In 1945, when Franklin D. Roosevelt died of a stroke, little did his physicians know that his long-standing hypertension, with recorded systolic blood pressures as high as 300, had a major role in his untimely death at the age of 63. The Framingham Heart Study, started in 1949, provided the first insights into the link between elevated blood pressure and cardiovascular disease, with its findings first published in 1961.(1) Since then, numerous studies have provided valuable information about hypertension as a risk factor for CVD, chronic kidney disease and peripheral vascular disease.

Etiology and Pathophysiology

Heart disease is the most common cause of death in hypertensive patients. Hypertension can lead to heart failure, atherosclerotic coronary artery disease and aortic aneurysm formation.(2) Approximately 95% of adults with high blood pressure have primary or essential hypertension, which results from a combination of genetic and environmental factors. Important environmental factors include excessive salt intake, sedentary lifestyle, obesity and excessive alcohol intake. In addition, the incidence of hypertension increases with age, with nearly three fourths of adults above the age of 70 suffering from elevated blood pressure.

Secondary hypertension accounts for less than 5% of all cases of hypertension. Common causes include obstructive sleep apnea, renal parenchymal disease, thyroid disease and renal artery stenosis. Other causes are pheochromocytoma, coarctation of the aorta, excessive aldosterone secretion and excessive cortisol secretion.

The physiology of blood pressure regulation depends upon the balance between cardiac output and peripheral vascular resistance. Retention of sodium is often the initiating step in hypertension, which leads to increased fluid retention and, consequently, raised blood pressure. This is usually mediated by an increase in peripheral vascular resistance, with cardiac output often remaining normal.(3) Various systems regulate blood pressure, such as the RAAS (renin-angiotensin-aldosterone system), the autonomic nervous system and local neurohormonal systems.

The RAAS provides an important link between peripheral vascular resistance and sodium homeostasis, affecting both. Renin is the first step of the pathway, secreted by the juxtaglomerular cells of the kidney in response to decreased sodium excretion, decreased pressure within the renal afferent arterioles and sympathetic nervous system stimulation. This renin then converts plasma angiotensinogen to angiotensin I, which is, in turn converted to angiotensin II by angiotensin-converting enzyme. Angiotensin II raises blood pressure by directly acting on smooth muscle cells and increasing peripheral vascular resistance. Angiotensin II also stimulates secretion of aldosterone, causing increased absorption of sodium from the distal nephron and leading to an expansion of blood volume. Aldosterone also has an adverse effect on cardiac remodeling and ventricular hypertrophy.

The autonomic nervous system mediates elevation of blood pressure by increasing sympathetic tone, which results in vascular remodeling and decreased compliance of blood vessels. Increased renal sympathetic stimulation also leads to increased secretion of renin and this provokes increased sodium absorption and peripheral resistance via the RAAS pathway.(4)

Classification of Blood Pressure

Hypertension is typically defined by the presence of elevated blood pressure on three consecutive readings performed on different days with the average of the last two readings being greater than 140 mmHg systolic and/or 90 mmHg diastolic. Normal blood pressure is considered a systolic blood pressure <20 mm Hg and diastolic blood pressure <80 mm Hg. Stage I hypertension is defined by systolic blood pressure (SBP) of 140–159 mm Hg or diastolic blood pressure (DBP) 90–99 mm Hg. Stage II hypertension is defined by systolic blood pressure greater ??JPY60 mm Hg or diastolic blood pressure ??JPY100 mm Hg. Individuals with systolic blood pressure 120–139 or diastolic blood pressure 81–89 are considered to have pre-hypertension; this term is utilized because the majority of such individuals will ultimately develop frank hypertension.(5)

Blood Pressure Measurement

Blood pressure should be taken after patients have emptied their bladder, and have been in a comfortable seated position, with their back well supported, for five minutes. Their legs should rest comfortably on the ground, uncrossed. Smoking, coffee or exercise should be avoided for 30 minutes prior to examination. The appropriate-sized blood pressure cuff should be chosen, as using over or undersized cuffs may lead to erroneous measurement. An oversized cuff will lead to underestimation of blood pressure while an undersized cuff will lead to overestimation of blood pressure.

Blood pressure measurements at the wrist or finger are less reliable than arm measurement. While blood pressure can be measured by either a conventional sphygmomanometer (using a stethoscope) or by an automated electronic device, electronic devices are preferred as the results are more reproducible. However, the accuracy of electronic instruments can decrease if they are not calibrated periodically.(6)

At the initial evaluation, blood pressure should be measured in both arms; if the readings are different, a diagnosis of subclavian artery stenosis should be considered and the arm with the higher reading should be used for measurements thereafter.

White coat hypertension is defined as elevated blood pressures in the clinic but normal blood pressures elsewhere. It can be diagnosed by either getting home blood pressure readings or ambulatory blood pressure monitoring. Ambulatory blood pressure monitoring involves wearing an arm cuff connected to a device that automatically measures and records blood pressures at regular intervals, usually over a 24-hour period. Ambulatory blood pressure monitoring can also be used for treatment resistance, episodic hypotension and autonomic failure.(7)

Home blood pressure monitoring is an inexpensive alternative to ambulatory blood pressure monitoring. Its use can improve patient adherence with their medications and provide greater feedback regarding blood pressure levels, resulting in better BP control. Furthermore, home blood pressure readings may be more predictive of adverse outcomes such as stroke or MI than clinic-based measurements. This is hardly surprising as blood pressure measurements are highly influenced by the daily circadian rhythm in addition to numerous other erratic factors such as stress, smoking, caffeine intake and exercise. Overall, multiple readings give a better sense of the average blood pressure than a single reading.

Potential problems with outpatient BP measurements include inaccurate technique and lack of accuracy of home blood pressure machines. The easiest way to check the accuracy of the home monitor is to ask the patient to carry the monitor to the clinic, and to simultaneously measure the blood pressure by the clinic monitor and the home monitor. This way, the technique of measurement can also be verified in the same sitting.

Lifestyle Management

Lifestyle management consists of weight reduction for those who are overweight, avoidance of excessive alcohol consumption (no more than one alcoholic drink/day in women and no more than two drinks/day in men), regular exercise, avoidance of excessive sodium consumption (various guidelines recommend no more than 2–3 grams of sodium/day), good sleep hygiene and formal stress reduction techniques such as mindfulness-based stress reduction. The reduction in BP from each lifestyle modification alone may be small, but in combination they may be additive.(8)

Furthermore, lifestyle interventions are synergistic with antihypertensive medications, improving BP control with lower doses or fewer classes of drugs than would otherwise be required. Nonadherence with an appropriate lifestyle is a common cause of resistant hypertension.(9) Lifestyle management also improves overall health, reducing the risk for other diseases such as depression, osteoarthritis, cancer and diabetes.

Sodium restriction in hypertensive individuals can reduce the SBP by 2–8 mm Hg and DBP by an average of 1.9 mm Hg. Rise in BP is seen only when sodium is combined with chloride; if sodium is combined with other anions it has, no effect on blood pressure The recommended sodium intake by most societies is 2.0–2.3 grams per day which equals to 5 to 6 grams of sodium chloride per day. To put that number in perspective, the average daily sodium intake by Americans is 3.4 grams per day. The vast majority of sodium intake is derived from processed foods and eating in restaurants. Only a small amount of total sodium intake results from cooking or adding salt at the table. It is, therefore, crucial for patients to learn how to read food labels to make educated decisions regarding sodium intake.(10)

Alcohol consumption should be restricted to two standard drinks per day for men (one standard drink contains 14 grams of ethanol, e.g., 12 oz. beer which is usually 5% alcohol or 5 oz. wine which is usually 12% alcohol) and one standard drink per day for women. For hypertensive individuals who consume more alcohol than this, reduction in alcohol consumption can reduce SBP by 2–4 mm Hg. The relation of alcohol with blood pressure is dose-dependent, and is most prominent when intake exceeds five drinks per day. The mechanism by which alcohol affects blood pressure has not been established.

Medications

All guidelines emphasize that the choice of drug in individuals with hypertension should be guided in large measure by coexistent diseases. Patients, for example, who have had prior myocardial infarction or left ventricular systolic dysfunction are often prescribed beta blockers for those index conditions with the added benefit that a beta blocker has antihypertensive properties. Similarly, ACE inhibitors and angiotensin-receptor blockers should be the antihypertensive of choice in individuals with diabetes, chronic kidney disease or left ventricular systolic dysfunction.(11)

Once antihypertensive drug therapy is initiated, follow-up is advised at monthly intervals until goal blood pressure is reached. Once goal blood pressure is reached, follow-up visits can be at less frequent intervals.

The various drug classes are as follows:

Diuretics: these drugs decrease blood pressure by sodium and volume depletion.

Sympathoplegic agents: these drugs decrease the blood pressure by vasodilation, inhibiting cardiac function or increasing venous pooling of blood. There are multiple classes of sympathoplegics subdivided according to their putative site of action.

Direct vasodilators: these agents decrease blood pressure either by lowering vascular resistance in the resistance vessels (arterioles) or by increasing venous capacitance [leads to decreased cardiac output (CO)].

Drugs that interrupt the RAAS: these drugs counteract the effects of angiotensin II (which increases peripheral vascular resistance and, potentially, also increases plasma volume.

The following table details the various classes of medications in each of these categories and illustrates their effect on various hemodynamic parameters.

Current Guidelines and Recent Trials

Since the JNC 1 guidelines in 1977, there have been seven other JNC committees — the JNC 8 guidelines were released in 2014.(12) The overall trend since 1977 has been a progressive lowering of systolic and diastolic blood pressure targets, as increasing evidence accumulated about the safety and efficacy of lower targets. The JNC 7 guidelines, released in 2003, advocated for a blood pressure target <140/90 mm Hg in in all individuals, including older adults >65 years of age. In high-risk individuals with chronic kidney disease (CKD) and diabetes, JNC 7 advocated for a goal blood pressure <130/80 mm Hg.

The JNC 8 guidelines, however, supported a more liberal approach, citing lack of evidence for lower blood pressure targets. The recommendations of JNC 8 are summarized in the table below.(13)

Since the publication of JNC 8, two important trials have added to the evidence base regarding blood pressure targets — HOPE 3(14) and SPRINT.(15) HOPE 3 enrolled a largely pre-hypertensive population of 12,705 individuals at intermediate risk of cardiovascular disease and randomized them to either candesartan/HCTZ combination or placebo. It was a pragmatic trial with use of fixed drug dosages and no titration to target. After a median follow up of 5.6 years, there was no statistically significant difference in outcomes between the two groups. In contrast, SPRINT enrolled a largely hypertensive population of 9,361 individuals at high risk of cardiovascular disease, and randomized them to systolic blood pressure target of <120 mm Hg versus <140 mm Hg. After a median follow up of 3.2 years, the trial was stopped early due to a significantly lower rate of the primary outcome in the intensive group, versus the standard group. The differences between HOPE 3 and SPRINT are summarized in Table 3 below.

While interpreting the positive findings of SPRINT, it must be borne in mind that the unobserved nature of BP measurements in the SPRINT protocol differs from routine clinical practice, and it is estimated that BP readings in usual clinic settings would be 5-10 mm Hg higher than the measurement method in SPRINT. Moreover, the treatment group had a significantly higher rate of adverse events despite a rigorous follow up protocol, which included a higher incidence of hypotension, syncope, electrolyte abnormalities and acute kidney injury. It would also be difficult to extrapolate the findings to a pre-hypertensive population, since SPRINT primarily enrolled a high-risk population, with only 10% of the enrolled population treatment naA?ve at baseline. Also, HOPE 3, which primarily enrolled a pre-hypertensive population, showed no significant improvement in outcomes in this population. While guidelines that incorporate the findings of SPRINT and HOPE 3 are awaited, we prefer an approach as outlined below.(16)

Strategies To Enhance Blood Pressure Control

Barriers to adequate blood pressure control include lack of awareness of diagnosis, failure to seek regular treatment for the condition and medication non-adherence. Community based screening programs can help uncover hypertension among people who do not visit a doctor regularly. Lack of insurance and high out of pocket costs are common barriers to seeking care from a physician. Medication non-adherence, overall, can have multiple causes — discovering and addressing non-adherence with prescribed medications can be challenging.(17)

At every visit, patients should be asked directly if they are having any difficulty taking their medications. This should be asked in an open ended and non-judgmental manner. Vigilance regarding psychosocial conditions is important, as untreated common mental health diseases often result in medication non-adherence.

Patient education should be carried out both by the physician and nursing staff. This can be supplemented by standardized brochures or materials made available on the web by professional organizations. Patients should be able to voice the expected benefits of treatment, understand how to interpret blood pressure numbers and know their blood pressure goal. The blood pressure at every visit should be communicated to the patient in writing.

Encourage the patient to sync his medication regimen with his daily routine, such as taking his medicines soon after meals. For lifestyle changes, encourage the patient to choose one change at a time, and come up with small, time-bound goals. This goal should be shared with other members of the family and be chosen by the patient himself. Motivational interviewing can be effective in helping improve blood pressure control, especially in patients who are ambivalent about the effort required.

Physicians can help enhance adherence by minimizing pill burden. A once-daily regimen is ideal. De-prescribing medications no longer necessary is also helpful. Adverse effects of drugs should be sought at every visit and concerns regarding them addressed. Patients who have difficulty with blood pressure control should be encouraged to use a home blood pressure machine for self-monitoring, and to bring in those devices to be checked for accuracy and correct technique at regular intervals.

Various lifestyle factors can be a barrier to blood pressure control, even with use of medications. This includes obesity, physical inactivity, sleep apnea, tobacco abuse and excessive dietary sodium or alcohol intake. Targeted and consistent efforts at improving these lifestyle factors are important, however progress can be slow. Meditation, yoga and mindfulness-based techniques can also be used to improve blood pressure, though the magnitude of the effect is modest (approximately 5 mm Hg reduction).

Besides non-adherence, other barriers to blood pressure control can include use of medications that increase blood pressure. Patients should be encouraged to bring all their medications, including over-the-counter (OTC) medications. Blood pressure can be increased by use of NSAIDs and pressor agents that are present in OTC cold remedies. Herbal compounds that can increase blood pressure include Ma Huang, ephedra and bitter orange. Other medications that can cause hypertension include oral contraceptive hormones, post-transplant medications such as cyclosporine and tacrolimus, steroid hormones and erythropoietin. Illicit drug use, especially cocaine, phencyclidine (PCP) and amphetamines, can lead to difficulty in controlling blood pressure.

Cultural factors obviously play a role in an individual's understanding of disease and they should be considered while developing a treatment plan. Many individuals, especially those who are young, may see taking daily medications as a sign of illness and therefore avoid them as they feel 'fine'. Spending time acknowledging their health care beliefs and frustration can lead to increased trust, communication and acceptability of the regimen.(18)

Many patient are not forthcoming about economic barriers that they experience, usually because of embarrassment or fears they may compromise the quality of their care by sharing economic concerns.

These individuals may skip appointments or take only some of their medication doses to decrease costs. Out of pocket medicine costs should be viewed as a side effect of drugs, and should be proactively discussed at every visit, just like any other common side effect. Eliciting out of pocket costs of care as a routine part of the interview can help improve understanding of economic barriers, which can be addressed by prescribing generic medications or referral to a social worker to see if the patient can qualify for special needs programs.

Social support systems are fundamental to a patient's worldview, and can serve as a useful adjunct in optimizing their care. With the permission of the patient, family members should be involved in the patient's care and given appropriate education regarding their loved one's needs and care.

Other healthcare professionals can play a key role in blood pressure control. Licensed nutritionists and nutrition educators can help with graded changes in lifestyle, suggesting healthy food choices. Multiple studies have shown that pharmacist-based interventions can improve blood pressure control by monitoring the patient's prescription refills and tracking adherence. Programs in which pharmacists check blood pressure and make changes to the dosing of prescribed anti-hypertensives have been shown to enhance blood pressure control.

Clinicians should also work with other health care professionals such as nurses, nurse case managers, optometrists, physician assistants and podiatrists to reinforce adherence to lifestyle measures and medications. Public health nurses and community health workers in high-risk areas can screen for hypertension in the community, make appropriate referrals, follow-ups and educate patients. All health care personnel should consistently educate patients about the benefits of making positive lifestyle changes, adhering to medications, risks of hypertension and the importance of achieving goal BP.

Resistant Hypertension

Resistant hypertension is defined as failure to achieve goal BP despite the use of full doses of an appropriate three-drug regimen that includes a diuretic.(19)

Improper measurement of blood pressure is a common cause of resistant hypertension. Attention should be paid to the trend of measurements over time, rather than a single measurement. Pseudo-hypertension can cause resistant hypertension in the elderly. Consideration of the diagnosis and eliciting Osler's sign (ability to palpate radial artery even after blood pressure cuff is inflated to above systolic pressure) is the key to preventing unnecessary workup and overtreatment.

Secondary causes of hypertension should be considered by physicians treating patients with resistant hypertension. These include kidney disease, renal artery stenosis, adrenal disorders, neurological disorders and obstructive sleep apnea.