Blood Pressure Regulation and Pathology

Introduction

Elevated blood pressure, also known as hypertension, affects ∼30% of the adult population in both developed and developing countries and is a major cause of morbidity and mortality. Hypertension is a major risk factor for many common chronic diseases, such as heart failure, myocardial infarction, stroke, and chronic kidney disease, and is increasingly being considered in vascular dementia. Epidemiological and clinical studies demonstrate that the morbid complications of hypertension-associated target organ damage and the risk of cardiovascular diseases and death rise gradually as blood pressure increases. Clinical trials have clearly shown that blood pressure reduction leads to reduced morbidity and mortality with decreased incidence of stroke, heart failure, myocardial infarction, and end-stage kidney disease. Blood pressure lowering is also associated with improved cognitive function in patients with vascular dementia. In spite of the large availability of excellent antihypertensive drugs, blood pressure control in the hypertensive population remains inadequate. Reasons for this are complex and multifactorial and relate, in part, to healthcare issues including poor access to care, lack of diagnosis, and sub-optimal management. In addition and of major significance, is the lack of understanding of the exact cause(s) of hypertension. This has led to an increase in incidence in age-adjusted stroke and end-stage renal disease and a rise in the prevalence of heart failure. Moreover, it is predicted that by 2026, the prevalence of hypertension and associated co-morbidities will increase globally by 60%.

Physiological control of blood pressure is based on Ohm’s law modified for fluid dynamics, where blood pressure is proportional to cardiac output and resistance to blood flow in peripheral vessels ( Figure 14.1 ). Blood flow depends on cardiac output and blood volume, whereas resistance is determined primarily by the contractile state of small peripheral arteries and arterioles. In general, cardiac output remains fairly stable, with increase in peripheral resistance being the major contributor to hypertension, particularly essential hypertension. Many physiological systems influence blood pressure including (1) baroreceptors that sense acute changes in pressure in vessels; (2) the renin–angiotensin system (RAS) that influences vascular tone, salt handling, and volume homeostasis; (3) the adrenergic system which regulates heart rate, cardiac contraction, and vascular tone; and (4) vasoactive factors produced by the blood vessels that cause vasorelaxation, such as nitric oxide, or vasoconstriction, such as endothelin-1 and reactive oxygen species (ROS). Many organs contribute to blood pressure control, including the central and peripheral nervous system, heart, and kidneys. In addition, the vascular system is increasingly implicated as an important organ involved in blood pressure control ( Figure 14.2 ). These systems act in an integrated manner to maintain adequate perfusion of tissues and organs in spite of varying metabolic demands. Various risk factors, both non-modifiable (age, gender, genes) and modifiable (body mass index, diet, alcohol, salt, sedentary lifestyle) have an impact on blood pressure, probably by influencing physiological systems that control blood pressure.

Definition of Essential (Primary) Hypertension

Blood pressure is a quantitative trait. In population studies, blood pressure has a bell-shaped distribution, which is slightly skewed to the right. There is a positive and continuous correlation between blood pressure and the risk of cardiovascular disease, kidney disease, and stroke, even in the normal range of blood pressures. This correlation is more robust for systolic blood pressure than with diastolic blood pressure. Because there is no clear-cut level of blood pressure where cardiovascular and renal complications start to occur, the definition of hypertension is arbitrary. As such, treatment of hypertension is largely empiric.

Essential, primary, or idiopathic hypertension is defined as high blood pressure in which secondary causes, such as primary hyperaldosteronism, phaechromocytoma, renovascular disease, kidney failure, and monogenetic causes of hypertension are excluded. Essential hypertension is a heterogeneous condition, and accounts for ∼ 95% of all patients with hypertension.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII) defined and classified hypertension in adults ( Table 14.1 ). This report, to be updated in 2013–2014 as JNC VIII, provides current guidelines for hypertension prevention and management.

Some key points of JNC VII, which are not dissimilar to other major guidelines, include:

• 1.

  In persons older than 50 years, systolic blood pressure (BP) of more than 140 mmHg is a much more important cardiovascular disease (CVD) risk factor than diastolic BP.

• 2.

  The risk of CVD, beginning at 115/75 mmHg, doubles with each increment of 20/10 mmHg; individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hypertension.

• 3.

  Individuals with a systolic BP of 120–139 mmHg or a diastolic BP of 80–89 mmHg should be considered as prehypertensive and require health-promoting lifestyle modifications to prevent CVD.

• 4.

  Thiazide-type diuretics should be used in drug treatment for most patients with uncomplicated hypertension, either alone or combined with drugs from other classes. Certain high-risk conditions are compelling indications for the initial use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers).

• 5.

  Most patients with hypertension will require two or more antihypertensive medications to achieve goal BP (<140/90 mmHg, or <130/80 mmHg for patients with diabetes or chronic kidney disease).

• 6.

  If BP is more than 20/10 mmHg above goal BP, consideration should be given to initiating therapy with two agents, one of which usually should be a thiazide-type diuretic.

• 7.

  The most effective therapy prescribed by the most careful clinician will control hypertension only if patients are motivated. Motivation improves when patients have positive experiences with and trust in the clinician. Empathy builds trust and is a potent motivator.

Genetics of Hypertension

Primary hypertension clusters in families. Individuals with two or more first-degree relatives with hypertension younger than 55 years of age have an almost four times greater risk of developing hypertension before 50 years of age. Epidemiological and family studies clearly demonstrate a significant heritability component for blood pressure. Blood pressure variability in populations attributed to genetic factors varies from 25–50%. Twin studies show greater concordance of blood pressure of monozygotic than dizygotic twins and population studies document greater similarity of blood pressure within families than between families. This aggregation within families is not only due to common environmental factors. Adoption studies demonstrate greater blood pressure concordance among biological siblings than adoptive siblings living in the same home.

Unravelling the genetics of hypertension is challenging because hypertension is a complex, polygenetic, quantitative disease, influenced by multiple environmental and physiological factors. Moreover, the two fundamental factors that determine blood pressure, namely cardiac output and total peripheral vascular resistance, are influenced by intermediary phenotypes, including the sympathetic nervous system, renin–angiotensin–aldosterone system, renal function, volume homeostasis, vascular structure, and many other systems. To further complicate this, these intermediary phenotypes are also regulated by complex interacting systems, including blood pressure itself.

Numerous approaches to study the genetics of hypertension have been used to identify putative blood-pressure-related genes. In the general population, studies of blood pressure variation are complicated by many factors that contribute to the trait in any single individual, including demographics, environment, and genetics. Moreover, blood pressure variation in the population is probably determined by numerous genes which each have a small, possibly additive effect. Accordingly very large sample sizes are required to identify variants using strategies such as genome-wide association studies (GWAS). To date, a number of large GWAS, each comprising ∼ 30000 subjects have been completed. Together these GWAS identified at least 14 distinct loci having statistically significant associations with blood pressure traits. However, each of the identified loci imparts only a small effect on blood pressure. Taken together, GWAS data have been disappointing, but certainly highlight the fact that many genetic variants influence blood pressure at the population level. Perhaps with the development of next-generation sequencing tools, which will provide opportunities to do whole-genome and exome sequencing, further insights into the genetics of hypertension will be possible.

While it has been very challenging to elucidate the genetics of hypertension in the general population, there has been enormous progress in the understanding of Mendelian forms of blood pressure variation in which mutations in single genes have large effects on blood pressure. To date about 20 genes have been found to be responsible for blood pressure variation, with mutations in eight genes causing Mendelian forms of hypertension and nine genes that cause Mendelian forms of hypotension ( Table 14.2 ). Typically, these single-gene mutations impart large effects on blood pressure. Of major significance, most of the described mutations influence renal salt reabsorption ( Figure 14.3 ), highlighting the importance of the kidney in the pathophysiology of hypertension.

Physiological Control of Blood Pressure

The pressure required to maintain perfusion of all tissues and organs depends on cardiac output and peripheral resistance. These primary determinants of blood pressure are in turn influenced by various factors. Changes in cardiac output usually contribute to acute changes in blood pressure. Chronic or established hypertension is characterized hemodynamically by normal cardiac output and increased peripheral vascular resistance. Major determinants of vascular resistance are structural thickening of the vessel wall and increased vascular tone due to increased vasoconstriction and/or decreased vasodilation ( Figure 14.1 ). Despite extensive research into the mechanisms that initiate these processes, the exact causes still remain elusive. Nevertheless, it is clear that heredity plays a role, along with contributions of numerous environmental factors. At the pathogenic level, many interacting systems influence cardiac output and vascular resistance. Considering the major importance of vascular resistance in the pathogenesis of hypertension, this chapter will focus on processes underlying changes in vascular function and structure.

Cardiac Output and Hypertension

Cardiac output is the product of stroke volume and heart rate. Accordingly, increased fluid volume (preload) or increased cardiac contractility or heart rate due to neural stimulation, are important. Although increased circulating fluid volume underpins increased preload, patients with established hypertension usually have a lower blood volume and total exchangeable sodium than normotensive individuals. This may relate to increased translocation of fluid across the capillary bed into the interstitial space and possibly to increased intracellular fluid volume. Increased heart rate has been attributed to neurogenic mechanisms of increased sympathetic activity and/or decreased parasympathetic drive.

The Sympathetic Nervous System and Hypertension

The sympathetic nervous system comprises the vasomotor center that activates efferent pathways, which innervate sympathetic ganglia. Activated sympathetic nerves secrete catecholamines (norepinephrine, epinephrine), which induce effects on the heart, kidneys, and blood vessels through presynaptic and post-synaptic receptors. Increased activity of the sympathetic nervous system seems to play an important pathophysiological role in hypertension, particularly in the early stages. This is evidenced by elevated plasma norepinephrine levels, increased norepinephrine spillover rate, increased heart rate and blood pressure variability, increased α-adrenergic vasoconstriction and increased vascular reactivity to norepinephrine. Catecholamine-induced vasoconstriction of renal efferent arterioles influences renal sodium retention, which may further contribute to blood pressure elevation. Changes in other neurotransmitters, such as neuropeptide Y, a norepinephrine cotransmitter, adenosine, and dopamine in hypertension may also reflect sympathetic nervous system involvement. Pathophysiological processes characterized by increased sympathetic activity and impaired baroreflex control include obesity, obstructive sleep apnea, and polycystic ovary syndrome, often associated with resistant hypertension.

Other contributory mechanisms of the sympathetic nervous system involve resetting of the mechanoreceptors, particularly the sinoaortic baroreceptors (high pressure), that are activated by increased arterial pressure, and the cardiopulmonary baroreceptors (low pressure), that are activated by increased central venous pressure. Baroreceptor activation leads to reduced heart rate and lower blood pressure by vagal stimulation and sympathetic inhibition.

Taken together, activation of the sympathetic nervous system and increased catecholamine secretion are major candidates underlying the cardiovascular pressor mechanisms that trigger blood pressure elevation and the trophic processes that maintain hypertension through effects on vascular structural changes, such as hypertrophy. Activation of the sympathetic nervous system also influences the RAS, a major player in established hypertension. Moreover, sympathetic overactivity has been implicated in the increased cardiovascular morbidity and mortality associated with early morning blood pressure surges. This has been attributed, in part, to increased α-sympathetic activation that occurs during prewakening. Targeting the sympathetic nervous system with anti-adrenergic drugs, anti-adrenergic devices (renal nerve denervation), and carotid baroreflex activation are increasingly being considered as effective antihypertensive therapies in patients with resistant hypertension.