthy person. It cannot be overemphasized that measurement of the lipid profile should be performed by a certified laboratory with the patient in a fasted state (at least 14 h) and after a careful review of the patient’s dietary habits. Secondary causes of dyslipidemia should be sought, which include certain drugs (diuretics, glucocorti-coids, cyclosporin), metabolic conditions (hypothyroidism, pregnancy, diabetes mellitus), and certain diseases (nephrotic syndrome, biliary obstruction).

The value of lowering abnormally elevated low-density lipoprotein cholesterol in both primary and secondary prevention of cardiovascular events has been well established by many large-scale, controlled clinical trials. The National Cholesterol Education Program (NCEP) guidelines are helpful when deciding how to assess cardiovascular risk in relation to blood lipid values. However, clinical judgment must always be used when applying such guidelines to actual practice situations.

Clearly, the NCEP guidelines try to predict those individuals at high risk for a cardiovascular event that might be modified by treatment of abnormal lipid values. For those who have had a previous myocardial infarction or stroke or who have evidence of peripheral vascular disease, I aggressively treat even marginally elevated cholesterol values. The optimal values for cholesterol for any given individual have not been defined.

Dietary measures and appropriate exercise constitute prudent advice for all patients who seek a healthy lifestyle. However, for patients at risk for cardiovascular events and elevated low-density lipoprotein-C, I begin treatment with lipid-lowering drugs immediately. Data from the literature suggest that this treatment will decrease the progression of spontaneous atherosclerosis as well as prevent the accelerated phase associated with increased plaque vulnerability.

Tabled Pharmacologic Agents for Treatment of Dyslipidemia in Adults lists drugs that are useful in the treatment of abnormal cholesterol. The “statins” have been remarkable for their ability to decrease morbidity and mortality in clinical trials associated with a reduction in low-density lipoprotein-C and, in some instances, an increase in high-density lipoprotein-C. The lack of significant adverse events make these drugs highly attractive as initial agents to prevent the development of atherosclerosis.

Table NCEP Expert Panel Guidelines (1993)

Cholesterol	High-density lipoprotein	Risks	Vascular disease	low-density lipoprotein	Action*	Goal
<200	>35				DEER, 5 yr
<240		<2			DEER, 1 yr	Chol < 200
>240	Or       <35	Or         2+	Or +	<130	Check low-density lipoprotein DEER, 5 yr
		<2		130-159	DEER, 1 yr	low-density lipoprotein < 130
		2+	Or +	>160c slOO	Step 1 diet or step 2 Repeat 6 mo DEER, 1 yr	low-density lipoprotein < 160 or <130 If 2+ risks
			+	>100c	Step 2 diet, 3 mo	low-density lipoprotein < 100
Risks1			Vascular disease	low-density lipoprotein		Goal
Male < 35 or female premenopausal; not high risk				a220		low-density lipoprotein < 190
<2				al90		low-density lipoprotein < 160
2+			+	al60 al30		low-density lipoprotein < 130 low-density lipoprotein < 100

“Risks are diabetes mellitus; age (male > 45; female > or premature menopause without hormone replacement therapy); family history of premature cardiovascular disease (Ml/sudden death in first-degree relative male <55 or female <65 yr); hypertension; high-density lipoprotein < 35 (subtract one risk factor if high-density lipoprotein > 60).

‘DEER, diet, exercise, and risk-reduction advice; Step 1 diet, decrease sources of saturated fat, total fat, and cholesterol (saturated fat -10% and total fat -30% of total calories; cholesterol < 300 mg/d).

“Although diet and exercise are the foundation of treatment, practically all of the conditions designated will require treatment with lipid-lowering drugs.

Table Pharmacologic Agents for Treatment of Dyslipidemia in Adults

	Effect on lipoprotein		Triglyceride
	low-density lipoprotein	HDL
First-line agents low-density lipoprotein lowering HMG CoA reductase inhibitor	↓↓	↑	↑
Triglyceride lowering Fibric acid derivative	↓↑	↑	↓
Second-line agents
low-density lipoprotein lowering Bile acid binding resins	↓	→←	↑
low-density lipoprotein and triglyceride lowering Nicotinic acid	↓	↑↑	↓

Diabetes mellitus and syndrome X

Diabetes mellitus and syndrome X are discussed together because the lipid abnormalities are often similar, i.e., decreased high-density lipoprotein-C and an increase in triglycerides. Syndrome X is characterized by the following:

1.  Hypertension

2.  Resistance to insulin-stimulated glucose uptake

3.  Hypertriglyceridemia

4.  Low plasma high-density lipoprotein-C

5.  Hyperuricemia

6.  Abnormal plasminogen activator-1

7.  Presence or absence of obesity

In patients with overt diabetes mellitus as well as syndrome X, the major concern is still to treat the low-density lipoprotein-C if it is elevated. However, the plasma triglyceride concentration should be given the first priority for treatment if the value is >500 mg/dL, in order to prevent pancreatitis.

The use of drugs that improve insulin resistance or hepatic glucose output (e.g., troglitazone or metphormin) may be of value in managing individuals with insulin-resistance syndromes, although definitive outcome trials have not yet been completed and reported.

Table Treatment of Dyslipidemia in Diabetes

Dyslipidemia	X	Optimal low-density lipoprotein < 100 mg/dL (2.60 mmol/L), primary therapy directed first at lowering low-density lipoprotein by diet, exercise, and drugs; when drugs are necessary, use statin, then bile acid binding resin.
	X	If triglycerides > 500 mg, treat as first priority.
	X	Initial therapy for markedly increased triglycerides is improved glycemic control; additional lowering with fibric acid derivatives or high-dose statins as necessary.
	X	Niacin should be used very carefully if at all.

Conclusion

Hypertension is associated with disturbances of blood lipids in many ways and contributes greatly to the overall risk for developing cardiovascular disease. In every patient who is diagnosed as having hypertension, an evaluation of blood lipids is required as part of an inventory of total cardiovascular risk. Failure to do so deprives the patient of the opportunity to receive therapy that may strikingly reduce cardiovascular morbidity and mortality.

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