The Natural History of Untreated Hypertension

Our knowledge about the natural history of untreated hypertension is mainly based on historical information from a relatively short duration of time (1900s to 1970s). During that period, there was a significant evolution in the understanding of the health-related impact of elevated blood pressure (BP) and in developing new antihypertensive medications ( Fig. 18.1 ) that solidified the awareness of the adverse association between untreated hypertension and cardiovascular morbidity and mortality. Therefore, from the early 1970s, it was no longer ethical to conduct observational studies or hypertensive clinical trials that included hypertensive individuals with untreated diastolic hypertension. Similarly, isolated systolic hypertension could not be left untreated starting in the 1990s.

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Schematic model of the evolution of understanding and approaches to hypertension in the 20th century.

The diagnosis of hypertension in ancient times was based on analysis of arterial pulse and it has been known for millennia that “hard pulse disease” (what we now call hypertension) is a major risk factor for apoplexy or the modern diagnosis of stroke, and usually resulted in untimely individual death. The first scientific reports about the association of hardening pulse with end-organ damage appeared in the early 19th century when Bright published a case series illustrating patients with hardening pulse, elevated blood urea, dropsy with albuminuria, and histological findings of left ventricular hypertrophy and hardening of the kidneys. However, these patients likely comprised a heterogeneous group with various etiologies of renal disease, and elevated blood pressure in many cases was secondary as a result of renal disease itself. Forty years later Mohamed described histologic findings of nephrosclerosis in individuals with hardening pulse that he believed were independent from primary renal disease; this was the first suggestion that hypertension itself can result in kidney damage. Subsequently, Gull and Sutton described hypertensive left ventricular hypertrophy, and Gowers reported retinal hypertensive changes. The development of a method for indirect BP measurement was the next crucial step in understanding of effects of elevated BP. The first sphygmomanometer was invented by Samuel Siegfried Karl Ritter von Basch in 1881 and later improved by Scipione Riva-Rocci in 1896. However, the Riva-Rocci method allowed only measurement of systolic blood pressure (SBP) through palpation of the pulse obliteration pressure. Systolic and diastolic blood pressure (DBP) differentiation and measurements became possible after Nikolai Korotkoff introduced auscultation of sounds into existing sphygmomanometric technique in 1905. This method allowed for routine accurate BP measurement and enabled the development of average age-specific BP charts and understanding of the relationship of different levels of BP and patient-related outcomes.

Early scientific reports from the 1910s to 1930s described hypertension as a disease with two variants. It was noted that many individuals with elevated BP, usually in the outpatient setting, were asymptomatic and had little abnormal physical and laboratory findings. This type of hypertension was considered to be “benign” and not requiring any treatment and many prominent physicians continued to advocate until the early 1950s that elevation of blood pressure was a physiologic response to maintain adequate blood flow to vital organs in the setting of aging vasculature. The second type of hypertension, which was often referred as malignant or accelerated hypertension, was mainly observed in the hospital setting when patients typically presented with markedly elevated BP (SBP in upper 200s and lower 300s, and DBP above 120 mm Hg) and suffering terminal complications of hypertension such as stroke, heart failure, papilledema, and renal failure. Only these extreme elevations in blood pressure were considered to require treatment, which at that time was mostly symptomatic because of a lack of other definitive therapies. The thresholds for abnormal BP were slowly decreasing, but remained much higher than what is accepted today. For example, the recommended BP levels for intervention were suggested as higher than 200/100 and 180/110 in two respected cardiology textbooks in the 1940s. The 1950 edition of Harrison’s Internal Medicine textbook still advocated that asymptomatic hypertension should not be treated.

One of the best case illustrations of natural history of untreated hypertension was written by one of the earliest hypertension treatment advocates, Dr. Marvin Moser, and described the medical history of the 32nd United States President, Franklin Roosevelt. It was first noted that Mr. Roosevelt suffered moderate BP elevations in the mid 1930s. Untreated hypertension in his case progressed from moderate elevations, 160/90s mm Hg, to a higher level (>180/110 mm Hg) over a 7-year period. This was associated with the sharp deterioration of Mr. Roosevelt’s health and the development of progressive heart failure and his untimely death (likely from stroke) in less than 1 year.

In this chapter we will review the important, although generally older, information from epidemiologic studies and clinical trials that led to the clear and inescapable conclusion that elevated BP is associated with adverse cardiovascular and renal outcomes. Fig. 18.2 depicts the framework of the discussion, which broadly characterizes the progression of prehypertension to hypertension to target organ damage to adverse clinical events, and finally to death.

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Schematic model of untreated hypertension.

Prehypertension and Hypertension

Hypertension is typically preceded by a gradual rise in BP from normal values into the prehypertensive range. Prehypertension is defined as SBP 120 to 139 mm Hg and/or DBP 80 to 89 mm Hg. Because hypertension is mostly asymptomatic, unless BP is measured regularly, it is often not possible to detect when these transitions occur. However, there are several indirect and direct observations supporting gradual progression of elevated BP. First, it was known from series of life insurance reports conducted from the 1920s through the 1960s and later confirmed by the National Health Examination Survey (NHES 1960 to 1962) and three separate Health and Nutrition Examination Survey (NHANES 1 to 3) that average SBP and DBP tends to increase with aging. NHANES 1 was conducted in 1971 to 1974, when hypertension treatment was still not uniform and it showed that the mean SBP at age 18 increased by 0.2 mm Hg per year until age 35, and after that the rise in mean SBP accelerates to an average 0.8 mm Hg per year. Although males aged 18 to 44 have higher mean SBP compared with females, with the difference in mean SBP up to 9 mm Hg, the rate of mean SBP rise per year among females in the 18 to 44 years age group exceeds the rates of the mean SBP rise in males, leading to “equalization” of mean SBP at around age 55. After the age of 55, the mean SBP in females starts to exceed the mean SBP in males by as much as 4 to 6 mm Hg. The mean DBP in males increases with aging; however, the rate of DBP increase is less pronounced as compared with SBP. In contrast to the mean SBP, the mean DBP in females rises in ages 18 to 64 and then remains stable thereafter. In addition, the mean DBP in men exceeds the mean of DBP in females until age 54 and becomes similar after age 55. As average BP rises with age, the proportion of individuals with prehypertension and hypertension increases with age as well. The prevalence of SBP 140 or higher and/or DBP 90 or higher mm Hg at age 18 to 34 in males and females is 13.8% and 6.3%, respectively, and increases to 65% and 74%, respectively, in the 65 to 74 age group (NHANES 1971 to 1974).

Several prospective cohort studies looked at rates of progression of normotension and prehypertension to hypertension. The Framingham Heart Study (FHS) was initiated in 1948 and included 5209 men and women aged 30 to 62 years who were subsequently followed for over 30 years. During an average of 26 years of follow-up, 23.6% and 36.2% of men and women with normal BP (defined as DBP <85 mm Hg) at baseline developed hypertension (defined as DBP ≥95 mm Hg) as compared with 54.2% and 60.6% of men and women with prehypertension (defined as DBP 85 to 89 mm Hg) at baseline. In the age-adjusted analysis, the presence of prehypertension was associated with a 3.4-fold increased risk of subsequent hypertension in both men and women, as compared with normal BP at baseline. The metabolic Life Style and Nutrition Assessment in Young Adults prospective cohort study evaluated the development of hypertension in 26,980 adolescents with mean age 17.4 years. Overall, 12.4% of young adults with normal BP (BP <120/80 mm Hg) and 17.1% of young adults with prehypertension (BP 120 to 139/80 to 89 mm Hg) developed hypertension during a maximum of 17 years of follow-up with the incidence of hypertension among men being four-fold higher as compared with women ( Fig. 18.3A ). In a Cox regression analysis adjusted for age and body mass index (BMI), the cumulative incidence of hypertension gradually increased for each 10/5 mm Hg BP increase from baseline BP less than 100/70 mm Hg with no evidence for a threshold ( Fig. 18.3B ). In a more modern investigation, the Trial of Preventing Hypertension (TROPHY), during 2-year and 4-year follow-ups, 40% and 60% of individuals, respectively, with prehypertension developed sustained hypertension. There is a consistent pattern among nonmodifiable (increasing age, African-American race) and modifiable (weight) risks factors that are shown to accelerate the conversion rates of prehypertension to hypertension.