Subcutaneous resistive arteries and coronary conductance

Arterial hypertension affects the heart through a variety of pathologies, including development of (a)symmetrical left ventricular hypertrophy (LVH), interstitial and perivascular fibrosis with diastolic dysfunction, left ventricular enlargement with systolic dysfunction and potential arrhythmias, endothelial dysfunction [1,2], stenoses of epicardial arteries and/or coronary microangiopathy [3–5]. All these mechanisms may reduce an adequate ratio of coronary blood flow to oxygen demand of myocardium causing angina, dyspnoea and major cardiac events [6]. The increase in coronary vascular resistance may be attributed to functional and morphological alterations in the resistive arteries [6,7]. In patients with hypertension and LVH coronary flow reserve (CFR) is reduced. This reduction in CFR has been attributed primarily to an increase in minimal coronary resistance because of structural changes of intramural coronary arteries. The latter typically show an increased perivascular fibrosis and massive medial hypertrophy, resulting in an increase in the ratio of the wall thickness to the luminal diameter in arterial hypertension. This process of vascular remodelling is fundamental to hypertension. In this issue of the journal, Rizzoni et al. [8] address the interesting concept that remodelling of resistance arteries is a generalized process in patients with hypertension, and suggest that remodelling of subcutaneous resistance vessels may reflect coronary remodelling. In 20 hypertensive individuals, coronary vasodilator capacity was estimated by transesophageal echocardiography after intravenous infusion of adenosine and, in parallel, quantitative histology was performed in resistive arteries obtained from a subcutaneous gluteal biopsy specimen. With increasing media : lumen ratio in the subcutaneous resistive vessels, the coronary vasodilator capacity decreased. Consequently, the coronary vascular resistance was positively correlated to the media : lumen ratio. The authors concluded that these findings were in line with the hypothesis of a generalized remodelling of resistive arteries throughout the body, and that the remodelling may play an important role in the reduction of coronary vasodilator capacity in patients with mild-to-moderate essential hypertension. Apart from these structural alterations of the vascular wall, other extravascular mechanisms, including increased left ventricular cavity pressure and wall stress, and increased perivascular fibrosis, may contribute to the reduced coronary vasodilator capacity [9]. In addition to these morphological changes associated with arterial hypertension, functional alterations may occur, which further deteriorate coronary conductance, such as endothelial dysfunction or a reduced expression or sensitivity of vasodilating signaling cascades in the vascular smooth muscle. These potential mechanisms comprise an increased oxidative stress, a decreased formation of nitric oxide, an impaired expression of guanylate cyclase or an altered sympathetic responsiveness of vascular smooth muscle and endothelium [10]. Although these issues were not addressed in the present study, they are likely to explain a signifcant degree of the variation between the measured coronary vasodilator capacity and the remodelling of subcutaneous resistive arteries, which is mirrored by a rather weak coefficient of correlation between these two parameters (r = 0.63). In other words, only 39% (r2) of the variation in coronary vasodilator reserve is explained by variations in remodelling indices of subcutaneous resistive arteries. Given these data, it is noteworthy to consider that functional alterations of the vascular wall, such as endothelial dysfunction, might occur also systemically, both affecting conductance and resistive arteries in systemic and coronary circulation [10,11]. Additionally, functional disturbances have been shown to precede morphological changes in the vascular wall and may trigger the development of vascular remodelling [12]. Another methodological aspect is related to the intravenous administration of adenosine. The resulting changes in systemic hemodynamics (heart rate and blood pressure) may affect the exact determination of coronary flow reserve. There is a high degree of variability of CFR under the influence of hemodynamic changes. This is particularly relevant because the epicardial coronary diameter may also change with varying systemic hemodynamics. In this case, the assessment of CFR by transesophageal Doppler flow velocity without reliable determination of epicardial cross-sectional area and thus assessment of volumetric blood flow would not be accurate. If the epicardial cross-sectional area changes between baseline and hyperemic measurements, flow velocity may be a pure indicator of volumetric flow. To circumvene these obstacles, the authors additionally estimated the minimal coronary resistance. In line with the hypothesis of a generalized impairment of vasodilator capacity, which in part may be explained by structural changes, the relation to changes in media : lumen ratio remained significant. Another interesting finding of the present study is that the coronary vasodilator capacity was not affected by the degree and the type of LVH. In a recent report it has been shown that the type of left ventricular remodelling (eccentric versus concentric) affects the coronary flow reserve in patients with more severe LVH [13]. In the present study by Rizzoni et al. [8], the lack of a significant impact of LVH on the coronary vasodilator capacity might be explained by the limited number of patients studied and the unbalanced distribution of individuals with and without LVH. What are the implications for clinical practice? Two important messages can be derived from this study. First, transesophageal echocardiography enables disturbances of coronary vasodilator capacity to be unmasked, even in those patients with only mild-to-moderate essential hypertension. Although it obviously does not reach the accuracy of invasive procedures, such as the Doppler flow measurements or the argon-dilution methods [14], this technique may be adequate to qualitatively assess disturbances of coronary conductance using a non-invasive approach and to relate these findings to functional stress tests and the patient's history. Second, as expected, remodelling of resistive vessels appears to be a systemic phenomenon in arterial hypertension. However, the impact of these morphological changes on vascular function (e.g. conductance capacity) may vary considerably in different vascular beds throughout the body.