Therapeutic Advances in Cardiovascular Disease

Recent research has focused on the development of evidence-based guidelines that are intended to regulate the conduct of physicians in the diagnosis and control of hypertension, with the goal of achieving greater effectiveness and equity at the lowest possible cost. In Latin America, guidelines are available for the management of hypertension at three levels: national, regional and international. The national and regional Latin American and Caribbean (LAC) guidelines are in fact adaptations of the international guidelines. The potential benefit of applying guidelines developed in other regions to local healthcare decision making is that it will enable decision makers to take advantage of existing analyses and transfer or adapt them to their local contexts. However, this adaptation precludes the assessment of their generalizability and potential transferability. In addition, this region is characterized by wide socioeconomic differences between its inhabitants, both among and within nations. Therefore, new guidelines for the LAC region must include recommendations that are common to all hypertensive patients in the region. Moreover, we advocate the inclusion of a specific section that makes comprehensive recommendations and provides strategies for implementation according to the socioeconomic conditions of particular groups. In addition to developing guidelines that are truly applicable to the LAC region, it seems sensible to consider information that is specific to this region. Furthermore, developing evidence-based guidelines is not enough to affect positively the burden of disease caused by hypertension. Therefore, professional programs are required for the implementation of such guidelines as well as the auditing of their results. Achieving these ambitious goals will require collaborative efforts by many groups including policymakers, international organizations, healthcare providers, universities and society.

Postprandial hypotension, defined as a fall in systolic blood pressure (SBP) of 20 mmHg or greater within 2  hours after a meal, is a risk factor for stroke, coronary events and mortality. The clinical suspicion is typically raised by episodes of postprandial syncope or falls, whereas asymptomatic postprandial hypotension is mostly neglected. The magnitude of the postprandial fall in SBP, as detected by 24-hour recording in apparently healthy middle-aged to elderly subjects, was proportional to the severity of the silent cerebrovascular damage. Postprandial hypotension can also be detected by self-measured blood pressure before and within 2 hours after meals using automatic devices. The review highlights the value of home blood pressure monitoring (HBPM) as a screening test for asymptomatic postprandial hypotension in hypertensive patients. Using a HBPM protocol that included duplicated blood pressure measurements before and after three consecutive lunches, we detected unsuspected postprandial hypotension in 27.4% of the 230 hypertensive patients screened. The prevalence of postprandial hypotension was 13.2% in controlled and 42.2% in uncontrolled hypertensive patients (p < 0.001), raising the dilemma of further lowering blood pressure in the setting of postprandial hypotension. The inclusion of preprandial and postprandial measurements in the protocol of HBPM is useful to identify hypertensive patients with postprandial hypotension and may guide adjustments in antihypertensive treatment according to postprandial blood pressure.

The renin-angiotensin system (RAS) plays a fundamental role in preserving the circulation and yet, it may be injurious to heart and blood vessels and may also allow, and sometimes hasten, kidney disease progression. Thus, effective RAS inhibition may be a major pharmacologic necessity to control hypertension, to decrease cardiovascular complication, and to inhibit kidney disease progression. Unfortunately, the beneficial effects attained in the management of renal disease sometimes are incomplete. The reasons for these inadequate outcomes may include angiotensin escape or excessive local angiotensin production. Two pharmacologic strategies have been proposed to overcome this drawback including higher than recommended doses of RAS inhibitors and the combination of two different RAS inhibitors. However, three large studies have shown that these more intensive pharmacologic approaches should be treated with caution when applied to high-risk patients, as organ perfusion may fall to critical levels that may cause severe complications. Nevertheless, intensive RAS inhibition (including combination therapy) may be the sole alternative in patients with chronic kidney disease (CKD) in whom other therapeutics options have failed. In these cases, adequate precautions including close clinical and laboratory follow up should prevent major complications.

Increased lifespan in the last few decades has substantially changed the scenario for renal artery stenosis. Indeed, because older populations show a higher prevalence of atherosclerotic disease, the incidence of atheromatous renal artery stenosis has also increased. Intuitively, one could surmise that stenosis removal should void both the hypertension and the kidney damage resulting from the obstructive stenosis. Surprisingly, a number of important clinical trials have failed to show the reversion seen in experimental models. The reasons for these differences may be linked to chronicity and inflammation associated with the atherosclerotic lesion. However, the failure to obtain a favorable response may also be related to abnormalities in the contralateral kidney. Indeed, this apparently normal kidney should work to compensate the hemodynamic effects of the ipsilateral stenosed kidney. Instead, structure and function in the contralateral kidney can be altered in renal artery stenosis to the point that this nonstenotic kidney may sustain both, hypertension and progressive kidney disease. Certainly, comparing the effects of clip removal in the Goldblatt model to angioplasty in clinical settings with atherosclerotic lesions may be totally inappropriate. Nevertheless, there remain certain clinical situations such as bilateral renal arterial disease, congestive heart failure, and progressive renal failure, where angioplasty may be an alternative. These approaches however are yet to be tested.

Experimental models of hypertension and patients with inappropriately increased renin formation due to a stenotic kidney, arteriosclerotic narrowing of the renal arterioles or a rare juxtaglomerular cell tumor have shown a progressive augmentation of the intrarenal/intratubular renin–angiotensin system (RAS). The increased intrarenal angiotensin II (Ang II) elicits renal vasoconstriction and enhanced tubular sodium reabsorption in proximal and distal nephron segments. The enhanced intrarenal Ang II levels are due to both increased Ang II type 1 (AT1) receptor mediated Ang II uptake and AT1 receptor dependent stimulation of renal angiotensinogen (AGT) mRNA and augmented AGT production. The increased AGT formation and secretion into the proximal tubular lumen leads to local formation of Ang II, which stimulates proximal transporters such as the sodium/hydrogen exchanger. Enhanced AGT production also leads to spillover of AGT into the distal nephron segments as reflected by AGT in the urine, which provides an index of intrarenal RAS activity. There is also increased Ang II concentration in distal nephron with stimulation of distal sodium transport. Increased urinary excretion of AGT has been demonstrated in patients with hypertension, type 1 and type 2 diabetes mellitus, and several types of chronic kidney diseases indicating an upregulation of intrarenal RAS activity.

In angiotensin (Ang)-II-dependent hypertension, collecting duct renin synthesis and secretion are stimulated despite suppression of juxtaglomerular (JG) renin. This effect is mediated by Ang II type 1 (AT1) receptor independent of blood pressure. Although the regulation of JG renin is known, the mechanisms by which renin is regulated in the collecting duct are not completely understood. The presence of renin activity in the collecting duct may provide a pathway for intratubular Ang II formation since angiotensinogen substrate and angiotensin converting enzyme are present in the distal nephron. The recently named new member of the renin–angiotensin system (RAS), the (pro)renin receptor [(P)RR], is able to bind renin and the inactive prorenin, thus enhancing renin activity and fully activating prorenin. We have demonstrated that renin and (P)RR are augmented in renal tissues from rats infused with Ang II and during sodium depletion, suggesting a physiological role in intrarenal RAS activation. Importantly, (P)RR activation also causes activation of intracellular pathways associated with increased cyclooxygenase 2 expression and induction of profibrotic genes. In addition, renin and (P)RR are upregulated by Ang II in collecting duct cells. Although the mechanisms involved in their regulation are still under study, they seem to be dependent on the intrarenal RAS activation. The complexities of the mechanisms of stimulation also depend on cyclooxygenase 2 and sodium depletion. Our data suggest that renin and (P)RR can interact to increase intratubular Ang II formation and the activation of profibrotic genes in renal collecting duct cells. Both pathways may have a critical role in the development of hypertension and renal disease.

Hypertension is a widespread condition that affects millions of people around the world and has a major impact in public health. The classic renin–angiotensin system is a complex system comprised of multiple peptides and pathways that have been the driver of drug development over the years to control hypertension. However, there are still patients whose hypertension is very difficult to control with current drugs and strategies, thus motivating further research in this field. In the past two decades, important discoveries have expanded our knowledge of this system and new pathways are emerging that are helping us understand the complex interaction taking place not only in the periphery, but also in the central nervous system where the renin–angiotensin system is also very active. A new arm, called the ACE2/Ang-(1-7)/Mas receptor axis, was shown to exert antihypertensive properties and serve as a counterbalance to the classic ACE/angiotensin II/AT1 receptor axis, in this way modulating or even counteracting the negative effects of angiotensin II in blood pressure regulation and water retention. Modulation of this new axis through ACE2 activation, ADAM17 regulation or AT1 receptor internalization are some of the novel avenues and challenges that have the potential to become a target for new drug research and development for the treatment of hypertension.

Angiotensin (Ang) (1–7) is the main component of the depressor and protective arm of the renin-angiotensin system. Ang-(1–7) induces vasodilation, natriuresis and diuresis, cardioprotection, inhibits angiogenesis and cell growth and opposes the pressor, proliferative, profibrotic, and prothrombotic actions mediated by Ang II. Centrally, Ang-(1–7) induces changes in mean arterial pressure and this effect may be linked with its inhibitory neuromodulatory action on norepinephrine neurotransmission. The present review is focused on the role of Ang-(1–7) as a protective agent in the brain.

The renin–angiotensin system (RAS) is a key component of cardiovascular physiology and homeostasis due to its influence on the regulation of electrolyte balance, blood pressure, vascular tone and cardiovascular remodeling. Deregulation of this system contributes significantly to the pathophysiology of cardiovascular and renal diseases. Numerous studies have generated new perspectives about a noncanonical and protective RAS pathway that counteracts the proliferative and hypertensive effects of the classical angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/angiotensin type 1 receptor (AT1R) axis. The key components of this pathway are ACE2 and its products, Ang-(1-7) and Ang-(1-9). These two vasoactive peptides act through the Mas receptor (MasR) and AT2R, respectively. The ACE2/Ang-(1-7)/MasR and ACE2/Ang-(1-9)/AT2R axes have opposite effects to those of the ACE/Ang II/AT1R axis, such as decreased proliferation and cardiovascular remodeling, increased production of nitric oxide and vasodilation. A novel peptide from the noncanonical pathway, alamandine, was recently identified in rats, mice and humans. This heptapeptide is generated by catalytic action of ACE2 on Ang A or through a decarboxylation reaction on Ang-(1-7). Alamandine produces the same effects as Ang-(1-7), such as vasodilation and prevention of fibrosis, by interacting with Mas-related GPCR, member D (MrgD). In this article, we review the key roles of ACE2 and the vasoactive peptides Ang-(1-7), Ang-(1-9) and alamandine as counter-regulators of the ACE–Ang II axis as well as the biological properties that allow them to regulate blood pressure and cardiovascular and renal remodeling.