Isolated Systolic Hypertension
Vinayak Agrawal*, Ravi R Kasliwal**,
Department of Cardiology,Medanta- The Medicity, Gurgaon,Haryana

Introduction
Isolated systolic hypertension (ISH) defined as systolic blood pressure (SBP) of at least 140 mm Hg and diastolic blood pressure (DBP) of less than 90 mm Hg, has been increasingly recognized as a serious health issue with huge socioeconomic implications especially in the elderly. Many authors prefer the term “systolic hypertension” (SH) instead of ISH as the term ‘isolated’ may deemphasize the enormous health risk involved. In this article, ISH and SH have been used interchangeably. According to JNC 7, the patient is divided into SH stage 1 = SBP 140-159 mmHg and DBP < 90 mm Hg; SH stage 2 = SBP > 160 mmHg and DBP < 90 mm Hg. However the European Society of Hypertension - European Society of Cardiology (ESC/ESH) guidelines 2007 15, propose an additional grade 3 with SBP of > 180 mm Hg (Table 1).

Table 1: Classification of isolated systolic hypertension

DBP- diastolic blood pressure, ESC- European Society of Cardiology, ESH- European Society of Hypertension, JNC- Joint National Committee, SBP- systolic blood pressure.

Evolution of ISH
Over the last two decades there has been a sea change in the understanding of the ISH and its implications. In 1980 report of Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) 1, SH was defined as SBP of at least 160 mm Hg and DBP of less than 90 mm Hg. However, the fifth report of the JNC (JNC 5)2 in 1993, which heavily relied on the data from the Systolic Hypertension in the Elderly Program (SHEP)3 trial, lowered the criterion for SH to the present day definition. In 2003, the seventh report from JNC (JNC 7)4 only reinforced this concept especially in persons older than 50 years.

Epidemiological data
Approximately 30% of individuals over 20 years age in the United States have hypertension (SBP >140 mm Hg and / or DBP > 90 mm Hg).5 The prevalence of hypertension (HT) progressively increases with age and almost two-thirds of those over 60 years of age have HT  and in about three-quarters of persons 75 years and older.6 Most hypertensive individuals under the age of 50 years have elevated DBP which then begins to fall after the of 50 years as SBP continues to rise.7 The  risk of cardiovascular disease approximately doubles for every 20/10 mm Hg increase in blood pressure within the range of 115/75 to 185/115 mm Hg.8 Elevated SBP is more risky than DBP for both cardiovascular and renal disease.9 Robust recent evidence has highlighted the more long term morbidity and mortality associated with elevated systolic BP levels. A meta-analysis of antihypertensive treatment trials focusing on patients with ISH found that SBP was significantly and positively correlated with mortality risk (P=.0001), whereas DBP showed a negative correlation (P=.05)8. This finding underscores the importance of pulse pressure, the difference between systolic and diastolic BP, as a predictor of risk. Framingham Heart Study11 supports these findings. In patients 60 years and older, pulse pressure emerged as the strongest predictor of risk because of the changing relation between systolic and diastolic BP. Elevated systolic BP is also more difficult to control especially in the elderly who show a higher prevalence of isolated systolic hypertension (ISH).8,9,10,11
Pathophysiology
The age related difference in predominance of DBP in less than and SBP in more than 50 years age group is explainable by the mechanisms responsible for elevated BP. In patients younger than 50 years, increased peripheral resistance is the major mechanism for elevated DBP. In older persons, arterial compliance, especially large-artery compliance, is decreased leading to increased arterial stiffness which leads to elevated SBP but lower DBP.11,12  This age-related increase in pulse pressure is thought to result from the reflected arterial wave from the vascular resistance bed. When the left ventricle ejects the blood into the aorta in systole, a pressure wave is generated at the site of the aorta. The wave formed is the summation of a forward wave, traveling from the heart to the periphery and a reflected wave, traveling backward to the heart. When aortic stiffness is

increased and wave reflections are large, the backward wave superimposes on the forward wave and increases the amplitude of the wave and hence the pulse pressure. The gold standard for measuring the arterial stiffness is Pulse Wave Velocity (PWV). Aortic stiffness measured by the carotid-femoral PWV is the most commonly used parameter. When left untreated, ISH may exacerbate large-artery stiffness, leading to further increases in systolic BP.

Blood Pressure Components and Cardiovascular Risk
There exists an unending debate regarding the cardiovascular risk attributed to the four components of BP: systolic, diastolic, pulse and mean pressure. DBP was considered more sinister till the publication of SHEP in 1993 which challenged this concept. Later studies like reports from Framingham Heart Study established the present day notion that in subjects < 50 years of age, DBP is the best predictor of risk while in > 60 years age group, SBP is a more important risk factor. A number of studies have suggested that pulse pressure (PP) may be the best predictor of CVS risk in the elderly but surprisingly gets no mention in JNC 7 . Multiple risk Factor Intervention Trial (MRFIT) 13 showed that highest risk group was patients with SBP > 160 mmHg and DBP <80 mmHg. However if SBP is normal (< 140 mm Hg), a low DBP in elderly doesn’t confer any significant risk.13 However, not all studies have found pulse pressure to be superior. There are no evidence based guidelines to suggest treatment of a high pulse pressure. Analysis of SHEP trial brought out two interesting facts. One, that baseline pulse pressure did not influence the treatment benefits and second, that a DBP < 70 mm Hg on treatment was associated with a higher CVS events.  Hence, in practical terms a SBP > 160 mm Hg and a very low diastolic pressure of < 70 mm Hg is associated with a higher CVS risk, without any undue importance to pulse pressure. Very low DBP may be harmful by impairing the coronary artery perfusion which occurs predominantly during diastole. However , some believe that high SBP and very low DBP is just a marker of age related  increased arterial stiffness leading to accelerated wave reflection from the periphery. In a recent data from Framingham Heart Study14, combining pulse pressure (PP) with mean arterial pressure (MAP) and SBP with DBP produced models that were superior to single BP components for predicting CVD, and the extent of CVD risk varied with the level of each BP component. The combination of PP + MAP (unlike combination of SBP + DBP) has a monotonic relation with risk and may provide greater insight into hemodynamics of altered arterial stiffness versus impaired peripheral resistance but is not superior to SBP+DBP in predicting CVD events.14 JNC-7 did not emphasize the importance of PP but the 2007 European Guidelines for the Management of Arterial Hypertension32 recommended that patients with systolic hypertension in association with low DBP of <60 to 70 mm Hg be regarded as having an additional risk as a result of “advanced organ damage.”  A recent study further extended the risk of CVD to individuals with pre-hypertension and DBP <70 mm Hg (PP > 60 mm Hg).15

Etiology of ISH
Simply put, ISH may occur in any condition which causes wide pulse pressure as in high cardiac output states like anemia, hyperthyroidism, aortic regurgitation, patent ductus arteriosus, arteriovenous fistulas, Paget’s disease of bone etc. However, most common and relevant causes of ISH is age and atherosclerosis. Both are associated with infiltration and deposition of calcium and collagen in sub-intimal layers and degradation of arterial elastin leading to reduced elasticity and compliance. This loss of compliance (stiff arteries) causes an increased recruitment of reflected arterial pressure waves from the periphery there by increasing the systolic pressure.16 Systolic hypertension itself accentuates this stiffening and accelerates the endothelial dysfunction. Knowledge of pathophysiological changes in older subjects like decreased elastic artery compliance, reduced plasma renin activity, increased salt sensitivity help in formulating pharmacological strategies.

Clinical evidence pertaining to ISH
Systolic hypertension as a risk factor for cardiovascular disease was suggested in epidemiological studies conducted in early 1970’s.17 The biggest boost came from the landmark trial Systolic Hypertension in the Elderly Program (SHEP)3 published in 1991, conducted in 4736 patients in which treatment with the diuretic agent chlorthalidone was given for an average of 4.5 years in patients with systolic blood pressure of 160 mm Hg or greater and diastolic pressure below 90 mm Hg. Chlorthalidone (12.5-25 mg/d) versus placebo was used. Atenolol (25-50 mg/d) was added next, if needed to achieve target SBP. Almost half of these received chlorthalidone only. There was a statistically significant 32% reduction in the incidence of cardiovascular disease (fatal and nonfatal combined), decreased incidence of stroke by 36% (p = 0.003), and congestive heart failure by 55%, as compared with placebo. Though not statistically significant, serum glucose, uric acid, and cholesterol levels were out of the specified ranges more frequently in the active treatment group.
Systolic Hypertension in Europe (Syst-Eur)
Syst-Eur18 compared dihydropyridine calcium channel blocker (CCB) nitrendipine (10-40 mg/d), versus placebo with sequential addition of enalapril (5-20 mg/d) and then hydrochlorothiazide (12.5-25 mg/d) if required to lower the SBP to achieve study goal. After 2 years, 60 % were on nitrendipine alone in the active treatment group. Treatment significantly reduced the risk of stroke by 42% and CVD was significantly reduced by 30%. Importantly, incidence of dementia was halved in the nitrendipine arm compared with the placebo group (7.7 vs 3.8 cases per 1000 patient-years) and the benefit persisted during extended follow-up. The most common reasons for stopping nitrendipine were edema and flushing.19,20

Table 2: Landmark hypertension trials in elderly patients

DBP- diastolic blood pressure, SBP- systolic blood pressure

Systolic Hypertension in China (Syst-China)
Pretreatment BP was >170/86 mm Hg and active treatment in Syst-China21 was started with nitrendipine (10 or 20 mg/d or 20 mg twice daily), with the possible addition of captopril (12.5 mg/d or twice daily or 25 mg twice daily), hydrochlorothiazide (in the same dosages as captopril), or both to achieve target SBP. Nitrendipine was the only medication given in 3/4th of the active treatment group. The final pressure obtained was 150 / 81 mm Hg. The relative risk (RR) for stroke was not statistically significant at 0.69. Significant reductions were observed in total cardiovascular events with incidence of CAD and CHF decreased by 6% and 58% respectively.
In these three landmark trials (SHEP, Syst-Eur and Syst-China) , the  SBP was above 160 mm Hg and DBP lower than 90 (SHEP) / < 95 mm Hg ( Syst-Eur, Syst-China) with mean age being 65-72 years.  The primary objective of these trials was to determine the effect of treatment of SH on stroke. These trials were not sufficiently powered to assess the effect on all cause / CVS mortality.

Meta-analysis
A meta-analysis22 of eight trials which included the above three major trials (SHEP, Syst-Eur and Syst-China), and also included a subset of elderly (> 60 years) patients with isolated systolic hypertension (systolic/diastolic blood pressure: > 160 / < 95 mm Hg) enrolled in 5 other trials.  Active treatment in these 5 trials was started with a diuretic or a beta-blocker. Altogether, in these 8 trials, 15,693 patients (7757 control and 7936 actively treated) with ISH were followed up for 3.8 years (median). It showed that anti-hypertensive agents belonging to different classes given for about 4 years reduced total mortality by 13%, and mortality due to CVD by 18%.  Overall, CVS events decreased by 26%, CAD by 23%, and stroke by 30%. Absolute benefit was greater in men, in older patients, and in those with previous cardiovascular complications or greater pulse pressure

Stage I Systolic hypertension: Un-explored territory
Most of the landmark SH trials have involved patients with SBP > 160 mm Hg or Stage II SH (Table 3). However, there are no large scale trials to assess the benefit of treatment in stage I SH or SBP between 140 and 159 mm Hg. Some observational studies suggest that an increased risk of stage I SH. Framingham Heart Study analysis23 of patients with stage I SH revealed a 40-60% greater risk of development of CVD, CAD, stroke and heart failure compared with those with normal BP. 1266 male physicians in Physicians Health Study 24 with stage I SH showed significant greater risk of CVD, stroke, CV death and all cause mortality. Though there are no robust data25 to suggest the benefits of treating stage I SH, the higher risk attributed to it makes it logical to be taken seriously and be treated..

 Table 3: Markers for sub-clinical organ damage in hypertension 32

Under-treated blood pressure levels
The existing clinical trial data suggest that SBP control is woefully short of acceptable rates of overall BP control.4, 26, 27 In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) 28 and Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial29, DBP control rates exceeded 90%, but SBP control rates were considerably less (60 to 70%). A survey of primary care physicians indicated that three-fourths of them failed to initiate antihypertensive therapy in older individuals with SBP of 140 to 159 mm Hg, and most primary care physicians did not pursue control to less than 140 mm Hg.4, 30
Systolic Hypertension in Very Old
The vulnerable class of individuals aged > 85 years (also called ‘oldest old’) requires a special mention. High cardiovascular risk accompanied with several co-morbidities like pulmonary diseases, peripheral vascular disease, renal dysfunction, osteomalacia, stroke etc make it imperative to carefully decide the treatment options especially to avoid drug related adverse effects. Both SHEP and Syst-Eur trials suggested that very old patients continue to benefit from blood pressure reduction. A recently concluded trial HYVET31 in 3845 patients aged 80 years or more in whom entry SBP was 160mmHg or more (average 173mmHg) were randomized to receive either placebo or active treatment, consisting of indapamide (1.5mg

daily) and the ACE inhibitor perindopril (2 and 4mg daily) with the target to attain a SBP value below 150mmHg. The indapamide–perindopril combination given reduced BP to 144/78 versus 161/84mmHg in placebo group. The trial was stopped after average treatment duration of less than 2 years due to distinct beneficial effects which included a 30% reduction in stroke (borderline statistical significance) and statistically significant reductions in congestive heart failure (64%), major cardiovascular events, and all-cause death (21%).

Management strategies in SH
The management of SH involves similar principles as that for hypertension in general.
a) Diagnosing systolic hypertension: The initial thrust should be on identifying the severity of SH according to JNC 7. These readings should be reassessed and confirmed on 2 separate office visits. It is important at this stage to mention the phenomenon of isolated office hypertension and normal home BP readings (White Coat hypertension). There are disparate opinions regarding the need for treating white coat hypertension but in general the decision to treat is an individual one. We, at our center, recommend ambulatory BP monitoring in such patients. Emphasis remains on life style modification and watchful follow-up of the patient with white coat HT for any early signs of target organ damage.
 b) Assessment of other major cardiovascular risk factors: Factors which affect prognosis include stage of SH, age (> 55 years male, > 65 years female), smoking, dyslipidemia, diabetes, impaired fasting glucose (IFG) or impaired glucose tolerance test, and family history of premature CVD (< 55 years in men, < 65 years in females). Further emphasis is given to identify sub-clinical or clinical target organ damage. In both hypertensive patients and the general population, the presence of electrocardiographic and echocardiographic LVH, carotid plaquing or thickened intima-media thickness, an increased arterial stiffness, a reduced eGFR (assessed by the MDRD formula), or microalbuminuria or proteinuria increases the total cardiovascular risk and stratifies the individual into high absolute risk range. (Table 3)  The need for this information is borne out of the fact that the life style modifications and the choice of drug therapy for hypertension are directly influenced by these risk factors (so called compelling indicators). Also, in a deviation from JNC 7, the 2003 European Society of Hypertension - European Society of Cardiology (ESC/ESH) guidelines 32 emphasized that the diagnosis and management of hypertension should be related to the quantification of global (total) cardiovascular risk. This is because hypertension tends to manifest as part of the cluster of cardiovascular risk factors much more often than alone which then have an exponential risk or multiplier effect on outcome measures.

c) Pertinent History : The diagnostic work up for SH should emphasize on identifying the secondary causes of HT as mentioned above and also to assess for the associated cardiovascular risk factors. A detailed history about the lifestyle and risk factors is of paramount importance. A family history of renal disease like polycystic kidney disease, or history of drug/substance abuse, oral contraceptives, steroids, non-steroidal anti-inflammatory drugs, or a clinical history of sudden onset palpitations, sweating headache and hypertension (pheochromocytoma), or a history of tetany and weakness (aldosteronism), history of snoring and somnolence (sleep apnea) are some of the examples highlighting the importance of a detailed history.
e) Clinical Examination: most importantly the correct methodology of measuring blood pressure should be implemented and supervised. A careful assessment of pulse rate and palpability of pulses, radiofemoral delay , presence of arrhythmia, presence of heart failure , telltale features of  Cushing’s disease, neurofibromatosis (pheochromocytoma) , enlarged, palpable kidneys as in polycystic kidney disease, renal bruit, aortic disease (aortic regurgitation, coarctation of aorta) are part of clinical evaluation of a hypertensive patient.
f) Laboratory investigations : include the ‘routine’ investigations (like hemogram, hematocrit, fasting plasma sugar and lipid profile, serum potassium, serum calcium, serum creatinine, serum uric acid, urine analysis, thyrotropin, estimated GFR, creatinine clearance) as well as more specific tests like glucose tolerance test, microalbuminuria by dipstick, electrocardiogram, echocardiogram, carotid ultrasound, , Ankle-brachial index, and pulse wave velocity. Advanced workup also includes measurement of renin, plasma/urine catecholamines, renal and adrenal imaging, CT/ MRI where ever considered necessary and ophthalmologic examination (fundoscopy) (Table 4).
g) Therapeutic approach

1.Lifestyle Modification- as the CVD risk factors often cluster together, hence lifestyle modifications counter the global risk factors to achieve the ultimate goal of reduction in long term cardiovascular morbidity and mortality. The life style measures are

2.Smoking cessation: smoking has not directly been shown to cause or aggravate HT. However, there is ample data to suggest that it is a powerful risk factor for CVD. Hence, smoking cessation is advocated as part of global CVD reduction.

Table 4: Investigational workup for isolated systolic hypertension

CT- computed tomography, GFR- glomerular filtration rate, MRI- magnetic resonance imaging

h) Pharmacological treatment:
Almost all major classes of anti-hypertensive drugs have been shown to be effective in ISH. Diuretics, β-adrenergic blockers,  angiotensin-converting–enzyme (ACE) inhibitors, angiotensin-receptor blockers, and calcium-channel blockers are proposed classes for use with similar blood pressure lowering effect and cardiovascular event reduction 35.  In approximately two thirds of patients with hypertension, two or more drugs may be needed to achieve target blood-pressure levels. JNC 7 recommends thiazide diuretics as initial drug therapy for most patients with hypertension, on the basis of their proven efficacy in reducing blood pressure and cardiovascular complications in clinical trials and their low cost. Other antihypertensive medications are preferred if existing co-morbidities compel such a use. Compelling indications include hypertensive patients with chronic kidney disease, (either an ACE inhibitor or an angiotensin-receptor blocker) 36-38; post myocardial infarction or heart failure patients (a beta-blocker and an ACE inhibitor)39,40 and elderly men with benign prostatic hypertrophy (α-1– receptor antagonist).   However, recent studies have questioned the wisdom of use of thiazide-type diuretics which have been implicated in causing carbohydrate intolerance and diabetes, especially in hypokalemic patients.41,42 This uncertainty should not however, discourage the use of diuretics as part of combination drug therapy since diuretics complement the action of the other drugs. The use of beta-blockers as first-line therapy for elderly patients with hypertension also came under the scanner after publication of a meta-analysis showing a 16% higher incidence of stroke (especially atenolol) than among those treated with other antihypertensive medications.43 Over-estimation of  blood pressure reduction by atenolol by standard cuff techniques as compared with aortic pressure calculated from applanation tonometry and radial-artery waveforms has been proposed as a reason for lower efficacy of beta-blockers and higher stroke rate. 44 On the other hand, calcium-channel blocker, ACE inhibitor, or diuretics have similar effects on central aortic- and brachial-artery pressures.45 Initial therapy with beta-blockers in elderly patients should be limited to those with compelling indications, such as coronary heart disease, myocardial infarction, congestive failure, or certain arrhythmias. More data on newer beta-blockers with peripheral vasodilator properties is needed. The joint guidelines of the European Society for Hypertension and the European Society of Cardiology (ESH/ESC)46  recommend any of the five major classes of antihypertensive drugs for first-line therapy without emphasizing on the initial use of  diuretics. Recent guidelines from Great Britain 47 discourage the use of both diuretics and beta-blockers for initial therapy and favor ACE inhibitors, angiotensin receptor antagonists, or calcium-channel blockers. However all the guidelines endorse achieving the target blood pressure goals as the prime directive to reduce hypertension related adverse events. This is of crucial importance because cardiovascular protection by antihypertensive treatment substantially depends on BP lowering per se, regardless of how it is obtained. The

combination of two antihypertensive drugs may offer several advantages. Whenever possible, use of fixed dose (or single pill) combinations should be preferred to ensure compliance to treatment. Several two-drug combinations are suitable for clinical use. However, trial evidence of outcome reduction has been obtained particularly for the combination of a diuretic with an ACE inhibitor or an angiotensin receptor antagonist (ARA) or a calcium antagonist, and in recent large-scale trials for the ACE inhibitor/calcium antagonist combination. The ARA/calcium antagonist combination also appears to be rational and effective. These combinations can thus be recommended for priority use.48,49

Follow up
Initial follow-up can be carried out at approximately monthly intervals until the target blood pressure of less than 140/90 mm Hg is achieved. If a second or third drug is required, an ACE inhibitor, angiotensin-receptor blocker, calcium-channel blocker, or beta-blocker can be added; the choice will depend on the patient’s clinical status and the clinician’s experience. A tablet combining the selected drugs is often desirable. Once the target blood pressure is achieved, follow-up can occur every 3 to 6 months depending on the response. Other risk factors for cardiovascular disease should be actively sought, annually assessed and treated. In patients with hypertension, the presence of subclinical organ damage should be actively sought and investigations based on urinary protein excretion (including microalbuminuria), eGFR (MDRD formula), and ECG (to look for left ventricular hypertrophy) are suitable for routine use. More advanced tests like echocardiography, exercise stress testing, etc which may not routinely be available should also be recommended when deemed appropriate. Serum potassium, kidney function tests, and blood glucose levels along with fasting lipid profile and urinalysis should be measured annually. A yearly ophthalmic (fundus) checkup is highly recommended.
Conclusion
Isolated systolic hypertension is a major risk factor for cardiovascular and renal disease, and recent evidence strongly advocates treatment of isolated systolic pressure. In most of the older patients, elevation of systolic blood pressure occurs because of reduced arterial elasticity secondary to age and atherosclerosis. Initial evaluation is aimed at a detailed history, physical examination followed by appropriate laboratory tests to identify concomitant disorders that influence prognosis and therapy. Therapeutic lifestyle changes and appropriate pharmacological treatment in sync with any associated compelling indications are advocated for management of ISH.

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