Improvement of the coronary microcirculation: a desirable goal helping to reduce the incidence of coronary events




Bernard I. LÉVY, MD, PhD
PARCC, INSERM U970 Lariboisière Hospital
75010 Paris, FRANCE

Improvement of the coronary microcirculation: a desirable goal helping to reduce the incidence of coronary events
by B. I . Lévy, France

In hypertensive patients, there is a large body of evidence suggesting the presence of severe alterations in microvascular structure and function that are mainly characterized by capillary rarefaction, endothelial dysfunction, and decreased vasodilation reserve. Abnormal microcirculation contributes to the impairment of tissue perfusion and, thus, to end organ damage. Reversal and prevention of microvascular damage are thus potentially important clinical goals. Cutaneous circulation has emerged as an accessible and representative vascular bed that could enable the study of the mechanisms of microcirculatory function and dysfunction. Increased skin capillary density and cutaneous endothelial function have both been observed in successfully treated essential hypertensive patients compared with untreated hypertensive patients, suggesting a tight relationship between blood pressure and capillary density. Furthermore, hypertensive patients controlled on a perindopril/ indapamide combination exhibit significantly greater capillary density and endothelial response to endothelial stimulation than blood pressure–controlled patients receiving non-ACE (angiotensin-converting enzyme) inhibitor treatment. ACE inhibitors inhibit the degradation of bradykinin and contribute to the accumulation of bradykinin and nitric oxide, both of which may be beneficial to diseased hearts. Finally, ACE inhibitors are also involved in hypoxiainduced neovascularization and could participate in the protection of target organs against ischemic damage. Vascular endothelial growth factor exerts a variety of pleiotropic effects, which include an acute protective effect. The pleiotropic effects of ACE inhibitors may be related to the results of a metaanalysis that showed that, out of the 19 major hypertension trials of the last decade, only 2, ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), with amlodipine/perindopril vs atenolol/bendroflumethiazide, and ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation), with perindopril/indapamide vs placebo, demonstrated a significant reduction in coronary events as well as in cardiovascular and total mortality.

Medicographia. 2012;34:32-38 (see French abstract on page 38)

A primary function of the microcirculation is to optimize nutrient and oxygen supply within tissues in response to variations in metabolic demand. The microcirculatory bed is also the site where the earliest manifestations of cardiovascular disease—in particular, inflammatory processes— occur.

The microcirculation is widely taken to encompass vessels <150 μm in diameter, which include arterioles, capillaries, and venules. The microcirculation largely determines tissue perfusion and hemodynamic vascular resistance. The small arteries, the main site of hemodynamic peripheral resistance, are named “resistance arteries.” However, there is no universally accepted anatomical definition of these resistance vessels. A definition based on arterial vessel physiology rather than diameter or structure has therefore been proposed, depending on the response of the isolated vessel to increased internal pressure.1 According to this definition, all those arterial vessels that respond to increasing pressure by a myogenic reduction in lumen diameter are included in the microcirculation, as well as the capillaries and venules. This definition includes the smallest arteries and arterioles in the microcirculation, and is in line with recent evidence that the small arterial and arteriolar components should be considered a continuum rather than distinct sites of resistance control.

In hypertension, the structure and function of the microcirculation are altered in at least three ways.2
_ First, the mechanisms regulating vasomotor tone are abnormal, leading to enhanced vasoconstriction and/or reduced vasodilator responses.
_ Second, there may be anatomical alterations to the structure of individual precapillary resistance vessels, such as an increase in the wall-to-lumen ratio of conduit arteries and larger arterioles.
_ Finally, there may be changes at the microvascular network level, involving a reduction in the density of the smaller resistance arterioles and capillaries within the vascular beds of various tissues (eg, muscle and skin). This is called vascular rarefaction.3

In several tissues, capillary density was found to be inversely correlated with blood pressure in both hypertensive and normotensive subjects.4 While it has been known for many years that increased wall-to-lumen ratio of arteries and microvascular rarefaction can be secondary to a sustained elevation of blood pressure, there is also evidence that abnormalities in the microcirculation may precede high blood pressure, and thus may be one of its causal components. Microvascular rarefaction, similar in magnitude to the rarefaction observed in patients with established hypertension, can even be demonstrated in subjects with mild intermittent hypertension and in normotensive subjects with a genetic predisposition to high blood pressure.5 Moreover, in hypertensive subjects, capillary rarefaction in muscles was shown to be able to predict an increase in mean arterial pressure over a period of two decades (Figure 1).6 Similarly, in a prospective population-based study of normotensive middle-aged persons, a smaller retinal arteriolar diameter was shown to indicate hypertension and predict its development.7 Thus, it seems likely that microvascular abnormalities can both result from, and contribute to, hypertension, and a “vicious cycle” may exist, in which the microcirculation maintains or even amplifies an initial increase in blood pressure.

Figure 1
Figure 1. Relationship of capillary density in mm2 to the change
in mean arterial pressure (MAP) over a period of 20 years in untreated
hypertensive subjects.

After reference 6: Hedman A et al. J Hypertens. 2000;18:559-565. © 2000,
Lippincott Williams & Wilkins.

In arterial hypertension, several mechanisms reduce the formation and number of microvessels. Impaired formation of microvessels (impaired angiogenesis) and microvascular rarefaction can, on the other hand, contribute to increased peripheral resistance and raise blood pressure.

Coronary microcirculation and myocardial perfusion in hypertension

Hypertension is an established risk factor for ischemic coronary disease as well as for myocardial infarction and its complications (heart failure, rupture, sudden death, and arrhythmias). Animal and clinical studies have shown that the major conduit coronary arteries are enlarged in pressure-overloaded, hypertrophied ventricles. This enlargement is accompanied by an increase in media-to-lumen ratio (hypertrophy) and in the extracellular component of the medial wall (fibrosis). Decrease in capillary density and the resulting increase in diffusion distance have been observed in many forms of hypertrophy, especially in the subendocardium. Myocardial pO2, which reflects oxygen consumption and oxygen supply, also depends on capillary density, radius, and permeability. Under chronic overload conditions, which result in adaptive cardiac hypertrophy, the increase in capillary density with increasing oxygen consumption presumably occurs to meet the additional metabolic demand. In hypertrophied failing hearts, the decrease in relative capillary density with increasing diastolic pressure may be explained by a compression of the capillary bed due to intraventricular blood pressure. In the normal and hypertrophied myocardium, there is a strong relationship between the intercapillary distance and the pO2 and pH of the interstitial tissue (Figure 2).

In most tissues, especially in the myocardium, the maximum distance for oxygen diffusion does not exceed 100 μm.8,9 Thus, capillary rarefaction may contribute to both altered tissue perfusion and altered oxygen supply to the myocardial cells.

Figure 2
Figure 2. Mean interstitial pH and pO2 as a function of the distance to the nearest blood vessel.

Abbreviations: DBP, diastolic blood pressure; SBP, systolic
blood pressure.
After reference 8: Helmlinger et al. Nat Med. 1997;3:177- 182. © 1997, Nature Publishing Group.

Although total flow may be elevated, the flow per gram of myocardium in the hypertrophied ventricle is generally normal at rest. However, relative subendocardial hypoperfusion may occur in hypertrophied ventricles. Even before the onset of the severe stage of hypertrophy, transmural distribution of flow in response to stress may be abnormal and can manifest as an abnormally low increase in subendocardial blood flow. Furthermore, when cardiac work increases (during exercise and all types of stress), myocardial hypoperfusion is obvious, especially in the subendocardial layers of the left ventricle. Therefore, coronary reserve is lower and minimum vascular resistance is higher in the hypertrophied myocardium.This suggests that vascular growth has not kept pace with the hypertension- related hypertrophic process.10

Finally, in the presence of hypertension and hypertrophy, autoregulation is impaired, especially in the subendocardium. The mechanism of angina in patients with hypertension with normal coronary angiograms has been linked to impaired vasodilator reserve, which is likely to be related to microvascular dysfunction and capillary rarefaction in the hypertrophic ventricle.

Microcirculation and treatment of hypertension

It is likely that the relative contributions of the macrovascular and microvascular networks will be different in different vascular beds and may vary between different forms and models of hypertension. Indeed, increased capillary density was reported in effectively treated essential hypertensive vs untreated hypertensive patients, suggesting a cause-and-effect relationship between blood pressure and capillary density.11

It is actually possible to discern a historical shift in the focus of antihypertensive therapy between these different mechanisms. Initially, antihypertensive therapy was directed mainly toward altering vasomotor tone and promoting vasodilation (with pure vasodilator drugs such as hydralazine, α-blockers, and then calcium blockers).

More recently, the focus was directed toward reducing or reversing the changes in resistance vessel structure (with the angiotensin-converting enzyme [ACE] inhibitors and the antagonists of angiotensin [Ang] II receptors), and in the last few years there has been a further evolution toward reducing or reversing microvascular network rarefaction (with the ACE inhibitors).

Antihypertensive agents that also have an effect on microvascular remodeling may thus provide significant clinical benefits. Although some classes of antihypertensive agents, such as the diuretics, are believed to have little beneficial action on the microcirculation, experimental and clinical studies suggest that others, such as the ACE inhibitors, improve microvessel structure and network density.12-15

Interestingly, addition of a blood volume– lowering agent, such as a thiazide- like diuretic, to an ACE inhibitor appears to confer additional benefits.16 Perindopril (per) and indapamide (ind) are both well-established, effective agents; the per/ind combination increased the capillary density in the ischemic tissue of spontaneously hypertensive rats and in the myocardium of stroke-prone hypertensive rats.17 In normotensive rats, the per/ind combination also induced an early and sustained effect on the postischemic revascularization process.18

The skin circulation is a unique site allowing simple, noninvasive, and reproducible assessment of capillary density and endothelial function and could be a valuable model of the overall microcirculation.19 There is evidence that capillary rarefaction in the skin may precede the clinical onset of essential hypertension, even in normotensive subjects with a familial predisposition to the disease.

Previous exploratory clinical studies showed that, in newly diagnosed patients with essential hypertension, per/ind improved coronary vasodilator reserve and myocardial blood flow.20 Similarly, coronary reserve increased after 12 months of treatment with perindopril.21

Figure 3
Figure 3. Systolic (SBP) and diastolic blood pressure (DBP) in control, treated, and untreated
hypertensive patients. Based on data from reference 27.

Capillary density and endothelial function in treated hypertensive patients

A meta-analysis has showed that the ACE inhibitors are effective in treating ischemic and nonischemic heart failure,22 making them one of the standard drugs for the treatment of heart failure as well as essential hypertension. ACE is known to produce Ang II, which can cause potent coronary and systemic vasoconstriction. Thus, Ang II may worsen the extent of ischemic and nonischemic myocardial damage. In the hypertrophied hypertensive heart, ACE inhibitors reduce left ventricular hypertrophy, attenuate myocardial fibrosis, and prevent ventricular remodeling, thus contributing to cardioprotection. ACE catalyzes the conversion of Ang I to Ang II and the breakdown of bradykinin (BK) into inactive peptides. Hence, the pharmacological effect of ACE inhibitors may be in part mediated via the inhibition of Ang II formation but also via BK accumulation. BK is generated from the action of kallikreins on their substrate, kininogen, and acts through at least two receptor subtypes, B1 and B2. The B2 receptor is constitutively expressed in various tissues and is responsible for the majority of BK effects. In contrast, B1 has a higher affinity for kinin metabolites and its expression is induced in pathological conditions. Activation of the B2 receptor leads to release of nitric oxide (NO) and prostacyclin, which modulate numerous biological functions, including vasodilation and sprouting of neocapillaries.23

In addition to mediating the generation of NO through B2-receptor activation and limiting the production of Ang II, BK also directly causes coronary vasorelaxation via B2-receptor activation.24,25 BK, which may be increased by treatment with ACE inhibitors, is reported to increase NO, endothelium-derived hyperpolarizing factor, and prostacyclin in several tissues and organs. In an experimental model of tissue ischemia, ACE inhibition with perindopril enhanced ischemia-induced angiogenesis through activation of the B2-receptor pathway. This proangiogenic effect was associated with the upregulation of endothelial nitric oxide synthase expression.26

We recently reported that hypertensive patients with blood pressure controlled with the per/ind combination exhibited normalized capillary density and endothelial function, whereas other antihypertensive treatments, excluding ACE inhibitors and diuretics, had less effect despite showing similar blood pressure control.27 A total of 193 consecutive patients were enrolled into one of four groups depending on their blood pressure and existing treatment:
_ Controlled hypertensive patients treated with per/ind (controlled- per/ind).
_ Controlled hypertensive patients treated with agents other than ACE inhibitors or diuretics, ie, mostly angiotensin receptor blockers (ARBs) or β-blockers (controlled-other).
_ Uncontrolled hypertensive patients treated with agents other than ACE inhibitors or diuretics (uncontrolled-other).
_ Untreated normotensive subjects.

Capillary density was significantly greater in controlled-per/ind patients (99±12 capillaries/mm2) than in all the other groups (P<0.05). Controlled per/ind patients also showed significantly better endothelial function than patients from all the other groups (P<0.05). Although similar brachial systolic blood pressure (SBP) and diastolic blood pressure (DBP) values were obtained both in the controlled-per/ind group and the controlled- other group (Figure 3, page 35), capillary density and endothelial function were significantly improved only with per/ ind treatment (Figures 4 and 5).

Altogether, the findings of this study highlight the fact that equivalent blood pressure control is not synonymous with equivalent microvascular benefits, therefore suggesting different long-term results for end organ damage. Most of the controlled-other patients were being treated with an ARB (48%) or a β-blocker (26%). β-Blockers do not have a clear effect on the vasomotor tone of arterioles or on endothelial relaxation. Although ARBs have been shown to improve the microcirculation in some studies, several studies reported that they do not increase coronary flow reserve. The effects of per/ ind on the microcirculation are likely to be attributable to both perindopril and indapamide. As an ACE inhibitor, perindopril downregulates the renin-angiotensin system, which is expressed both systemically and in the tissues, and contributes to low-grade inflammation. Ang II stimulates the expression of nuclear transcription factor-κB, which regulates the expression of inflammatory cytokines such as interleukin-6 and monocyte chemoattractant protein–1. Thus, downregulation of Ang II synthesis through inhibition of ACE suggests a mechanism by which perindopril decreases inflammation-related damage to the microcirculation. The mechanism by which indapamide contributes to the normalization of the microcirculation, however, is less clear, although in at least one study, indapamide normalized the cross-sectional area of vessel walls and attenuated the rightward shift of the stress-strain curve in spontaneously hypertensive rats. These data are consis- tent with those recorded in animal models, where microvascular benefits of per/ind treatment were accompanied by improvements in blood pressure and cardiac hypertrophy, and with the data from REASON (PREterax in regression of Arterial Stiffness in a contrOlled double-bliNd study), the large clinical study in which 1 year of treatment with per/ind decreased brachial and central SBP and pulse pressure as well as left ventricular ejection time and aortic augmentation index.

Figure 4
Figure 4. Capillary density.

Capillary density was assessed by intravital video capillaroscopy in the skin of
the dorsum of the middle phalanx of the nondominant hand. Mean values ±
standard deviations are presented. Per/Ind, perindopril/indapamide.
After reference 27: Debbabi et al. Am J Hypertens. 2010;23:1136-1143. © 2010,
American Journal of Hypertension Ltd.

Figure 5
Figure 5. Change in endothelial function.

Cutaneous perfusion changes were evaluated on the forearm skin by laser
Doppler flowmetry and correspond to the endothelium-dependent vasodilation.
Mean values ± standard deviations are presented.
Abbreviations: HTC other, hypertension controlled with other therapy; HTC
per/ind, hypertension controlled with perindopril/indapamide; HTNC, hypertension
not controlled, NT, normotensive.
After reference 27: Debbabi et al. Am J Hypertens. 2010;23:1136-1143. © 2010,
American Journal of Hypertension Ltd.

Conclusion

The experimental, clinical, and epidemiological results reported in the present review are in favor of a paradigm shift in cardiovascular medicine, with the development of strategies aiming to identify the hypertensive patients at higher risk of ischemic end organ damage and the use of treatments able to normalize blood pressure levels, the microcirculatory network, and tissue perfusion. This could be linked to the evidence provided by a recent meta-analysis,28 which showed that only 2 out of the 19 major hypertension trials of the last decade: ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), with amlodipine/perindopril vs atenolol/bendroflumethiazide and ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation), with perindopril/ indapamide vs placebo, demonstrated a significant reduction in coronary events and cardiovascular and total mortality. _

References
1. Levy BI, Ambrosio G, Pries AR, Struijker-Boudier HA. Microcirculation in hypertension: a new target for treatment? Circulation. 2001;104:735-740.
2. Serné EH, Gans RO, ter Maaten JC, Tangelder GJ, Donker AJ, Stehouwer CD. Impaired skin capillary recruitment in essential hypertension is caused by both functional and structural capillary rarefaction. Hypertension. 2001;38:238-242.
3. Feihl F, Liaudet L, Levy BI, Waeber B. Hypertension and microvascular remodelling. Cardiovasc Res. 2008;78:274-285.
4. Serné EH, Gans RO, ter Maaten JC, ter Wee PM, Donker AJ, Stehouwer CD. Capillary recruitment is impaired in essential hypertension and relates to insulin’s metabolic and vascular actions. Cardiovasc Res. 2001;49:161-168.
5. Noon JP, Walker BR, Webb DJ, et al. Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure. J Clin Invest. 1997;99:1873-1879.
6. Hedman A, Reneland R, Lithell HO. Alterations in skeletal muscle morphology in glucose-tolerant elderly hypertensive men: relationship to development of hypertension and heart rate. J Hypertens. 2000;18:559-565.
7. Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar diameter and risk for hypertension. Ann Intern Med. 2004;140:248-255.
8. Helmlinger G, Yuan F, Dellian M, Jain RK. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med. 1997;3:177-182.
9. Batra S, Rakusan K, Campbell SE. Geometry of capillary networks in hypertrophied rat heart. Microvasc Res. 1991;41:29-40.
10. Levy BI. Microvascular plasticity and experimental heart failure. Hypertension. 2006;47:827-829.
11. Debbabi H, Uzan L, Mourad JJ, Safar M, Levy BI, Tibiriçà E. Increased skin capillary density in treated essential hypertensive patients. Am J Hypertens. 2006; 19:477-483.
12. Dahlöf B, Hansson L. The influence of antihypertensive therapy on the structural arteriolar changes in essential hypertension: different effects of enalapril and hydrochlorothiazide. J Intern Med. 1993;234:271-279.
13. Black MJ, Bertram JF, Johnston CI. Effect of angiotensin-converting enzyme inhibition on myocardial vascularization in the adolescent and adult spontaneously hypertensive rat. J Hypertens. 2001;19:785-794.
14. Dupuis F, Atkinson J, Limiñana P, Chillon JM. Captopril improves cerebrovascular structure and function in old hypertensive rats. Br J Pharmacol. 2005; 144:349-356.
15. Buus NH, Bøttcher M, Jørgensen CG, et al. Myocardial perfusion during longterm angiotensin-converting enzyme inhibition or beta-blockade in patients with essential hypertension. Hypertension. 2004;44:465-470.
16. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.
17. Rakusan K, Cicutti N, Maurin A, Guez D, Schiavi P. The effect of treatment with low dose ACE inhibitor and/or diuretic on coronary microvasculature in strokeprone spontaneously hypertensive rats. Microvasc Res. 2000;59:243-254.
18. Silvestre JS, Kamsu-Kom N, Clergue M, Duriez M, Lévy BI. Very-low-dose combination of the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide induces an early and sustained increase in neovascularization in rat ischemic legs. J Pharmacol Exp Ther. 2002;303:1038-1043.
19. Holowatz LA, Thompson-Torgerson CS, Kenney WL. The human cutaneous circulation as a model of generalized microvascular function. J Appl Physiol. 2008; 105:370-372.
20. Mourad JJ, Hanon O, Deverre JR, et al. Improvement of impaired coronary vasodilator reserve in hypertensive patients by low-dose ACE inhibitor/diuretic therapy: a pilot PET study. J Renin Angiotensin Aldosterone Syst. 2003;4:94-95.
21. Schwartzkopff B, Brehm M, Mundhenke M, Strauer BE. Repair of coronary arterioles after treatment with perindopril in hypertensive heart disease. Hypertension. 2000;36:220-225.
22. Flather MD, Yusuf S, Køber L, et al; ACE-Inhibitor Myocardial Infarction Collaborative Group. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. Lancet. 2000;355:1575-1581.
23. Margolius HS. Kallikreins, and kinins. Some unanswered questions about system characteristics and roles in human disease. Hypertension. 1995;26:221- 229.
24. Schini VB, Boulanger C, Regoli D, Vanhoutte PM. Bradykinin stimulates the production of cyclic GMP via activation of B2 kinin receptors in cultured porcine aortic endothelial cells. J Pharmacol Exp Ther. 1990;252:581-585.
25. Wolfgang L, Gabriele W, Bernward AS. ACE-inhibition induces NO-formation in cultured bovine endothelial cells and protects isolated ischemic rat hearts. J Mol Cell Cardiol. 1992;24:909-919.
26. Silvestre JS, Bergaya S, Tamarat E, Duriez M, Boulanger CM, Levy BI. Proangiogenic Effect of angiotensin-converting enzyme inhibition is mediated by the bradykinin B2 receptor pathway. Circ Res. 2001;89:678-683.
27. Debbabi H, Bonnin P, Levy BI. Effects of blood pressure control with perindopril/ indapamide on the microcirculation in hypertensive patients. Am J Hypertens. 2010;23:1136-1143.
28. Bertrand ME, Mourad JJ, Fox KM, Boersma E, Van Vark L. Impact of ACE inhibitors and angiotensin II receptor blockers on all-cause mortality in hypertension trials. Eur Heart J. 2011;32(abstract suppl):13.

Keywords: ACE inhibitor; capillary density; coronary disease; endothelial dysfunction; hypertension; myocardial perfusion