Essential hypertension

Abstract

Essential hypertension (EH) is characterized by chronic elevation of blood pressure (BP) due to an unknown etiology. It affects nearly 95% of hypertensive patients [1]. Genetic causes account for about half of EH (see below). In the US, more than 65 million adults have EH [2]. Since EH is usually asymptomatic and requires lifelong treatment; as a result, only 70% of these people become aware that they have elevated BP, only 59% are being treated, and only 34% have well controlled BP [2]. Sustained high BP due to undiagnosed, untreated or suboptimally treated hypertension leads to target organ damage. Epidemiological data indicate that EH is a major modifiable risk factor for coronary heart disease, stroke, congestive heart failure and renal failure [2]. Since its pathogenesis is left unclear, treatment of EH remains largely empiric, with physicians selecting one or several different kinds of antihypertensive medicines until BP is adequately controlled. Because of the high prevalence of EH, the inability to make treatment specifically directed at the underlying etiology, and the need for lifelong treatment and follow-up, the care of patients with EH has become one of the largest expenses in the American health care budget. In the past several decades, a wide variety of physiological studies have established that many signaling pathways affect short-term BP regulation [3]. These include the renin-angiotensin II(AII)-aldosterone system, sympathetic nerve-adrenergic receptor system, a series of genes participating in control of renal salt handling [4], endothelin (ET) and its A receptor (ETA) signaling in vascular smooth muscle (VSM) cells, pathways which all result in vasoconstriction, and factors produced by vessel endothelial cells that cause vasodilation (e.g. nitric oxide) (Figure 1). While the effect of these systems has been established for short-term BP regulation, determining which of these pathways contributes to EH as primary alterations or secondary responses has proven difficult. However, study of monogenic forms of EH has consistently shown that genetic hypertension originally derives from variations of genes involved in renal salt handling [3, 4]. Activation of any one of these pathways leads to resistance arterial remodeling and increased vascular tone, resulting in high BP. Once elevated vascular tone is established, it cannot be returned to the original normal point, even though available anti-hypertensive drugs alone or in combination can effectively and temporarily reverse the vascular tone to normal. The critical issue to be elucidated in the next decade is what common downstream gene activation in these signaling pathways triggers irreversible vascular remodeling, to cause a new set point for vascular tone. If a target gene responsible for the final common pathway converging from these different signaling systems is identified, a novel antihypertensive medicine against this gene activity could permanently alter vascular remodeling and reverse elevated vascular tone to normal. Such a therapy could replace lifelong treatment, which not only brings about a huge expense in health care, but also can cause lack of adherence and compliance to the medical regimen, leading to inadequate blood pressure control. Figure 1 This diagram depicts those different causal factors with ageing trigger vessel remodeling and permanently increased vascular tone leading to EH through unknown BP signaling molecules. ET: endothelin, ETA: ET receptor A, NO: nitric oxide Another important issue is what factors cause EH. With advances from molecular biology, it is well accepted that EH is an age-dependent, complex common trait resulting from the interaction of environmental, epigenetic and genetic determinants (Figure 1). However, the pathogenesis of EH is largely not understood despite intense efforts.