Chronic hypertension natural history

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-In-Chief: Yazan Daaboul, Serge Korjian

Overview

Hypertension is a well-established risk factor for several serious diseases. Chronic uncontrolled hypertension can be complicated by target organ damage. Most common damaged organs include the cardiovascular system, the brain, the kidneys, and the retina. The risk of cardiovascular complications is significantly increased even with small incremental increases in blood pressures. Blood pressure values should never be regarded as distinct stages or grades, but rather as a continuum of risk. Ultimately, hypertension should never be evaluated in isolation as a cardiovascular risk; it should always be integrated with other risk factors for the decision of optimal management and how aggressive the lowering of blood pressure values must reach.

Prognosis

The overnight blood pressure may be the most predictive[1].

Earlier, an article that was retracted found that the 24-hour blood pressure monitoring better predicts complications that the office blood pressure[2].

Complications

Because patients with hypertension usually have other concomitant cardiovascular risk factors, such as dyslipidemia and diabetes mellitus, the isolated effect of hypertension on cardiovascular outcomes may be difficult to assess. However, the Framingham Heart Study and other trials and observational studies well-established that hypertension has an additive effect, among other risk factors, in its contribution to cardiovascular disease and events.[3][4][5][6] While some risk factors are directly induced by hypertension and its vascular effects, such as renal insufficiency, stroke, and heart failure, the mechanism of other complications, such as dyslipidemia, insulin resistance, and atherogenesis, is not as straightforward.[7] These complications are not only worsened by hypertension, but also may predispose to hypertension and together are risk factors for cardiovascular disease, events, and mortality.[7]

Almost half of all deaths in the USA are attributed to cardiovascular diseases, such as coronary artery disease and stroke. Hypertension is considered a strong risk factor for the development of cardiovascular events in target organs, such as the heart, the brain, the kidneys and within the arterial system.[8] Even more recent data has shown that the 11-year all-cause mortality risk increases with higher SBP and DBP even in the non-hypertensive ranges: compared to men with SBP < 110 mmHg, those with SBP between 120 and 129 had a 1.16 risk of cardiovascular death. The risk increases gradually with increased blood pressure values to reach almost 1.6 times when SBP is only between 140 and 149 mmHg. The risk exceeds two-folds when SBP is > 150 mmHg and exceeds three-folds when SBP > 180 mmHg.[9] The risk of diastolic blood pressures is also significantly associated with cardiovascular disease and death.[9] While higher SBP and DBP have been found to be risk factors for cardiovascular disease, too much lowering of both SBP and DBP is currently under further investigation with the recent introduction of the J-curve phenomenon, defined as increased risk at very high and very low systolic and diastolic blood pressures.[10][11] Whether very low diastolic blood pressures are a cardiovascular risk per se or due to their association with an increased systolic blood pressure and high pulse pressure, the real mechanism remains poorly understood.[12][13][10] When followed for 10 years, patients with hypertension had a 20% risk of fatal and non-fatal cardiovascular events.[14][15]

Newer studies confirm similar findings for non-hypertensive patients who are older than 65 years and fall in the high-normal blood pressure category.[3] In fact, the recent introduction of a pre-hypertension category in clinical practice to non-hypertensive patients was only an emphasis of the association of high blood pressure levels, even among those with high normal blood pressure values, with fatal and non-fatal cardiovascular complications.[16][17] In 2001, Vasan and colleagues[3] compared 2967 men and 3892 women, most of whom were white and whose blood pressures were categorized as optimal (SBP<120 mmHg, DBP<80 mmHg), normal (SBP at 120-129 mmHg, DBP at 80-84 mmHg), or high-normal (SBP at 130-139 mmHg, DBP at 85-89 mmHg). They noted the following associated cardiovascular outcomes during a 12-year follow-up in these patients based on the time-dependent progression of blood pressures: death from a cardiovascular etiology, myocardial infarction, stroke, and congestive heart failure. Using subjects with optimal blood pressure values as controls, the study showed that more cardiovascular end-points were associated with worse categories of blood pressure.[3] High-normal blood pressures had a 1.6- and a 2.5-fold hazard ratio for cardiovascular disease in male and female patients, respectively. Similar but attenuated associations were also concluded even when blood pressure values and co-variants were modeled as time-dependent variables during follow-up.[3] In the study, crude event rates increased remarkably between patient categories and age groups. Among patients older than 65 years with high-normal blood pressures, the crude event rate was 28.1 and 19.5 events per 1000 person-years among male and female patients, respectively; whereas it was only 9.2 and 4.7 events per 1000 person-years in male and female patients younger than 65 years. While the five-year cardiovascular complications are significantly reduced by 25% in elderly patients when blood pressure values are appropriately lowered.[18] it is currently unknown whether patients with high-normal blood pressure values similarly benefit from blood pressure lowering,[3]

Finally, it is important to emphasize that the risks of cardiovascular complications are significantly increased even with small incremental increases in blood pressures. Blood pressure values should never be regarded as distinct stages or grades, but rather as a continuum of risk. Ultimately, hypertension should never be evaluated in isolation as a cardiovascular risk. It should always be integrated with other risk factors for the decision of optimal management and how aggressive the lowering of blood pressure values must reach.


Cardiac

Hypertensive heart disease is defined as the development of left ventricular hypertrophy, atherogenic coronary artery disease, and/or heart failure due to hypertension.[6] Coronary artery disease is perhaps the most common hazard of long-standing hypertension.[19] It equally affects males and females, all ethnicities, and ages.[9] Hypertensive patients are at two to three-fold increased risk of all clinical forms of atherosclerotic heart disease, including angina, myocardial infarctions, and sudden death.[7] According to the MRFIT trial (Cohort of Men Screened for the Multiple Risk Factor Intervention Trial) that studied more than 300,000 White men between 35 and 57 years for more than 10 years, both high systolic and diastolic blood pressures were significantly associated with coronary artery disease in a continuous and graded fashion.[20][21][22][23][17] Elevated systolic blood pressure levels in patients older than 45 years was particularly notorious.[22] The Framingham Heart Study showed that unrecognized myocardial infarctions were also significantly higher in patients with hypertension vs. those who are not, even when adjusting for use of anti-hypertensive therapy, diabetes, and left ventricular hypertrophy.[18]

Other cardiac complications of hypertension include ventricular hypertrophy, which acts as a consequence and as a predictor of future cardiovascular disease.[24][25][26][27][28][29][30] More than 70% of patients with heart failure have a past history of hypertension.[31][19] According to the first National Health and Nutrition Examination Survey (NHANES I) in 2001, hypertension comprised 10% of the population attributable risk of heart failure.[32] Although the pathophysiology of heart failure in hypertension is complicated, it is believed that it may be caused by both the mechanical chronic pressure that overloads the left ventricle, and causes fibrosis of the myocardium and dysfunctional filling during diastole[33] along with neuro-hormonal alterations that are not usually seen in non-hypertensive subjects.[34] Electrocardiography (ECG) findings consistent with left ventricular hypertrophy (LVH) were independently associated with up to 3.7 times and 1.9 times risk of coronary artery disease among 40-64 year old men and women, respectively.[25][28] Relevant ECG abnormalities, such are premature ventricular beats, increased voltages or repolarizations, were significantly increased as systolic and diastolic blood pressures increased.[7][35][28][36] Finally, ejection fraction may or may not be preserved in heart failure. The frequencies of systolic and diastolic left ventricular dysfunction are approximately the same.[32][37]


Stroke

When adjusting for confounding factors, such as smoking, diabetes, and dyslipidemia, the risk of fatal stroke remained significantly high, reaching up to 3-fold in patients with systolic prehypertension values and progressively worsened to reach approximately 20-fold increase in fatal stroke in patients with SBP > 180 mmHg.[17] Although SBP was more associated with stroke than DBP, both are still considered significant factors in the development of stroke in both genders in patients of all ethnicities above the age of 35.[17] While earlier reports hypothesized that hypertensive patients are at higher risk of hemorrhagic strokes compared to atheroembolic strokes, the Framingham Heart Study showed that paradoxically, both mild and severe hypertension were in fact significantly much more associated with more atheroembolic stroke at a rate of 70% and 56%, respectively.[38]


Renal

A significant relationship between elevated blood pressure values and the 12-year risk of death from renal etiology was made in 1993.[39] Renal disease due hypertension is called nephronagiosclerosis or hypertensive nephropathy. It is attributed to small and medium-size renal arteriolopathy that cause characteristic intimal hyperplasia, hyalinosis, and smooth muscle hypertrophy in the arteriolar media.[40] The mechanism of nephroangiosclerosis and vascular modifications have been poorly identified, but involvement of inflammatory cascades are proposed.[40] Nephroangiosclerosis was shown to be responsible for approximately 25-33% of new cases of end-stage renal disease (ESRD), according to data collected from the End-Stage Renal Disease Program.[40][41] Additionally, the HDFP trial in 1989[42] demonstrated that both higher SBP and DBP were also associated with higher creatinine levels, with a frequency of 8% of elevated creatinine in patients with SBP > 200 mmHg vs. only 2% in patients with SBP between 120 and 139 mmHg. Hypercreatininemia at baseline, defined in the study as serum creatinine levels more than 1.7 mg/dL, was associated with approximately a three-fold increase in mortality. Accordingly, kidney function was considered an independent predictor of mortality.[42] The study enrolled 10940 black and white patients and measured creatinine periodically for 5 years.[42] Creatinine increase was significantly higher in blacks and in older patients.[42] In another trial that assessed renal outcome following anti-hypertensive therapy, DBP < 95 mmHg was associated with stable kidney function.[43]


Ophthalmic

In hypertension, the microvasculature in the retina constricts and undergoes intimal thickening, medial hyperplasia, and subsequent hyaline degeneration.[44] As such, hypertensive retinopathy is a common complication among patients with long-standing hypertension and may be the earliest manifestation.[45] In fact, hypertension has a range of eye manifestations that lead to vision less, especially among adults above the age of 40 years. Ischemic and non-ischemic occlusion of the retinal vein and artery in central and peripheral vessels, retinal emboli, ischemic optic neuropathy, glaucoma, and age-related macular degeneration are also common ophthalmic manifestations significantly associated with hypertension.[45][46] According to Cugati and colleagues, central vein occlusion was seen in 0.4% of the cases, whereas branch retinal vein occlusion was seen in 1.2% among 3654 patients aged 49 and older when followed-up for 10 years.[47] Studies have confirmed that eye involvement in hypertension heralds stroke, heart failure, and other cardiovascular events and mortality.[45][46] Ophthalmic complications of hypertension are significantly reduced with the use of appropriate anti-hypertensive medications and optimal blood pressure control. There are currently 3 grades of retinopathy: mild retinopathy is defined as generalized and focal arteriolar narrowing, arterial wall opacification, and arteriovenous nipping. Moderate retinopathy is defined as flame-shaped or blot-shaped hemorrhages with cotton-wool spots, hard exudates, and/or microaneurysms. Finally, severe retinopathy is defined as signs of mild or moderate retinopathy with optic disc swelling.[45][46]


Peripheral

Blood pressure is also consistently and independently associated with the development of peripheral vascular disease (PVD) in the young and the elderly.[8] High SBP by only 20 mmHg and DBP by only 10 mmHg was associated with more claudication in both men and women at all ages.[8] At the time of diagnosis of hypertension, up to 5% of patients, especially among the elderly, have symptomatic peripheral arterial disease (PAD), such as intermittent claudication.[48] The converse is also true; where approximately half of patients diagnosed with PAD were also found to have hypertension.[48] Patients with PAD are at further increased risk of future cardiovascular events.

References

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