The key role of microvascular structure assessment in treated hypertensive patients

Hypertension-related end-organ damage results from blood pressure load and neurohormonal activation and it is mainly a consequence of the vascular injury that takes place in hypertension [1]. This includes the development of atherosclerosis as well as the changes in the structure and function of large and small resistance arteries [2]. Remodeling of resistance arteries may play an important role in the development of hypertension, and may also contribute to the pathogenesis of its cardiovascular complications. Essential hypertension is characterized by increased total peripheral vascular resistance to blood flow, which occurs generally as a result of energy dissipation in small resistance arteries and arterioles (with a lumen diameter of 100–300 μm), particularly in younger individuals, whereas late in life large artery stiffening results in raised SBP. Chronically elevated blood pressure and stretch initiate complex signal transduction cascades leading to vascular remodeling and contributing not only to blood pressure elevation but also to hypertensive complications [3]. In hypertension, resistance arteries undergo vascular remodeling (reduced vascular lumen with increased media thickness) that may be functional, mechanical and structural [2]. This may occur without any significant change of the total amount of wall tissue (inward eutrophic remodeling) [4]. Eutrophic vascular remodeling generally occurs in mild-to-moderate hypertension. In eutrophic vascular remodeling, there is no true hypertrophy, as the outer diameter and the lumen are reduced and the media cross-section does not increase [2,5]. It is believed that myogenic tone (the intrinsic ability of vessels to constrict in response to an increase in intraluminal pressure) may contribute to the structural alterations within the arterial wall [6]. With chronic vasoconstriction, the remodeled extracellular matrix may prevent vessels from returning to their vasodilated state [2,6]. However, if the myogenic reflex is dysfunctional or hypertension is longstanding or severe, autoregulatory mechanisms are overwhelmed and blood vessels develop real hypertrophy in response to the increased wall stress [2]. This type of vascular remodeling is characterized by an increased media cross-section. Although both eutrophic and hypertrophic remodeling may occur in the same subject in different vascular beds, hypertrophic remodeling of resistance arteries is more prevalent in diabetic individuals [7,8] and renovascular hypertension [9]. Currently, the most reliable method of direct evaluation of the microvascular structure is the measurement of the media-to-lumen ratio by the micromyography technique [10,11]. Increased media-to-lumen ratio is the most reproducible parameter for comparison of small arteries within single subjects studied repeatedly and between individuals [2,5]. Increased media-to-lumen ratio of resistance arteries is the most prevalent and possibly the earliest alteration that occurs in the cardiovascular system of hypertensive patients [12], and may precede endothelial dysfunction. Moreover, this parameter is associated with increased prevalence of cardiovascular events, particularly in high-risk patients [13]. Although there is no direct evidence in terms of reduction of cardiovascular events, the correction of the abnormal structure of resistance arteries in essential hypertension may be an important treatment goal in addition to blood pressure reduction. The invasiveness of micromyography may limit its applicability to large populations, although this technique is minimally invasive [14]. Therefore, a noninvasive approach for investigation of the microcirculation would represent a major advancement in the risk stratification of hypertensive patients. It has been shown that regional minimal vascular resistances are elevated in hypertensive patients as compared with normotensive individuals [15–20] under conditions of maximal vasodilatation. In these conditions, muscle tone is eliminated and diameter is determined merely by the structure of the vessels. This suggests narrowing of the resistance arteries and a stiffening of vessel wall. Thus, measurement of minimal vascular resistance (mean blood pressure divided by maximal postischemic blood flow) has been used as an indirect index for the evaluation of structural alterations in resistance arteries in a number of studies in humans. It has been shown that the forearm minimal vascular resistance is related to media-to-lumen ratio of small resistance vessels directly measured by micromyography [21], suggesting that direct and indirect evaluations of vascular morphology may provide similar results. The indexes of microvascular structure are static parameters that reflect the intrinsic structural alterations that occur in the wall of resistance arteries in hypertensive patients. These indexes are not influenced by the circadian variation of blood pressure both in physiological and pathological conditions. The study from Eftekhari et al.[22] published in the current issue of the Journal of Hypertension provides evidence that changes in systemic vascular resistance index (SVRI) during long-term antihypertensive therapy are not associated with changes in microvascular structure, assessed as forearm minimal vascular resistance, in a cohort of hypertensive patients treated with antihypertensive drugs including calcium channel blockers and renin–angiotensin–system (RAS) blockers. SVRI represents the average of resting resistance in all vascular beds, which is determined by the variation in vascular structure and function of resistance arteries. Moreover, this parameter reflects the variation in blood pressure, cardiac output and heart rate as well [23]. In the study by Eftekhari et al., a dissociation between blood pressure and forearm minimal vascular resistance changes was also observed, suggesting that the reduction of blood pressure alone does not explain the structural changes of resistance arteries occurring during treatment. Thus, variations in SVRI and blood pressure cannot predict any modification in resistance arteries structure after antihypertensive treatment. The direct measurement of microvascular structure is, therefore, necessary in order to determine whether the prognostically important parameters of vascular remodeling are improved after antihypertensive treatment, independent of the blood pressure reduction. This further strengthens the evidence that the correction of forearm resistance artery structure obtained with antihypertensive treatment depends on the vasodilatation achieved rather than on the blood pressure reduction ‘per se[24]. Indeed the abnormal small artery structure is reversed mainly by drugs that evoke vasodilatation [25,26], particularly the RAS blockers, which also antagonize the effects of angiotensin II and aldosterone on vascular remodeling [27,28]. Hence, change in blood pressure appears a poor indicator of change in resistance vessel structure, and the correction of the abnormal structure of resistance arteries may be an important treatment goal in essential hypertension in addition to blood pressure reduction. Reduced coronary flow reserve and vasodilator capacity has been observed in essential hypertensive patients. This is possibly due to the microangiopathy of small coronary vessels. An important finding of the prospective cohort study from Eftekhari et al.[22] is that structural changes in the forearm and coronary circulation produced by antihypertensive treatment occur in parallel. This further extends the evidence of the association between impaired small artery structure in the forearm and coronary circulation as well as the relationship between subcutaneous small artery structure and coronary flow reserve or vasodilator capacity in patients with essential hypertension [29,30]. Remodeling of small resistance arteries of the heart may play an important role in the reduction of coronary vasodilator capacity in patients with mild-to-moderate essential hypertension. As the structural changes of resistance arteries are homogeneously distributed along the cardiovascular system, the study of the remodeling of peripheral resistance arteries can offer important information on the structural, and possibly functional, modifications in the coronary circulation in hypertensive patients. In conclusion, the study by Eftekhari et al. [22] further underlines the pivotal role of resistance arteries structure alteration in the pathophysiology of hypertension and in the development of target-organ damage. Moreover, this study highlights the potential utility of the direct assessment of the parameters of vascular remodeling in the follow-up of hypertensive patients on antihypertensive treatment. It should be stressed, however, that the approach used by Eftekhari et al. in the present study is not free of limitations. Indeed, a noninvasive and easily repeatable procedure such as the forearm minimal vascular resistance does not allow the evaluation of important parameters of vascular remodeling (such as the ones distinguishing between eutrophic and hypertrophic remodeling), which also impacts on the cardiovascular prognosis. Furthermore, the sensitivity and specificity of this noninvasive technique needs to be further elucidated in large clinical interventional studies. Finally, the limited sample size of the study itself may represent a factor that does not allow generalizing the study findings to the different groups of hypertensive patients. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.