Stagnation and the Critical Need for Hypertension Subtyping

Many individuals in the hypertension community have historically failed to recognize the many different pathogenetic origins and phenotypic expressions of the hypertension syndrome. Why is recognition and acceptance of this heterogeneity so important now? Despite the fact that hypertension is the single most important risk factor for cardiovascular disease, in large measure, the field is stagnant. Unless we agree on a scientifically accurate, clinically meaningful classification system for hypertension, the rate of basic discovery will slow even further, and improvements in clinical management will lag. Those who think that this is just melodrama should simply look at the number of new investigators coming into the field, the numbers of new drugs under development, and the diminishing rate of improvement in cardiovascular disease.

Clinically, the most prevalent forms of hypertension, isolated systolic and white‐coat hypertension, are poorly responsive to agents that easily lower diastolic blood pressure. Does this pattern signify that isolated diastolic, isolated systolic, and reactive forms of hypertension arise from fundamentally different mechanisms? At present, our antihypertensive drug armamentarium largely consists of arteriolar dilators. Shouldn't we also be working on approaches to reduce vasoreactivity and central arterial stiffness? Agents such as collagen cross‐link breakers actually lower systolic but raise diastolic blood pressure. Here, our failure to recognize systolic hypertension as distinct from diastolic hypertension leads directly to the inability of the US Food and Drug Administration to approve these agents as antihypertensives, which by convention must lower both systolic and diastolic blood pressure. Reliable solutions to most of the important therapeutic dilemmas in hypertension would be facilitated by applying our knowledge of the diverse mechanisms that underlie the particular hypertension phenotype. Would anyone argue that the subtyping of diabetes into insulin insufficiency and insulin resistance has provided marked improvements in therapy based on improved understanding of pathophysiology?

From a translational research perspective, there are many different animal models of hypertension, each with a unique natural history and phenotypic expression. No single animal model describes all aspects of human hypertension; their only common feature is the chronic elevation of mean arterial pressure. In humans, aside from some rare monogenetic forms of hypertension, there does not seem to be a strong genetic fingerprint. Does it therefore follow that hypertension is an acquired characteristic? Or could the contribution of several major genetic components have been confounded by our failure to subtype the syndrome into relevant “intermediate phenotypes” or “endophenotypes”? If wide pulse pressure hypertension is related predominantly to increased aortic impedance, or if white‐coat hypertension is related to altered neural control, why should either condition be closely related to a gene that controls arteriolar structure or function?

In fairness, we have made some meaningful advances in shifting the paradigm in hypertension. Isolated systolic hypertension, which accounts for more than half of all hypertension cases, is now recognized worldwide as a greater public health problem than diastolic blood pressure, especially in older people. ¹ Since the Clinical Advisory Statement in 2000, all major public health guidelines worldwide now emphasize the importance of systolic blood pressure. But we must go further. We know that increased aortic impedance resulting from either decreased aortic diameter or increased wall stiffness causes wide pulse pressure hypertension. ² Yet where is this fact evident in our approach to the treatment of isolated systolic hypertension, where our drugs are those designed to treat diastolic hypertension? Also problematic is the close relationship between aging and increased pulse pressure and the obvious question: What is normal aging and what is pathologic?

An equally frustrating conundrum is what to do about blood pressure variability and the very large number of people (at least 20% by many estimates) with reactive or white‐coat hypertension. In large measure, current clinical and research approaches ignore this important group. The natural history of white‐coat hypertension appears to be quite different from that associated with sustained hypertension, with far less morbidity and target organ damage. In any given person, the level of blood pressure is also heavily influenced by how the individual interacts with his or her environment, including responses to mild physiologic stimulation (postural adaptation, physical exercise, mental stress, seasonal change, or digestion of a meal). ³ The mechanisms and practical implications of blood pressure variability remain grossly underinvestigated. Is intermittent hypertension thus truly similar to sustained hypertension? Should affected individuals receive the same drugs as those with sustained hypertension?

We continue to overlook these potentially important distinctions within the hypertension syndrome; attention to these attributes could improve research and clinical care. What then to do? First, we must agree on the need for a rational classification system. Ideally, such a system should be based on the diverse characteristics of human hypertension and have (1) a pathophysiologic base that aids translational research, (2) a strong relationship to the natural history of the condition, and (3) the ability to guide therapy. Human hypertension encompasses a complex series of alterations in the relationship between blood flow and structure‐function aspects of large and small arteries relative to how the organism adjusts to its current environment. ⁴ These alterations vary over the long term with age and duration of hypertension and also over the short term during normal physiologic stimulation. Another difficulty is that a given hypertensive individual may have more than one hemodynamic abnormality. Similar to the classification systems used to characterize mental illness, hypertension classification categories are not mutually exclusive. A possible approach is outlined in the Table.

Table.

Proposed Hypertension Subtypes

Subtype (Phenotype)	Basic Mechanisms	Clinical Presentations
I. Small vessel (arteriolar) hypertension	Increased arteriolar resistance and wall thickness	Elevated diastolic and mean arterial pressures
II. Large vessel (aortic) hypertension	Increased aortic impedance	Wide pulse pressure, isolated systolic hypertension
III. Neurovascular hypertension	Altered central command, neural reflexes, and vascular sensitivity	White‐coat syndrome, exaggerated diurnal change, postural hypotension

There are many barriers to achieving a consensus on a new blood pressure classification system. Traditionally, physicians have had trouble accepting paradigm shifts, in part because significant “unlearning” is necessary. Another barrier will arise from the typically retrogressive evidence‐based medicine approach that tends to block innovation. Clearly, hypertension is not simply increased vascular resistance, as most physicians learned in medical school. At the same time, current trends to consider hypertension as a secondary aspect of an underlying cardiometabolic or vascular inflammatory condition are probably not beneficial, because such lumping will lead to less effective individualized treatment. It will be a challenge to define precisely the characteristics and cutoffs for each hypertension subtype. Nevertheless, even if the new system is imperfect, it will, in the long run, be far superior to our current inaction.