Vascular remodeling is classified as hypertrophic, eutrophic, or hypotrophic ^[1][2][9,10]. Remodeling can also be inward (reduced luminal diameter) or outward (increased luminal diameter) ^[1][9]. Inward remodeling is the most common type of vascular remodeling in hypertension (HTN), causing a reduction in the luminal diameter under passive conditions, and outward remodeling is generally seen during antihypertensive treatment ^[1][9].

Increased peripheral resistance, predominantly observed in small blood vessels, is one of the most distinctive features of HTN. The functional and structural alterations of small resistance vessels that occur either before or as a result of chronically elevated BP in their turn intensify the effects of vasoconstrictors (ex. of the renin–angiotensin–aldosterone system, RAAS) ^[3][11]. In HTN, increased peripheral resistance is because of structural rather than functional changes in the resistance vasculature. This was first demonstrated in the 1950s by the work of Folkow, and was later supported by animal studies, which suggested that the morphological changes seen in HTN are similar in different vascular beds ^[2][4][5][10,12,13].

Classically, there are two distinct components of BP: mean arterial pressure (MAP) and pulse pressure (PP) ^[6][14]. MAP reflects a steady pressure, related to vascular resistance and hence small arteries, whereas PP reflects a pulsatile pressure, which has three determinants, stroke volume, arterial stiffness and wave reflections ^[6][14]. Arterial stiffening is defined as resistance to deformation or a loss of elastic compliance due to changes in the geometry and microstructure of the vascular wall ^[7][15].

Arterial stiffness, as well as wave reflections, have continued to be a focus of investigations in HTN since the 1970s ^[3][11]. In clinical studies and animal models, it was clearly demonstrated that in addition to increased vascular resistance, vascular elasticity was also consistently impaired in HTN, thus indicating the presence of increased stiffness in large artery walls ^[3][8][11,16]. It is well known that arterial stiffness is one of the earliest features of adverse structural and functional changes within the arterial wall, and is recognized as an independent predictor of cardiovascular (CV) mortality in patients with essential HTN ^[9][10][17,18]. Notably, in recent years, findings from animal- and population-based studies support the notion that arterial stiffness may be not only a complication of HTN, but also a risk factor for the development of high blood pressure ^[11][5].

The mechanical properties of large elastic blood vessels, including elasticity and the ability to store energy during deformation, which is essential for peripheral perfusion during diastole, are altered and reduced by vascular wall stiffening, leading to an increase in cardiac afterload ^[7][12][15,19]. Additionally, the increased forward propagation of pulsatile waves transmits pressure oscillations to end-organs, which fosters damage to the microcirculation and promote CV morbidity and mortality ^[7][15].

Myocardial ischemia in HHD can be induced by a variety of factors, relates to the degree of increase in left ventricular (LV) mass and has important clinical implications ^[13][6]. At the beginning of the development of HHD, coronary flow may be increased because of higher BP, greater LV end-systolic stress, and LV hypertrophy (LVH). On the one hand, the presence of LVH could be associated with decreased vascular density, which seems to result from inadequate angiogenesis. The direct compression of the endocardial capillaries can result as a response to the increasing muscle mass ^[13][14][6,20]. Breisch and colleagues studied the effects of pressure overload hypertrophy in the LV myocardium at different times after constriction of the aorta in adult cats, and found that the capillary density and coronary reserve decreased with the increasing extent of hypertrophy. The authors assumed that such alterations in flow reserve and capillary density might play an important role in the transition from a compensated to a failing heart ^[13][15][6,21]. Tomanek et al. also showed that late-onset HTN in middle-aged and senescent rats is characterized by microvascular alterations, including decrements in numerical density and the inadequate growth of capillaries that reflect an absolute reduction in the number of these vessels in the context of the presence of cardiocyte hypertrophy ^[16][22]. There is an assumption that alterations in pericytes, which surround capillary endothelial cells, may also contribute to the paucity of microvessels in HHD ^[14][20]. On the other hand, increased perivascular fibrosis is accompanied by an increase in oxygen diffusion distance, leading to the impairment of oxygen supply to cardiomyocytes ^[14][17][18][7,20,23]. Of note, impaired endothelium-mediated dilation, first of all of the resistance coronary arteries, may play an important role in abnormal coronary blood flow regulation, even in early stages of coronary atherosclerosis, which is commonly encountered in HTN ^[10][18], and could lead to chronic subendocardial ischemia and impaired myocardial mechanical function ^[12][19][19,24]. The presence of ongoing cardiac ischemia may also explain the increased CV risk, including the increased incidence of atrial fibrillation, ventricular arrhythmias, myocardial infarction and sudden cardiac death, attributed to HHD ^[20][21][2,25].

Currently, no widely available technique allows for the direct visualization of the coronary microvasculature in vivo in humans ^[14][20]. The function of coronary microcirculation can be indirectly assessed using coronary flow reserve (CFR) in response to various vasoactive stimuli. CFR is an integrated measure of flow through both the large epicardial arteries and the coronary microcirculation. In the absence of an obstructive stenosis of the epicardial arteries, reduced CFR is considered to be a biomarker for coronary microvascular dysfunction ^[14][18][20,23], and could possibly help to explain the phenomena of silent ischemia, chest pain, and coronary insufficiency in HHD, especially without angiographic signs of coronary stenosis ^[10][22][18,26].

It should be noted that in hypertensive animal models and patients with HHD and LVH, perivascular fibrosis together with endothelial dysfunction may contribute to impaired CFR by the external compression of intramural coronary arteries ^[14][20]. However, interestingly, Vancheri FT et al. indicated that the impairment of CFR in hypertensive patients is independent of the presence and degree of LVH ^[19][24]. Reduced diastolic myocardial perfusion pressure because of increased arterial stiffness also contributes to CFR impairment in hypertensives. Additionally, perivascular fibrosis has been shown to be inversely correlated with CFR in heart failure (HF) ^[18][23][23,27]. Several observations have found early alterations in CFR and LV diastolic function in arterial HTN, including borderline HTN, even before the development of LVH ^[22][26]. On the other hand some studies in experimental models of HTN as well as in hypertensive patients came to the conclusion that resting coronary blood flow may—even in the presence of LVH—be normal ^[22][26].

A new index of the coronary vasodilatory capacity—the microvascular resistance reserve (MRR)—is now recommended ^[24][28]. It was introduced to characterize the vasodilator reserve capacity of the coronary microcirculation while accounting for the influence of concomitant epicardial disease and the impact of vasodilators administration on aortic pressure ^[24][28]. Boerhout and colleagues concluded, with reference to the global ILIAS (Inclusive Invasive Physiological Assessment in Angina Syndromes) Registry data, that MRR is a robust indicator of the microvascular vasodilator reserve capacity, and is significantly associated with major adverse cardiac events (MACE) at 5-year follow-up in vessels with functionally significant epicardial disease ^[25][29].

Recent studies using the positron emission tomography (PET)-derived flow/mass ratio showed the prevalence of coronary microvascular dysfunction in the absence of obstructive epicardial coronary artery disease in HTN and HF with preserved ejection fraction (HFpEF) ^[26][27][30,31]. The authors of this researchtudy concluded that subendocardial ischemia is one of the central pathways in HFpEF pathogenesis, and that higher troponin levels at rest and during exercise, in combination with coronary microvascular dysfunction, serve as identification criteria for patients with HFpEF at especially high risk for adverse CV outcomes ^[26][30]. Thus, the inability of myocardial perfusion to meet the myocardial oxygen demand may be a potential explanation of adverse CV outcomes in patients lacking angiographically confirmed obstructive coronary artery disease, in particular in pathological patterns of LV remodeling ^[26][30].

It is considered that the progression from initial changes in HHD to hypertensive HF cannot be explained only by the myocardial response to elevated BP; both coronary and peripheral vasculopathies are assumed to play an essential role ^[19][24]. However, the full extent of their contribution to this process is still uncertain. In addition to the hemodynamic effects of chronically elevated BP on LV wall stress, cardiomyocyte hypertrophy and coronary artery stiffening, as well as non-hemodynamic and cardiometabolic factors, may contribute significantly to the impaired myocardial perfusion and resultant HHD development ^[26][30]. Future investigations of the coronary microvascularisation should include the mechanisms by which ventricular perfusion adapts to meet the functional demands imposed by the hypertensive ventricle, and can facilitate risk assessment in HHD ^[26][30].

The evaluation of pulmonary vascular remodeling, including increased arterial wall thickness and alveolar wall remodeling, in chronic HTN and HF has received considerable attention in the last decade ^[28][32]. The sustained elevation of pulmonary capillary pressure, resulting from recurrent retrograde increases in LV enddiastolic filling pressure in patients with chronic HF, affects the capillary diffusion efficiency and associated gas exchange ^[29][33]. Additionally, as a result of the increased activation of neurohumoral mediators leading to myofibroblast proliferation with collagen and interstitial matrix deposition, excessive alveolar wall thickening is responsible for the development of a restrictive lung syndrome. As result, compliance is reduced and gas exchange impaired, contributing to shortness of breath and pulmonary hypertension (PH) in HF patients ^[29][30][31][33,34,35]. Furthermore, hypoxia promotes vasoconstriction in the pulmonary circuit and tachyarrhythmias, particularly atrial fibrillation, which may precipitate PH in patients with HF ^[32][36]. Over time, pulmonary arteriolar remodeling mainly contributes to the increase in pulmonary vascular resistance and reduced pulmonary artery compliance ^[32][36].

Farrero et al. showed that, in adult patients with HFpEF and hypertensive controls, endothelial dysfunction and abnormal collagen metabolism can be characterized as PH risk markers ^[33][37].

Despite significant recent developments in our understanding of the pathophysiology of PH associated with hypertensive HF, important evidence gaps remain as regards the targeting of an ideal approach to the management of hypertensive and HF patients developing PH.

Over the past few years, arterial stiffness and wave reflections have been widely investigated in hypertensive subjects. It was shown that not only systolic BP and diastolic BP, but also PP is an independent marker of CV risk in hypertensive subjects, especially those with recurrent myocardial infarction and congestive HF ^[34][38].

Observational studies have shown that the extent of arterial remodeling is linked to clinical outcomes ^[11][5]. As a prominent example, in the Framingham Heart Study (FHS), greater arterial stiffness (assessed by carotid-femoral pulse wave velocity, PWV) was associated with increased risk of a first CV event ^[35][39]. Similarly, a recent meta-analysis of 17,635 participants showed that aortic stiffness, assessed by measurement of aortic PWV, was associated with a 30% higher risk of cardiovascular diseases (CVD), and predicts future CV events and mortality, even after accounting for other established CV risk factors ^[11][36][5,40]. In the population-based Rotterdam Study, it was found that among apparently healthy normotensive subjects, arterial stiffness independently predicts stroke and coronary heart disease ^[37][41]. Long-term longitudinal studies have shown that elevated PP leads to an approximately two-fold increase in CV risk, whereas MAP represents a significantly lower component ^[38][39][42,43]. Aortic PP is considered as a more reliable parameter for the evaluation of CV risk than brachial PP ^[3][11].

Blacher J et al. showed, based on the pooled results of three placebo-controlled trials in elderly patients with HNT (the European Working Party on High Blood Pressure in the Elderly trial (EWPHE), the Systolic Hypertension in Europe Trial (Syst-Eur), and the Systolic Hypertension in China Trial (Syst-China)), that increased PP, but not MAP, is a powerful predictor of CV risk in older hypertensive patients ^[39][43].

Humans and hypertensive animal models studies, as well as epidemiological studies, have shown that both small and large arteries are primary targets for antihypertensive therapy ^[3][40][41][11,44,45]. Studies investigating the effects of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, and selective aldosterone antagonists have concluded that BP reduction alone causes the regression of aortic wall hypertrophy, whereas the aortic collagen content is affected by factors that are independent of BP lowering ^[3][40][11,44]. In addition, AT1 or mineralocorticoid receptor blockade against the background of a low-sodium diet also reduced wall stiffness, independently of changes in BP ^[3][40][41][11,44,45].

The REASON project (preterax in regression of arterial stiffness in a controlled double-blind study), a multicenter, randomized, double-blind, two-parallel-group study, which included 471 adult hypertensive patients, showed that a combination therapy with perindopril plus indapamide improved arterial stiffness and reduced PP amplification, whereas atenolol reduced heart rate, but did not affect PWV ^[42][46]. Additionally, the CAFE (Conduit Artery Function Evaluation) study confirmed the superiority of a stable amlodipine ± perindopril regimen over atenolol ± thiazide-based treatment in lowering central aortic pressure in hypertensives, and underlined the importance of central aortic PP in terms of clinical outcomes ^[43][47]. However, a meta-analysis of individual data from seven short-term (less than 4 weeks) and nine long-term (4 weeks and more), double-blind, randomized therapeutic trials, conducted by Ong KT et al., showed that in long-term trials, ACE inhibitors, calcium antagonists, β-blockers, and diuretics all significantly reduced arterial stiffness beyond BP reduction in essential hypertensive patients, whereas in short-term studies, the decrease in arterial stiffness was less under calcium channel blockers (CCB) treatment than under ACE inhibitors ^[44][48].

The interesting effects of sacubitril/valsartan compared with olmesartan were noted by Schmieder et al. in a double-blind, randomized study of hypertensive patients ^[45][49]. Against the background of reductions in LV mass, measured by MRI, and central pulse pressure, there was no significant difference in local distensibility between the two groups for the short-term period of follow-up (12 weeks) versus the long-term period (52 weeks) of follow-up ^[45][49].

The reversibility of arterial stiffness and wave reflections in response to drug treatment raises many questions related to the CV risk reduction and the treatment of HTN. Improvements in both, beyond lowering blood pressure, would be a promising aspect of further risk reduction in the treatment of hypertensive patients, and should be a focus of further research.