Genetics in Hypertension
Hypertension as a disease process was borne out of epidemiolog studies demonstrating that people with elevated blood pressure had a greater risk of developing strokes and heart attacks than matched people with normal blood pressure. The hope was that treating hypertension would reduce the risk of cardiovascular disease to the rates seen in normotensive subjects. However, epidemiologic studies performed in the past 10-20 yr have demonstrated that the treatment of hypertension has resulted in very impressive reductions in the incidence of strokes among hypertensive patients, but very disappointing decreases in the incidence of coronary artery disease. Poor blood pressure control rates among hypertensive patients are undoubtedly contributing to the disappointing reduction in coronary artery disease in hypertensive subjects, and this is certainly an area that requires urgent attention. However, even in well-controlled hypertensive patients, the rate of coronary artery disease remains higher than in normotensive subjects with similar blood pressures. The main reason for this discrepancy is probably related to hypertension not being simply a disease of high numbers but, rather, a complex inherited syndrome of cardiovascular risk factors, all of which contribute to heart disease in hypertensive patients. Furthermore, because high blood pressure may be a late manifestation of this disease process, it is possible that patients with the hypertension syndrome may develop cardiovascular disease before they develop high blood pressure. Thus, it is becoming obvious that simply treating blood pressure is not enough. The treatment plan should include aggressive management of the syndrome as a whole rather than isolated treatment of the various risk factors.
This chapter demonstrates that hypertension is an inherited syndrome of cardiovascular risk factors, all of which appear to be genetically linked, clinically manifest independent of one another, and contribute to the development of cardiovascular disease in these patients. This realization has many important implications toward our approach to the treatment of patients with this syndrome. The management plan and the selection of antihypertensive agents need to focus both on reducing blood pressure to goal levels and on achieving this with “syndrome friendly” drugs.
Lipids in the hypertension syndrome
Hypertension and lipid abnormalities often coexist. Each is an independent risk factor for cardiovascular events. Moreover, the likelihood of coronary events appears to be exaggerated when the two problems occur together. The explanation for this phenomenon is not clear. However, studies in models of genetic hypertensive rats indicate that the vascular smooth muscle of these animals binds with a greater affinity to low-density lipoprotein than do the cells from normotensive controlled animals.
The presence of high blood pressure and hyperlipidemia is so common in hypertensive patients that many have argued that the high blood pressure itself may play a role in altering lipid metabolism, resulting in lipid abnormalities. Recent data, however, have demonstrated that high blood pressure and hyperlipi-dimia are genetically inherited and probably genetically linked, but are separate variables that may frequently present independently of one another. In a study comparing age-, sex-, and body mass index-matched normotensive patients with and without a family history of hypertension, the patients with a family history of hypertension (hypertensive-prone patients) had significantly greater total cholesterol levels than those without a family history of hypertension. This would suggest that the abnormalities of lipids precede the abnormalities of blood pressure in patients likely to develop high blood pressure over the next few years. Thus, we see two important cardiovascular risk factors in these hypertensive prone patients, both of which appear to be inherited, occur independently of one another, and contribute to the development of heart disease. This may have important therapeutic implications, because studies using the occurrence of coronary events to judge the success of treatment of hypertensive patients have shown that the treatment of hypertension alone, or hypercholesterolemia alone, produces only modest results. Only when both problems were controlled simultaneously was there a marked reduction in coronary artery disease.
Left ventricular hypertrophy
Left ventricular hypertrophy is commonly regarded as a “normal” finding in hypertensive patients with little consequence. There is, however, a very strong relationship between left ventricular muscle mass and the incidence of cardiovascular events. A recent report from the Framingham Heart Study has confirmed that echocardiographically measured Left ventricular hypertrophy, independent of other associated risk factors, is a powerful predictor of cardiovascular events or death. Hypertensive patients with Left ventricular hypertrophy have a fivefold increased risk of myocardial infarction and a threefold increased risk of sudden death compared with similar hypertensive patients who do not have Left ventricular hypertrophy.
Echocardiography M-mode techniques have made it possible to measure the thickness of the left ventricular walls and chamber size, thus enabling accurate calculations of left ventricular muscle mass. Because of the sensitivity of the echocardiographic measurements, the prevalence of Left ventricular hypertrophy in hypertension is now known to be far greater than previously supposed. In a survey of an unselected clinic population of hypertensive patients, electrocardiography and chest radiographic estimates of the prevalence of Left ventricular hypertrophy were in the range of 5-10%. Echocardiography in the same patients indicated that almost 50% had increased left ventricular muscle mass.
Although sustained high blood pressure can produce hypertrophy of the left ventricle, there is good evidence that Left ventricular hypertrophy can develop early on in the course of hypertension and may actually precede the onset of high blood pressure.
In a study of young individuals (age <30 yr) with mild hypertension, it was found that approximately half of these patients had values for septal and posterior wall thickness that were greater than the highest values found in an age-control group. Interestingly, subsequent blood pressure measurements indicated that many of these young hypertensive patients had normal or borderline blood pressure values; the echocardiographic wall thickness in this subgroup, however, was not different from the increased measurements in the patients whose blood pressure was in the hypertensive range.
In a separate study, in which echocardiographic findings in normotensive children of normotensive patients were compared with those of age-, sex-, and body mass index-matched normotensive children of hypertensive parents, the offspring with hypertensive families had significantly greater left ventricular wall thickness and muscle mass. Thus, in hypertensive-prone patients, abnormalities of left ventricular muscle mass may occur prior to the development of high blood pressure. Left ventricular hypertrophy is therefore another risk factor that is commonly associated with high blood pressure, but presents independent of high blood pressure and frequently before its onset.
It is generally believed that regression of Left ventricular hypertrophy as a result of antihypertensive treatment will be associated with a reduction in cardiovascular outcomes. However, this has not been shown in outcome studies, and current studies are under way to assess the impact of Left ventricular hypertrophy regression on cardiovascular mortality and mobility. Nonetheless, the selection of a drug that will reduce blood pressure and cause regression of left ventricular hypertrophy in hypertensive patients appears to be logical, although the final results of the outcome studies are still pending.
Ventricular and arterial compliance
Hypertension is characterized by structural changes in the arterial circulation. Hypertrophy and hyperplasia of arterial and ventricular walls in association with increased laying down of connective tissue elements are common findings in hypertensive patients. These changes stiffen the walls, resulting in reduced arterial compliance and reduced ventricular compliance (diastolic dysfunction). Comparisons of normotensive and hypertensive subjects have established that changes in cardiovascular compliance frequently precede the increase in blood pressure in hypertensive subjects. Moreover, studies have suggested that abnormalities of compliance can precede the abnormalities of blood pressure and may not worsen the increasing blood pressure. In a recent study comparing arterial function in normotensive subjects from hypertensive parents with that of normotensive subjects from normotensive parents, it was demonstrated that the patients with a family history of hypertension (hypertensive-prone patients) had abnormalities of arterial function despite the fact that they were still normotensive. Similarly, in a study using an invasive technique to measure arterial compliance, normotensive subjects from hypertensive parents demonstrated a significant reduction in arterial compliance (arterial stiffening) compared with normotensive subjects from normotensive parents. These findings suggest that the abnormalities of arterial structure and function frequently associated with hypertension may precede the onset of high blood pressure and, in fact, may play a role in the pathogenesis of increasing blood pressure.
A similar patient model was used to assess ventricular compliance in hypertensive-prone subjects. Transmitral flow characteristics, measured by Doppler echocardiography, have been used as an index of left ventricular filling during diastole; an increased ratio of late to early left ventricular filling reflects reduced compliance of the left ventricular wall. In advance stages, this may result in congestive heart failure in hypertensive patients. It appears likely that the changes in ventricular compliance in hypertensive patients also precede the onset of high blood pressure. Among a group of normotensive male college students, matched for age, blood pressure, and left ventricular mass, those with a family history of hypertension had delayed diastolic filling compared with those who did not have a family history of hypertension.
Thus, the changes in compliance, frequently associated with hypertension, appear to precede the onset of blood pressure and occur independently of blood pressure. Furthermore, it has been demonstrated that reduced compliance causes an increase in blood pressure and therefore may play a role in the pathogenesis of increased blood pressure.
Abnormal glucose and insulin metabolism
Obesity
Recent large studies have demonstrated that hypertensive patients had a greater body mass index than well-matched normotensive male and female subjects in every age group. Obesity is associated with metabolic complications that are considered to be risk factors for cardiovascular disease, including insulin resistance, hyperinsulinemia, glucose intolerance-NIDDM, hypertension, and changes in the concentrations of plasma lipids and lipoproteins. Only recently has truncal obesity, characterized by a large waisthip ratio (apple shape obesity), been shown to predict the risk of coronary artery disease. The mechanisms that link obesity and hypertension-lipid abnormalities are not clear. In view of the efficacy of weight loss and exercise in reducing blood pressure, it has been speculated that insulin provides the link between obesity and increases sympathetic nervous system activity. The hyperglycemic clamp technique has been used to compare obese hypertensive patients with obese normotensive patients and lean control subjects to determine whether additional hyperinsulinemia and insulin resistance is associated with obesity when hypertension was also present. Both of these groups were similar and showed greater insulin concentrations and insulin resistance than their lean counterparts, but obesity and hypertension were not additive in these effects. When obese and nonobese patients with NIDDM with and without hypertension were compared, it was shown that there was a greater insulin resistance and that hypertension was present in lean individuals with NIDDM, but not in their obese counterparts.
Endocrine changes
The sympathetic nervous system and the renin angiotensin system are believed to play an important role in the pathogenesis of high blood pressure. Many of the modern antihypertensive drugs function by interrupting these systems in order to reduce blood pressure. It has been demonstrated, in recent studies, that plasma neuroendocrine levels and plasma renin activity were significantly elevated in normotensive subjects with hypertensive parents compared with matched normotensive subjects from normotensive parents. It is interesting that these increases in neuroendocrine levels occur prior to the development of elevated blood pressure and that hypertensive-prone patients with significantly elevated neuroendocrine and angiotensin II levels can be absolutely normotensive. These findings suggest that the hypertensive effects of these hormonal systems are not entirely owing to their vasoconstrictor properties, but may also be owing to their influences on the structure and function of cardiovascular smooth muscle.
Renal changes
Because of recent interest in milder forms of hypertension, early changes in renal function have been observed. It has been demonstrated that there are differences in renal functional reserve in children of normotensive compared with children of hypertensive parents. Thus, despite apparently normal renal function, children of hypertensive parents appear to be less able than children of normotensive parents to increase their creatinine clearance in response to protein load and also are more likely to exhibit microalbuminurea. These data were confirmed in a later study that demonstrated significantly more microalbuminurea in normotensive adults with a family history of hypertension than matched normotensive adults without a family history of hypertension.
These data suggest that early changes in renal function may precede the development of high blood pressure and may occur independently of high blood pressure. Moreover, the reduction in renal function may play a role in causing high blood pressure.
Normotensive subjects with hypertension syndrome vs hypertensive subjects
There are convincing data to suggest that many of the components of the hypertension syndrome precede the onset of high blood pressure. Furthermore, normotensive subjects who are prone to developing hypertension (by virtue of a strong family history of hypertension) have significantly more cardiovascular risk factors than matched normotensive subjects without a family history of hypertension, and are thus more likely to develop cardiovascular disease. The question arises: How do normotensive subjects with a family of hypertension (who are seldom treated) compare with true hypertensive subjects (who are usually treated) in terms of cardiovascular risk factors?
A recent study comparing the cardiovascular risk factor in normotensive patients with a family history of hypertension with hypertensive patients (matched for age and body mass index) with and without a family history of hypertension, no differences were found in the plasma levels of insulin, norepinephrine, renin activity, and cholesterol. There were also no differences in insulin sensitivity, microalbuminuria, or systolic blood pressure response to exercise. All three groups, however, were significantly worse in each of these parameters than the control group (normotensive subjects without a family history of hypertension).
Thus, in terms of cardiovascular risk, “normotensive hypertensive” subjects (who are not treated) have a similar cardiovascular risk factor profile and therefore are at similar risk of cardiovascular disease as hypertensive subjects (who are treated to protect them from developing cardiovascular disease). The only difference is that the normotensive subjects have not yet developed high blood pressure, which seems to be a late manifestation of this disease. Because, universally, blood pressure measurement is used to isolate patients with the hypertension syndrome in order to initiate treatment to protect them from developing heart disease, it is possible that physicians are treating these patients too late in the disease process. If physicians were to isolate and treat these patients earlier, before they develop high blood pressure, there might be a bigger impact on the course of this disease, thereby possibly protecting the patients from developing high blood pressure, and from developing heart disease.
It is conceivable, although by no means proven, that the hypertension syndrome may be reversible prior to the onset of high blood pressure and that the development of high blood pressure is a marker of irreversible vascular changes after which physicians can only control the disease. Evidence for this statement is the fact that early in the disease process, aerobic exercise may frequently reverse many of the cardiovascular risk factors associated with hypertension and may prolong or prevent the onset of high blood pressure. This is not the case in hypertension, which is not weight induced. In addition, studies of controlled hypertensive patients have demonstrated that cardiovascular disease in these patients is more common than in age-matched, sex-matched, normotensive subjects, suggesting that there is more to hypertension than high blood pressure.
Conclusion
There are increasing data to suggest that in many patients, high blood pressure may be a late manifestation of a complex inherited syndrome of cardiovascular risk factors. Moreover, it is possible that patients with the hypertension syndrome will develop cardiovascular disease prior to the development of high blood pressure. It appears that high blood pressure may represent a late phase of the disease process, indicating advanced or even irreversible vascular damage, and that in order to significantly affect these patients, treatment would have to be started prior to the onset of the increase in blood pressure.
The problem is that blood pressure is the tool used to isolate patients with the disease syndrome. We may be missing the boat. We need to investigate tools that will help isolated patients early in the course of the disease. One possibility would be the use of noninvasive measures of arterial compliance, which appears, in most patients, to be abnormal years before the onset of the increase of blood pressure.
Another dilemma is the approach to treatment of these patients. Exercise and diet are clearly beneficial and may often be the only modality required. But, it would appear that in some patients, early drug intervention with drugs such as angiotensin-receptive blockers and angiotensin-converting enzyme inhibitors may be quite helpful in reversing the disease and perhaps preventing the onset of high blood pressure.
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