“One important characteristic of biology is its diversity, its variation. It’s why personalized medicine is so important.”
Personalized medicine refers to the use of diagnostic and screening methods that exploit knowledge of the patient’s unique molecular or risk profile to achieve optimal health and medical outcome through improved management of the patient’s disease or predisposition toward a disease. High blood pressure (hypertension) is the most common modifiable risk factor for vascular disease, which in turn accounts for more morbidity and mortality than any other category of disease. This invited review attempts to explain why individualized approaches are imperative to improve the detection, evaluation, treatment, and prevention of hypertension; to recount the history of the pursuit of this “holy grail”; and to propose approaches to overcoming the many obstacles to realization of personalized medicine for hypertension.
Rationale for Personalized Medicine for Hypertension
Ischemia of vital organs, especially the brain, heart, and kidneys, causes most of the morbidity and mortality associated with hypertension. Arteriosclerosis is the disease process, encompassing two main patterns, atherosclerosis and arteriolosclerosis, that contribute to thickening of arterial walls, reduction of lumen diameters, and impairment of blood supply leading to ischemia, dysfunction, and ultimately failure of target organs. Because increased resistance to blood flow, ie, the primary vascular disorder of hypertension, involves medial thickening and consequent luminal narrowing in small, muscular arteries and end-arterioles, hypertension emerges as the strongest risk factor, after age, for arteriolosclerotic manifestations of target organ complications.
History of Personalized Medicine for Hypertension
Appreciation of the need for individualization of hypertension care is documented in the Joint National Committee (JNC) Reports on the Detection, Evaluation, and Treatment of High Blood Pressure. In the 1970s, secondary causes of hypertension were recognized to require different diagnostic and therapeutic approaches. The remaining majority of cases of so-called “essential hypertension” had been described by Page as a “mosaic” of heterogeneous mechanisms contributing to the elevation of blood pressure. Furthermore, Guyton and colleagues modeled the redundant and counterbalancing multiplicity of physiological and biochemical systems interacting to regulate blood pressure, long before “systems biology” came into vogue. Although blood pressure lowering in response to mono or combination drug therapies had been shown to differ widely among individuals, the first JNC report in 1977 recommended that the initial diagnostic evaluation be limited to patient history and physical examination. Notwithstanding the admonition that “all patients must receive individualized therapy programs,” a standardized, stepped-care approach to treatment was advocated for all patients, beginning with a thiazide diuretic. The measured patient characteristics, namely, blood pressure levels, age and sex, race, presence of target organ damage (eg, left ventricular hypertrophy), and comorbidities (eg, diabetes) were considered in the decision whether to initiate drug therapy, not drug selection. Moreover, there was no discussion of matching of drug mechanism of action to the mechanism of blood pressure elevation.
Subsequent JNC reports have not deviated substantially from the initially proposed approach. In the “individualized” approach now encouraged, treatment is chosen based on age, race, comorbidities, and issues of cost and potential side effects, but still without other information that may increase the likelihood of selecting an efficacious drug by virtue of matching its mechanism of action with the underlying pathophysiologic disturbance. The latest JNC report, for example, states that “testing for identifiable causes of hypertension is not indicated generally unless blood pressure control is not achieved or the clinical and routine laboratory evaluation strongly suggests an identifiable secondary cause.” Furthermore, “thiazide-type diuretic should be used as initial therapy for most patients, either alone or in combination with one of the other classes.” Thus, despite the long-standing appreciation of the ideal of personalized medicine, controversies surrounding the practicality and expense have been resolved consistently in favor of standardized “one-size-fits-all” approaches.
An alternative framework for personalization of antihypertensive drug therapy was articulated by Laragh and colleagues several years before the first JNC report. This “vasoconstriction-volume analysis” was based on the concept that the renin–angiotensin–aldosterone system determines blood pressure levels by regulating vascular tone and intraarterial volume. Based on measurements of plasma renin activity, 3 main subtypes of essential hypertension were described: low (27% of the population), normal (57%), and high (16%). When aldosterone excretion was measured, 8 of 9 theoretically possible hormonal patterns could be identified that were proposed to define “criteria for more rational drug therapy, specifically tailored to correct a particular abnormal biochemical profile.” This construction was proposed to have “etiologic, prognostic, and therapeutic implications.” In particular, volume expanded and low renin hypertension, “with presumably more open arterial bed and better tissue perfusion,” was thought to be “less prone to cardiovascular complications” and to “respond to diuretics alone.” In contrast, “vasoconstrictor hypertensions (high renin and some normal renin) respond to anti-renin–aldosterone therapy alone.”
One large, carefully conducted study has tested the utility of the renin-based approach to personalization of antihypertensive drug therapy in men.24 The plasma renin profile, indexed for urinary sodium excretion, was compared with an age-race subgroup method for predicting response to single-drug therapy in 1031 ambulatory men with stage 1 and 2 hypertension (ie, diastolic blood pressure of 95 to 109 mm Hg), who were randomized to 1 of 6 antihypertensive drugs: hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, or prazosin. The expected differences in renin profiles were observed among age-race subgroups: blacks tended toward a low-renin profile whereas whites tended toward medium and high-renin profiles. However, the comparison of renin profiling and age-race subgroup methods for selection of an initial antihypertensive drug did not reveal a significant difference in predictive ability between the two methods. Because age-race subgrouping is cost-free and requires no sample collection or laboratory testing, renin-sodium profiling could not be recommended.
To our knowledge, no other measurement proposed to characterize the hypertensive phenotype or guide antihypertensive drug selection has begun to approach the notoriety of plasma renin activity, nor has the cost-effectiveness of any been demonstrated, including plasma renin activity. Other approaches proposed for the selection of antihypertensive drug therapy are empirical and do not depend on biochemical measurements. Such limited progress in developing more individualized therapy for hypertension is remarkable in light of the extensive understanding of anatomic, physiological, and biochemical mechanisms regulating blood pressure, and corresponding successes of the pharmaceutical industry in developing drugs that safely target these mechanisms to lower blood pressure. Major obstacles appear to have been the difficulty and expense of directly measuring relevant processes within cells, tissues, and organs of individual patients in vivo. The need to make direct measurements may in part be overcome by measures of genomic variation, which influences the relevant processes in remote compartments, but can be performed on the DNA extracted from easily accessible cells.
# Kessler A. The End of Medicine : How Silicon Valley (and Naked Mice) Will Reboot Your Doctor. New York: Collins; 2006.
# Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension. 2004; 44: 398–404.
# Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ and the National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003; 42: 1206–1252.
Published online before print April 30, 2007, doi:10.1161/HYPERTENSIONAHA.107.087049