Introduction
The concept of 'hypertension' as a clinical entity has been a work in progress for decades. At some point, the diagnosis of hypertension began to be linked to specific levels of blood pressure. The Joint National Committee (JNCI-JNC7) reports provide a perspective and an understanding that a clearer and precise definition might avoid the dead-end that the current concept of hypertension has been leading the scientific community. The definition of hypertension has changed with each new JNC report as have the levels of blood pressure that are considered goals of therapy.
Blood pressure is a necessary physical force required to move blood through the body. There is, for each individual, an optimal blood pressure at rest and during physical activity ensuring that the proper quantity of blood is available for physiological needs, while not exposing the arterial system to excess force. An increase in blood pressure above the optimal level for an individual indicates that the cardiovascular (CV) system is abnormal in some way. If the pressure remains above optimal, damage to the circulation and organs receiving blood will be damaged.
It is not definitely known what causes arterial blood pressure to initially increase in most individuals with an elevated blood pressure. If the stiffness of the proximal arterial system increases, i.e. a decrease in vascular compliance, then an increases in systolic blood pressure follows. If there is a primary or reactive increase in the distal, pre-capillary arteriolar resistance, the diastolic and mean arterial blood pressure will also increase. Abnormalities in vascular function precede the initial increases in blood pressure.
There are now ample data that show a linear increase in CV risk for adverse outcomes for virtually all blood pressure values with risk beginning at approximately 115mmHg systolic.1-7 Blood pressure is therefore not only a 'test' of CV function, but participates in the pathophysiological process resulting in vascular and target organ damage, becoming a 'target' for therapy. Small increases in blood pressure are associated with increases in all target organ morbid outcomes, i.e. stroke, coronary artery disease (CAD), renal disease, and peripheral vascular disease.
Hypertension is not a threshold disease even though the current definition of hypertension is commonly equated with a blood pressure threshold (≥140/90mmHg). In fact, it is the global cardiac risk that is important for any given level of blood pressure. Other factorsk, including age, gender, tobacco use, presence of diabetes mellitus, and lipid levels, help to define the true scope of total risk. Any CV risk factor, taken in isolation, has limited prognostic value.
Due to the application of blood pressure criteria to the definition of hypertension, most randomized clinical trials of blood pressure-lowering agents have been conducted in subjects with blood pressures above 140/90mmHg. The greater proportion of clinical CV adverse events occurs in subjects with lower blood pressures, including stroke and myocardial infarction (MI). Data are accumulating, demonstrating that decreasing blood pressure in subjects not previously considered to be 'hypertensive' by previous criteria is beneficial. The Heart Outcomes Prevention Evaluation (HOPE) study (mean blood pressure at entry 139/79mmHg),8 the Perindopril Protection against Recurrent Stroke Study (PROGRESS)9 (mean blood pressure at entry 129/78mmHg), and the Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT)10 study (mean blood pressure at entry 129/78mmHg) all demonstrated that active treatment reduces the CV event rate by as much as 43% compared with placebo.
The recording of blood pressure continues to remain one of the most important aspects of the clinical assessment of patients. However, the levels of blood pressure have to be evaluated in light of the total CV risk. In those with blood pressures clearly in the abnormal range or those with detectable target organ damage, the recognition that hypertension is present is straightforward; however, the assessment is more complex for individuals with blood pressures in ranges that are closer to optimal. For example, blood pressures of 120-130mmHg systolic are of great significance in individuals with diabetes mellitus, the metabolic syndrome, renal disease, and congestive HF due to systolic LV dysfunction. Improving clinical care for individuals with hypertension involves coordination of two simultaneous goals—lowering blood pressure and protecting the heart, vasculature, and target organs.
Blood Pressure and the Hypertension Phenotype
The hypertension phenotype is represented at one end of the spectrum with clearly abnormal blood pressures and evidence of target organ damage. However, at the other end of the spectrum are those with barely increased blood pressures and other indicators of CV risk, which allows the condition to be labeled hypertension. Blood pressure is a continuous variable and may represent a 'test' of CV function, as well as a quantifiable risk factor for CV and renal disease.
Optimal arterial blood pressure provides sufficient force to maintain the circulation without causing damage to the heart and vasculature whereas chronic blood pressure elevations above optimal for an individual damage the vasculature. The reason for the chronic increase in blood pressure is not clear for most patients with hypertension. The aging process, with genetic and environmental components, e.g. oxidative stress, infection and inflammation, and radiation, may contribute to alterations in the CV system that increase blood pressure and ultimately damage target organs. The primary abnormality may lie with the resistance vessels, whereas it is equally likely that the initiating process involves the large, conduit vessels. Some clues may come from an inspection of the measured components of blood pressure—systolic, diastolic, and mean. The information revealed by systolic blood pressure or pulse pressure is intrinsically different from that of diastolic blood pressure or mean blood pressure. Systolic blood pressure is dependent on cardiac output and the compliance of the large central arteries, while diastolic blood pressure is closely related to the state of constriction of small blood vessels.11
Global CV Risk
Physicians must think in terms of global risk when assessing and advising patients. Since there is no threshold value for blood pressure as a marker of 'hypertension', it is apparent that blood pressure must be considered in the context of total CV function and risk. The importance of risk factors other than high blood pressure is well described in the JNC7 report.12 Age and overweight/obesity are the two most important risk factors for the development and progression of hypertension. The metabolic syndrome is a cluster of three or more risk factors, including obesity, insulin resistance, dyslipidemia, and hypertension, which are recognized to further increase the risk of atherosclerotic CV disease.13 Atherosclerotic vascular remodeling may occur before an increase in blood pressure occurs. However, once there is an increase in blood pressure, a mutual exacerbation occurs.
The Need for a New Definition of Hypertension
A writing group of the American Society of Hypertension (ASH) has recently offered a definition of hypertension that is not dependent on threshold values of blood pressure. The need for a new definition of hypertension was stimulated by the creation of a category of 'pre-hypertension' (systolic/diastolic blood pressure 120-139/ 80-89mmHg, respectively), in the JNC7. As previously discussed, since hypertension is not a threshold disease, the 'pre-hypertension' category contains normal individuals as well as those who have CV disease. The designation of pre-hypertension is not trivial, representing a large population, estimated to be as high as 40% among men and 23% among women in the US.14 Importantly, the number of CV events occurring in this sizable population is large.3,15,16 Identification of a subgroup with early cardiac and vascular disease will not be possible on the basis of blood pressure levels alone.
A New Definition and Classification of Hypertension
At the 20th Annual Scientific meeting of the ASH, a writing group (WG) presented a new definition of hypertension:
"Hypertension is a progressive cardiovascular syndrome arising from complex and interrelated etiologies. Early markers of the syndrome are often present before blood pressure elevation is sustained; therefore, hypertension cannot be classified solely by discrete blood pressure thresholds. Progression is strongly associated with functional and structural cardiac and vascular abnormalities that damage the heart, kidneys, brain, vasculature, and other organs, and lead to premature morbidity and death."
This proposed new classification recognizes that hypertension represents a disease continuum—as knowledge of early cardiovascular disease (CVD) evolves, the most useful and appropriate terminology for classifying individuals along that continuum can also be expected to change. The four categories currently used to classify hypertension in JNC7 are normal, pre-hypertension, and hypertensive stages 1 and 2. The proposed ASH classification describes patients as either normal or hypertensive, based on their CV status as well as blood pressure. The progression of hypertension—from early to progressive to advanced—may be best represented as stages 1, 2, and 3 of hypertension. Each stage of hypertension is characterized by the presence or absence of CV risk factors, early markers of hypertensive CVD, and target-organ damage. The ASH classification amplifies the JNC7 definition (see Table 1).
However, in contrast to the JNC7 definition, ASH affords greater priority to CV risk factors (see Table 2), early markers indicating the presence of CVD (see Table 3), and evidence of hypertensive target organ damage and overt CVD (see Table 4). These other risk factors for, and early markers of, CVD are therefore used to reflect the interactions of blood pressure with the CV risk or disease, and therefore better determine the potential for CV events and the need for treatment not only of blood pressures but of co-existing risk factors and co-morbidities. This approach also highlights that simple blood pressure measurements may not be indicative of the dynamic nature of blood pressure.
Implications
Therapeutic strategies designed around a new definition of hypertension will require a better understanding of the mechanisms that increase blood pressure and the various phenotypes that result. The primary goal would be to prevent hypertension and the increase in blood pressure that accompanies the condition. Randomized clinical trials will provide additional data when global risk is utilized as the treatment target.