Current Hypertension Reviews - Volume 3, Issue 1, 2007

It is time to recognize that the quality, not quantity, of myocardium in hypertensive heart disease is responsible for adverse cardiovascular events. Experimental and clinical available data indicate that myocardial fibrosis due to the exaggerated accumulation of collagen type I and type III fibers predisposes to an enhanced risk of diastolic and/or systolic ventricular dysfunction, symptomatic heart failure, ischemic heart disease, and arrhythmias in patients with hypertensive heart disease. Thus, management of these patients must not only focus on detection and regression of left ventricular hypertrophy. Far more sensible are interventions aimed to detect and target hypertensive myocardial fibrosis. The available data on the use of biochemical and/or imaging methodologies to address excessive accumulation of collagen fibers in the myocardium of hypertensive patients are promising. On the other hand, preliminary data suggest that the goal of reducing myocardial fibrosis is achievable in patients with hypertensive heart disease treated with specific antihypertensive agents. Collectively, these findings set the stage for larger trials where-in noninvasive measures and reparative strategies of myocardial fibrosis to prevent heart failure could prove useful.

Calcium channel blockers (CCB) represent a class of drugs widely used for treatment of hypertension and coronary heart disease. Some case-control studies published 10 years ago that included patients treated with short acting dihydropyridines reported several apparently harmful actions of this class of drugs, such as increased risk of myocardial infarction, cancer and gastrointestinal bleeding. However, in the last six years a large body of evidence derived from various controlled clinical trials has clearly demonstrated that long-acting CCB are beneficial drugs for treating hypertension and coronary heart disease. Studies such as INSIGHT, NORDIL, ALLHAT, VALUE and ASCOT have shown that CCB are not inferior to other antihypertensive drug classes in preventing cardiovascular disease in hypertensives. In fact, the combination of a CCB and an ACE inhibitor is clearly superior in comparison to classic combination of a diuretic and a beta-blocker. Moreover, CCB have a particularly good profile in preventing stroke and carotid and coronary atherosclerosis progression. Finally, the results of another group of trials, such as INVEST, ACTION and CAMELOT have shown that CCB decrease the risk of new events and procedures and also impairs atherosclerosis progression when used in patients with stable coronary heart disease.

Beta-blockers are recommended as first line therapy in the treatment of essential hypertension since several decades and this recommendation has been endorsed by most if not all national and international guideline committees. Some concerns about their efficacy in elderly hypertensive patients have been raised in the mid-90ies. With the recent publication of the LIFE and ASCOT-BPLA trials showing the superiority of a losartan-based and an amlodipine-based regimen versus an atenolol-based regimen in preventing stroke, additional questions have been raised about the position of beta-blockers in the management of hypertensive patients. Conventional beta-blockers such as atenolol have a well known negative impact on metabolic parameters which may limit their efficacy in protecting patients from the development of cardiovascular events. More recent data have also suggested that atenolol leads to lesser decrease in central blood pressures than amlodipine and this may explain why atenolol does not provide as much protection against stroke than calcium antagonists and angiotensin receptor blockers. With these new evidence, it appears legitimate to call in question the place of beta-blockers as first choice therapy in essential hypertension.

Beta-adrenergic receptor blockers are one of the oldest class of cardiovascular drugs still in use. Several short and long-term clinical outcomes prospective studies have demonstrated their effectiveness and safety for the treatment of hypertension, coronary artery disease, myocardial infarction, heart failure and sudden death. Despite their proven benefits, some investigators have cautioned against their use, and others, more recently, have suggested the complete withdrawal from their use in the treatment of hypertension. In this review, evidence based information will be presented which will demonstrate that beta-blockers are an effective and safe antihypertensive class of drugs across all age, gender and race groups. In addition, evidence will be provided that these agents are useful drugs in the treatment of hypertensive patients with co-morbid conditions such as diabetes mellitus, peripheral arterial disease and lung disease, and therefore they should continue to be used in the treatment of these patients, either alone or in combination with other antihypertensive drugs.

Albuminuria is the increased excretion of the serum protein albumin into the urine. Albuminuria is classically seen as an important diagnostic marker of declining kidney function, however, more recently albuminuria has also been implicated as a marker for cardiovascular and peripheral vascular disease indicating an important link between processes governing both cardiovascular and renal function. This review will discuss i) a common mechanism for albuminuria that accounts for albuminuria seen in hypertension and other albuminuric states and ii) possible linking factors between albuminuria, hypertension and cardiovascular disease.

The renin-angiotensin system (RAS) is a major physiological regulator of body fluid volume, electrolyte balance, and arterial blood pressure. Systemic suppression of the RAS through angiotensin converting-enzyme (ACE) inhibition and/or angiotensin receptor blockade (ARB) is an established and effective therapeutic approach for a range of cardiovascular disorders. One of the functions of renin is to catalyze the cleavage of angiotensinogen to angiotensin I (Ang I), which is the first and rate-limiting step of the RAS. Ang I is then converted by ACE to angiotensin II (Ang II), a potent endogenous vasoconstrictor. Interruption of the formation of Ang II by renin inhibitors offers a therapeutic profile that is distinct from that of the more well-known RAS antagonists, since both ACE inhibition (via ACE-independent pathways) and ARB, result in an increase in Ang II formation. This review will focus on the development and relevant clinical studies involving the renin inhibitors. The therapeutic implications of renin inhibitors, either employed alone, or in combination with ACE inhibitors or ARBs, will also be discussed.

The epithelial Na+ channel (ENaC) forms the rate limiting step in transepithelial Na+ absorption across aldosterone- responsive tissues such as the distal nephron. After more than a decade of investigation it is clear that the mechanisms of ENaC regulation are complex with an array of ENaC-regulatory proteins having been identified. A variety of monogenic syndromes of low renin hypertension have been identified that serve, through different mechanisms, to upregulate distal tubular ENaC activity. One of the most extensively studied, Liddle's syndrome, results predominantly from mutations in the C-termini of β and γ-ENaC subunits leading to a failure of Nedd4-2 (neuronal precursor cell-expressed and developmentally down-regulated protein 4-2) mediated channel endocytosis and an increased expression of ENaC at the cell surface. The role of ENaC subunit polymorphisms as determinants of essential hypertension has been investigated in a number of studies. The T594M mutation in the β-subunit of ENaC, for example, has been screened in large study populations and there is conflicting evidence that it co-segregates with blood pressure. Reasons for such controversies are discussed. The authors conclude that ENaC is a pivotal convergence point in blood pressure regulation and that future studies must identify better ways to measure distal tubular ENaC activity and investigate the importance of combination polymorphisms of ENaC subunits and their regulatory proteins as genetic determinants of hypertension.

An increased concentration of homocysteine (Hcy) is considered an independent and graded cardiovascular risk factor. Hcy can be non-specifically activated by methionyl-tRNA synthetase to Homocysteine thiolactone (HTL). HTL is hydrolyzed to Hcy by the paraoxonase/Thiolactonase (PON1) enzyme. PON1 is a calcium-dependent esterase synthesized in the liver and contained in plasma High-Density Lipoproteins (HDLs). The PON1 gene is polymorphic. High thiolactonase activity was associated with L55 and R192 alleles, whereas low thiolactonase activity was associated with M55 and Q192 alleles. This study provides a brief overview of some of the mechanisms by which Hcy affects vascular function and the evidence that accounts for their relevance in hypertension. The hypothesis by which alleles encoding high thiolactonase forms of PON1 might confer vascular protection under certain environmental conditions is discussed. We also evaluated these alleles and conditions in patients and controls from our institutional records.

Hypertension is a serious complication in children after renal transplantation, it is an important risk factor not only for graft loss but also for cardiovascular morbidity and mortality of transplanted patients. The etiology of posttransplant hypertension is multifactorial - pretransplant hypertension, damaged native kidneys, immunosuppressive therapy (steroids, cyclosporine, tacrolimus), renal graft artery stenosis and chronic allograft nephropathy are the most common causes. Ambulatory blood pressure monitoring (ABPM) is the best method for blood pressure (BP) evaluation in children after renal transplantation, it often discloses especially night-time hypertension. The prevalence of posttransplant hypertension ranges between 60-90% depending on the method of BP measurement and definition of hypertension. Left ventricular hypertrophy (LVH) is a frequent end-organ damage in hypertensive children after renal transplantation occurring in 50-80% of them. All classes of antihypertensive drugs are used in the treatment of posttransplant hypertension, it has never been proven that one class would be better than another in BP lowering effects or in slowing the progressive loss of graft function associated with chronic allograft nephropathy. Control of hypertension in transplanted children is poor - only 20-50% of treated children have normal BP. The reason for this poor BP control seems to be an inadequate antihypertensive therapy rather than a true resistance of posttransplant hypertension. The unsatisfactorily low control of hypertension can be improved by increasing the number of antihypertensive drugs, especially of angiotensin converting enzyme inhibitors and diuretics. Reduction or elimination of steroids, cyclosporine or tacrolimus is able to reduce BP in transplanted children, however, it could be associated with a risk of acute rejection. Nephrectomy of the diseased native kidneys also decreases BP in transplanted patients but it is performed very rarely in children. There is still a great potential for improvement of antihypertensive treatment that could result in improvement of both graft as well as patient survival in children after renal transplantation.

Preeclampsia is defined as new onset hypertension with proteinuria during pregnancy. The initiating event in preeclampsia is postulated to be reduced uteroplacental perfusion which leads to widespread dysfunction of the maternal vascular endothelium. Inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF alpha) are thought to be important links between placental ischemia and cardiovascular and renal dysfunction. Supporting a potential role of cytokines in preeclampsia are findings that plasma levels of TNF and IL-6 are elevated in women with preeclampsia. Important blood pressure regulatory systems such as the renin-angiotensin system, sympathetic nervous system, and endothelial factors interact with pro-inflammatory cytokines such as IL-6 and TNF. Pro-inflammatory cytokines also affect vascular function and endothelium-derived factors involved in blood pressure regulation. Thus, endothelial dysfunction associated with preeclampsia may be mediated by cytokines. Recent studies have indicated that chronic reductions in placental perfusion in pregnant animals are associated with enhanced production of inflammatory cytokines, such as TNF alpha and IL-6. In addition, chronic infusion of either TNF alpha or IL-6 into normal pregnant rats results in significant increases in arterial pressure and a decrease in renal hemodynamics. TNF alpha activates the endothelin system in placenta, renal and vascular tissues whereas IL-6 stimulates the renin-angiotensin system. Collectively, these findings suggest that inflammatory cytokines play a role in causing hypertension in response to chronic reductions in uterine perfusion during pregnancy by activating multiple neurohumoral and endothelial factors.

The heme oxygenase (HO) system has received significant attention in recent years as a possible novel target for antihypertensive therapy. HO is the rate limiting enzyme in the metabolism of heme releasing bioactive molecules carbon monoxide (CO) and bilirubin each with beneficial cardiovascular actions. Induction of HO-1 has been demonstrated to lower blood pressure in several animal models of hypertension In addition to its blood pressure lowering effects, HO can also reduce target organ injury and protect against ischemic injury. Growing experimental evidence suggests that increases in either CO or bilirubin alone may also lower blood pressure and provide protection against hypertensive and ischemic end-organ damage. In this review, we will discuss the current understanding of the actions of the HO on the kidney and cardiovascular systems and how the HO system or its products may be manipulated for antihypertensive therapy.