Hypertension and hypercholesterolemia are independent risk factors for atherosclerotic cardiovascular disease (ASCVD) by acting directly on the endothelium and activating the renin-angiotensin ...aldosterone system (RAAS) and mevalonate pathways. This review examines how the severity and duration of these risk factors may influence the cardiovascular risk through a reciprocal interplay leading to oxidative stress and pro-inflammatory response.
The review highlights the clinical evidence supporting the benefits of statins and angiotensin-converting enzyme (ACE) inhibitors for hypertension, lipid disorders and ASCVD management, both individually and combined, at all stages of the cardiovascular continuum.
Drug strategies incorporating an ACE-inhibitor and a statin, and in particular perindopril and atorvastatin, have consistently demonstrated reductions in the rate of ASCVD events in patients with hypertension and lipid disorders, cementing their position as first-line therapies for the management of atherosclerosis complications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic ...tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.
Despite a similar beneficial effect on blood pressure lowering observed with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor (AT1R) blocker (ARBs), several ...clinical trials and meta-analyses have reported higher cardiovascular mortality and lower protection against myocardial infarction with ARBs when compared with ACEIs. The European guidelines for the management of coronary syndromes and European guidelines on diabetes recommend using ARBs in patients who are intolerant to ACEIs. We reviewed the main pharmacological differences between ACEIs and ARBs, which could provide insights into the differences in the cardiac protection offered by these 2 drug classes. The effect of ACEIs on the tissue and plasma levels of bradykinin and on nitric oxide production and bioavailability is specific to the mechanism of action of ACEIs; it could account for the different effects of ACEIs and ARBs on endothelial function, atherogenesis, and fibrinolysis. Moreover, chronic blockade of AT1 receptors by ARBs induces a significant and permanent increase in plasma angiotensin II and an overstimulation of its still available receptors. In animal models, AT4 receptors have vasoconstrictive, proliferative, and inflammatory effects. Moreover, in models with kidney damage, atherosclerosis, and/or senescence, activation of AT2 receptors could have deleterious fibrotic, vasoconstrictive, and hypertrophic effects and seems prudent and reasonable to reserve the use of ARBs for patients who have presented intolerance to ACE inhibitors.
Abstract
Obstructive disease of the epicardial coronary arteries is the main cause of angina. However, a number of patients with anginal symptoms have normal coronaries or non-obstructive coronary ...artery disease (CAD) despite electrocardiographic evidence of ischaemia during stress testing. In addition to limited microvascular vasodilator capacity, the coronary microcirculation of these patients is particularly sensitive to vasoconstrictor stimuli, in a condition known as microvascular angina. This review briefly summarizes the determinants and control of coronary blood flow (CBF) and myocardial perfusion. It subsequently analyses the mechanisms responsible for transient myocardial ischaemia: obstructive CAD, coronary spasm and coronary microvascular dysfunction in the absence of epicardial coronary lesions, and variable combinations of structural anomalies, impaired endothelium-dependent and/or -independent vasodilation, and enhanced perception of pain. Lastly, we exemplify mechanism of angina during tachycardia. Distal to a coronary stenosis, coronary dilator reserve is already recruited and can be nearly exhausted at rest distal to a severe stenosis. Increased heart rate reduces the duration of diastole and thus CBF when metabolic vasodilation is no longer able to increase CBF. The increase in myocardial oxygen consumption and resulting metabolic vasodilation in adjacent myocardium without stenotic coronary arteries further acts to divert blood flow away from the post-stenotic coronary vascular bed through collaterals.
Increasing evidence shows that hypertension, which causes damage to small and large cerebral vessels, is the most important, modifiable, vascular risk factor for the development and progression of ...cognitive decline and dementia.11 Hypertension is, therefore, a major cause of coronary heart disease, stroke, arrhythmias, heart failure, renal disease, and dementia. Since the 1980s, mortality rates related to stroke and coronary heart disease have decreased in industrialised countries, partly because of improved blood pressure control. In summary, in terms of epidemiological transition, causes of cardiovascular death have clearly evolved over the past three decades: end-stage cardiovascular disease (atrial fibrillation, renal disease, dementia, and heart failure) is becoming more frequent than coronary heart disease and stroke. Because hypertension is the most prevalent cardiovascular risk factor for all these diseases, modification of antihypertensive strategies could have a considerable effect in delaying these degenerative diseases, thus further improving life expectancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Cerebrovascular impairment is frequent in patients with Alzheimer disease and is believed to influence clinical manifestation and severity of the disease. Cardiovascular risk factors, especially ...hypertension, have been associated with higher risk of developing Alzheimer disease. To investigate the mechanisms underlying the hypertension, Alzheimer disease cross talk, we established a mouse model of dual pathology by infusing hypertensive doses of angiotensin II into transgenic APPPS1 mice overexpressing mutated human amyloid precursor and presenilin 1 proteins. At 4.5 months, at the early stage of disease progression, only hypertensive APPPS1 mice presented impairment of temporal order memory performance in the episodic-like memory task. This cognitive deficit was associated with an increased number of cortical amyloid deposits (223±5 versus 207±5 plaques/mm; P<0.05) and a 2-fold increase in soluble amyloid levels in the brain and in plasma. Hypertensive APPPS1 mice presented several cerebrovascular alterations, including a 25% reduction in cerebral microvessel density and a 30% to 40% increase in cerebral vascular amyloid deposits, as well as a decrease in vascular endothelial growth factor A expression in the brain, compared with normotensive APPPS1 mice. Moreover, the brain levels of nitric oxide synthase 1 and 3 and the nitrite/nitrate levels were reduced in hypertensive APPPS1 mice (by 49%, 34%, and 33%, respectively, compared with wild-type mice; P<0.05). Our results indicate that hypertension accelerates the development of Alzheimer disease–related structural and functional alterations, partially through cerebral vasculature impairment and reduced nitric oxide production.
A chronic and gradual increase in pulse pressure (PP) is associated with cognitive decline and dementia in older individuals, but the mechanisms remain ill-defined. We hypothesized that a chronic ...elevation of PP would cause brain microvascular endothelial mechanical stress, damage the neurovascular unit, and ultimately induce cognitive impairment in mice, potentially contributing to the progression of vascular dementia and Alzheimer disease. To test our hypothesis, male control wild-type mice and Alzheimer disease model APP/PS1 (amyloid precursor protein/presenilin 1) mice were exposed to a transverse aortic constriction for 6 weeks, creating a PP overload in the right carotid (ipsilateral). We show that the transverse aortic constriction procedure associated with high PP induces a cascade of vascular damages in the ipsilateral parenchymal microcirculationin wild-type mice, it impairs endothelial dilatory and blood brain barrier functions and causes microbleeds, a reduction in microvascular density, microvascular cell death by apoptosis, leading to severe hypoperfusion and parenchymal cell senescence. These damages were associated with brain inflammation and a significant reduction in learning and spatial memories. In APP/PS1 mice, that endogenously display severe cerebral vascular dysfunctions, microbleeds, parenchymal inflammation and cognitive dysfunction, transverse aortic constriction–induced high PP further aggravates cerebrovascular damage, Aβ (beta-amyloid) accumulation, and prevents learning. Our study, therefore, demonstrates that brain microvessels are vulnerable to a high PP and mechanical stress associated with transverse aortic constriction, promoting severe vascular dysfunction, disruption of the neurovascular unit, and cognitive decline. Hence, chronic elevated amplitude of the PP could contribute to the development and progression of vascular dementia including Alzheimer disease.
Hypertension is a multifactorial systemic chronic disorder through functional and structural macrovascular and microvascular alterations. Macrovascular alterations are featured by arterial ...stiffening, disturbed wave reflection and altered central to peripheral pulse pressure amplification. Microvascular alterations, including altered wall-to-lumen ratio of larger arterioles, vasomotor tone abnormalities and network rarefaction, lead to disturbed tissue perfusion and susceptibility to ischemia. Central arterial stiffness and microvascular alterations are common denominators of organ damages. Vascular alterations are intercorrelated, amplifying the haemodynamic load and causing further damage in the arterial network. A plausible precursor role of vascular alterations in incident hypertension provides new insights for preventive and therapeutic strategies targeting macro and microvasculature. Cumulative metabolic burden and oxidative stress lead to chronic endothelial injury, promoting structural and functional vascular alterations, especially in the microvascular network. Pathophysiology of hypertension may then be revisited, based on both macrovascular and microvascular alterations, with a precursor role of endothelial dysfunction for the latter.
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