Marie Briet

Large and Small Artery Cross-Talk and Recent Morbidity-Mortality Trials in Hypertension

The results of recent large clinical trials in hypertension invite re-evaluation of the mechanisms of action of antihypertensive drugs on large and small arteries in the context of their effects on cardiovascular outcomes. By increasing our understanding of the relationship between large and small artery damage, target organ damage, and clinical end points, the trials provide us with new insights into the management of hypertension. This short review aims at analyzing the following: (1) whether β-blockers may exert deleterious effects on cardiovascular CV prevention through the reduction in heart rate (HR) or the lack of arterial remodeling; (2) whether long-term arterial remodeling can explain the “legacy” effect of multifactorial treatment in patients with hypertension and type 2 diabetes mellitus (T2D); and (3) to which level diastolic BP (DBP) can be safely lowered in elderly patients with isolated systolic hypertension (ISH). Because these issues have the concept of large/small artery cross-talk in common, we analyzed it first. The damaging effect of local pulse pressure (PP) has been well demonstrated on large arteries and, to a lesser extent, on small arteries. Elevated PP can stimulate hypertrophy, remodeling (increased media:lumen ratio), or rarefaction in the microcirculation, leading to increased resistance to mean flow. Recent studies showed a close relationship between microvascular damage in the heart, brain, retina, and kidney and either PP or arterial stiffness. Indeed, significant relationships have been demonstrated between brachial PP and glomerular filtration rate,1,2 microalbuminuria,2 or white matter lesions3; between arterial stiffness and glomerular filtration rate,4,5 urinary albumin,5 retinal arteriolar narrowing,6,7 white matter lesions,3 or cognitive function8; and between carotid stiffness and glomerular filtration rate.4,5 Although not all of these relationships are independent of confounding factors,3 there is a large amount of evidence for linking the pulsatility …

Large Artery Stiffening and Remodeling Are Independently Associated With All-Cause Mortality and Cardiovascular Events in Chronic Kidney Disease

Chronic kidney disease, even at moderate stages, is characterized by a high incidence of cardiovascular events. Subclinical damage to large arteries, such as increased arterial stiffness and outward remodeling, is a classical hallmark of patients with chronic kidney disease. Whether large artery stiffness and remodeling influence the occurrence of cardiovascular events and the mortality of patients with chronic kidney disease (stages 2–5) is still debated. This prospective study included 439 patients with chronic kidney disease (mean age, 59.8±14.5 years) with a mean measured glomerular filtration rate of 37 mL/min per 1.73 m2. Baseline aortic stiffness was estimated through carotid-femoral pulse wave velocity measurements; carotid stiffness, diameter, and intima-media thickness were measured with a high-resolution echotracking system. For the overall group of patients, the 5-year estimated survival and cumulative incidence of cardiovascular events were 87% and 16%, respectively. In regression analyses adjusted on classical cardiovascular and renal risk factors, aortic stiffness remained significantly associated with all-cause mortality (for 1 SD, Cox model–derived relative risk [95% CI], 1.48 [1.09–2.02]) and with fatal and nonfatal cardiovascular events (for 1 SD, Fine and Gray competing risks model–derived relative risk [95% CI], 1.35 [1.05–1.75]). Net reclassification improvement index was significant (29.0% [2.3–42.0%]). Carotid internal diameter was also independently associated with all-cause mortality. This study shows that increased aortic stiffness and carotid internal diameter are independent predictors of mortality in patients with stages 2 to 5 chronic kidney disease and that aortic stiffness improves the prediction of the risk.

Arterial Remodeling Associates with CKD Progression

In CKD, large arteries remodel and become increasingly stiff. The greater pulsatile pressure reaching the glomerulus as a result of increased aortic stiffness could induce renal damage, suggesting that the stiffening and remodeling of large arteries could affect the progression of CKD. We measured carotid-femoral pulse wave velocity, aortic pressure and carotid remodeling and stiffness parameters in 180 patients with CKD (mean measured GFR, 32 ml/min per 1.73 m(2)) and followed them prospectively for a mean of 3.1 years. During follow-up, carotid stiffness significantly increased (+0.28 ± 0.05 m/s; P<0.0001) but aortic stiffness did not. Carotid intima-media thickness decreased significantly during follow-up and the internal diameter of the carotid increased, producing increased circumferential wall stress (+2.08 ± 0.43 kPa/yr; P<0.0001). In a linear mixed model, circumferential wall stress significantly associated with faster GFR decline after adjustment for risk factors of cardiovascular disease and progression of CKD. In a multivariable Cox model, carotid circumferential wall stress and pulse pressure independently associated with higher risk for ESRD. None of the arterial stiffness parameters associated with progression of CKD. In conclusion, maladaptive remodeling of the carotid artery and increased pulse pressure independently associate with faster decline of renal function and progression to ESRD.

Endothelial Function and Chronic Exposure to Air Pollution in Normal Male Subjects

Exposure to urban air pollution, ultrafine particles or gases, is associated with acute cardiovascular mortality and morbidity. We investigated the effect of ambient air pollution on endothelial function in 40 healthy white male nonsmokers spontaneously breathing ambient air in Paris, France. Air pollutant levels (nitrogen, sulfur and carbon oxides, and particulate matter) were averaged during the 5 days preceding arterial measurements. Brachial artery endothelium-dependent flow-mediated dilatation and reactive hyperemia induced by hand ischemia and endothelium-independent glyceryl trinitrate dilatation were measured using a radiofrequency-based echo-tracking device at 2-week intervals. Flow-mediated dilatation was independently and negatively correlated with the average levels of sulfur dioxide (P<0.001) and nitrogen monoxide (P<0.01). Sulfur dioxide levels explained 19% of the variance of flow-mediated dilatation. An increase in gaseous pollutants, 2 weeks apart, was significantly associated with a decreased in flow-mediated dilatation. No association was found between air pollutants and glyceryl trinitrate–induced vasodilatation. Reactive hyperemia was significantly and positively correlated with particulate matter with aerodynamic diameters <10 &mgr;m and <2.5 &mgr;m (P<0.0001 and P<0.001, respectively) and nitrogen dioxide (P<0.01). An increase in particulate matter, 2 weeks apart, was significantly correlated with an increase in reactive hyperemia. Endothelial function was impaired by ordinary levels of pollution in healthy young males, in an urban area, and may be reduced by 50% between the least and the most polluted day. Gaseous pollutants affect large artery endothelial function, whereas particulate matter exaggerates the dilatory response of small arteries to ischemia.

Arterial Stiffness as Surrogate End Point: Needed Clinical Trials

Classic risk scores may underestimate the risk of cardiovascular (CV) events in specific risk groups suitable for primary prevention, such as asymptomatic hypertensive subjects.1 Particularly, those considered as at intermediate risk may benefit the most from a reassessment of their CV risk using novel biomarkers.2 In primary prevention, some imaging biomarkers, such as arterial stiffness, enhance risk prediction to a higher extent than circulating biomarkers.3 Whether novel biomarkers are ready for routine clinical use is a matter of controversy.1–4 Particularly, whether an imaging biomarker can be substituted to clinical events in outcome trials and be considered as surrogate end point has rarely been demonstrated.1–4 The aims of the present Brief Review are to address the concepts of “imaging biomarker” and “surrogate end point”; to focus on arterial stiffness as putative surrogate end point for future CV events; and to suggest additional studies to demonstrate its value as surrogate end point. Particularly, we will discuss experimental designs of randomized clinical trials demonstrating that a therapeutic strategy that normalizes arterial stiffness is more effective in preventing CV events than usual care. ### “Circulating” Biomarkers Versus “Tissue” or “Imaging” Biomarkers Although classic risk scores, such as the Framingham risk score5 and the European Systematic Coronary Risk Evaluation,6 detect patients at high risk of CV events, they are largely influenced by aging, leading to undermanagement of CV risk in other risk groups, particularly those considered as at intermediate risk. A very large number of newer biomarkers have been proposed in the literature2,4 to increase risk prediction beyond classic risk scores. According to the Biomarkers Definition Working Group of the National Institutes of Health,7 a biomarker is “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to …

Vascular Actions of Aldosterone

Aldosterone exerts direct effects on the vascular system by inducing oxidative stress, inflammation, hypertrophic remodeling, fibrosis, and endothelial dysfunction. Aldosterone exerts its effects through genomic and nongenomic pathways in a mineralocorticoid receptor (MR)-dependent or independent manner. Other aldosterone receptors such as GPR30 have been identified. A tight relation exists between the aldosterone and angiotensin II pathways, as well as with the endothelin-1 system. There is a correlation between plasma levels of aldosterone and cardiovascular risk. Recently, an increasing body of evidence has underlined the importance of aldosterone in cardiovascular complications associated with the metabolic syndrome, such as arterial remodeling and endothelial dysfunction. Blockade of MR is an increasingly used evidence-based therapy for many forms of cardiovascular disease, including hypertension, heart failure, chronic kidney disease, and diabetes mellitus.

Treatment of Arterial Remodeling in Essential Hypertension

Essential hypertension is associated with large and small vascular remodeling that impacts cardiovascular prognosis. Longitudinal follow-up of hypertensive patients has shown that large arterial stiffness decreases partly independently of blood pressure reduction, suggesting specific pharmacological effects of antihypertensive therapy. Inhibitors of the renin-angiotensin-aldosterone system are among the agents that have been shown to affect vascular remodeling to a greater degree. Lifestyle modifications, including exercise and weight reduction, also improve large and small vascular remodeling. New antihypertensive drugs, including neprilysin inhibitors associated with an angiotensin receptor blocker, aldosterone synthase inhibitors and new devices such as renal denervation and baroreceptor stimulation, may exert beneficial effects on vascular remodeling and are currently under evaluation.

Importance of arterial stiffness as cardiovascular risk factor for future development of new type of drugs

Cardiovascular risk prediction relies on classical risk factors such as age, gender, lipids, hypertension, smoking and diabetes. Although the value of such scales of risk is high for populations, its value for individual is reduced and too much influenced by non‐modifiable risk factors (age and gender). Biomarkers of risk have been deceiving and genome wide scan approach is too recent. Target organ damage may help in selecting patients at high risk and in determining intervention. Aortic pulse wave velocity, an index of aortic stiffness, has been widely validated as providing additional risk predictions beyond and above classical risk factors, and has now entered into official guidelines. Many interventions (dietary, behaviour, drug treatment) were shown to influence arterial stiffness positively, but little evidence of a direct effect of intervention on arterial stiffness independent of blood pressure is available. New pharmacological targets and new drugs need to be identified. To become a surrogate endpoint for drug development, there is a need to demonstrate that regression arterial stiffness is associated with improved outcome. In parallel to this demonstration, points to be improved are the homogenization and spreading of the technique of measurement, the establishment of a reference value database.

Protective role of vascular smooth muscle cell PPARγ in angiotensin II-induced vascular disease

AIMS Vascular peroxisome proliferator-activated receptor γ (PPARγ) activation improves vascular remodelling and endothelial function in hypertensive rodents. The goal of this study was to determine that vascular smooth muscle cell (VSMC) PPARγ exerts a vascular protective role beyond its metabolic effects. METHODS AND RESULTS We generated a model of adult inducible VSMC-specific Pparγ inactivation to test the hypothesis that PPARγ counteracts angiotensin (Ang) II-induced vascular remodelling and endothelial dysfunction. Inducible VSMC Pparγ knockout mice were generated by crossing Pparγ floxed mice with mice expressing a tamoxifen-inducible Cre recombinase Smooth muscle (Sm) myosin heavy chain promoter control. Eight-to-ten-week-old SmPparγ(-/-) and control mice were infused with a nonpressor dose of Ang II for 7 days. Blood pressure was unaffected. Mesenteric arteries showed eutrophic remodelling in Ang II-infused control mice and hypertrophic remodelling in Ang II-infused SmPparγ(-/-) mice. Endothelium-dependent relaxation to acetylcholine was reduced in SmPparγ(-/-) mice and further impaired by Ang II infusion, and was unaffected by an inhibitor of NO synthase, suggesting a defect of NO-mediated relaxation. SmPparγ deletion increased the sensitivity to Ang II-induced contraction. SmPparγ(-/-) mice exhibited enhanced Ang II-induced vascular NADPH oxidase activity and adhesion molecule ICAM-1 and chemokine monocyte chemotactic protein-1 expression. The antioxidant Superoxide dismutase 3 expression was decreased by SmPparγ deletion. Ang II infusion increased the expression of CD3 T-cell co-receptor chain δ and decreased Adiponectin in perivascular adipose tissue of SmPparγ(-/-) mice. CONCLUSION Inducible Pparγ inactivation in VSMCs exacerbated Ang II-induced vascular remodelling and endothelial dysfunction via enhanced vascular oxidative stress and inflammation, revealing the protective role of VSMC PPARγ in angiotensin II-induced vascular injury.

Deficiency of T-regulatory cells exaggerates angiotensin II-induced microvascular injury by enhancing immune responses.

Aims: T-regulatory lymphocyte (Treg) adoptive transfer prevented angiotensin (Ang) II-induced hypertension and microvascular injury. Scurfy mice are deficient in Treg because of a mutation in the transcription factor forkhead box P3 (Foxp3) gene. Enhanced Ang II effects in the absence of Treg would unambiguously demonstrate their vascular protective role. We hypothesized that adoptive transfer of Scurfy vs. wild-type T cells will exacerbate Ang II-induced microvascular damage in T and B-cell-deficient recombination-activating gene 1 (Rag1) knockout mice. Methods and results: Rag1 knockout mice were injected with vehicle, 107 T cells from wild-type or Scurfy mice or 106 wild-type Treg alone or in combination with Scurfy T cells, and then infused or not with Ang II (490 ng/kg per min, subcutaneous) for 14 days. Ang II increased SBP in all the groups, but DBP only in wild-type and Scurfy T-cell groups. Ang II-induced endothelial dysfunction and oxidative stress in perivascular adipose tissue (PVAT) of mesenteric arteries of the wild-type T-cell group, whereas these were exaggerated in the Scurfy T-cell group. Ang II enhanced microvascular remodeling and stiffness in vehicle and Scurfy T-cell groups. Ang II increased monocyte chemotactic protein-1 expression in the vascular wall and PVAT, monocyte/macrophage infiltration and proinflammatory polarization in PVAT and the renal cortex, and T-cell infiltration in the renal cortex only in the Scurfy T-cell group. Treg coinjection in the vehicle and Scurfy T-cell groups prevented or reduced the effects of Ang II. Conclusion: FOXP3+ Treg deficiency exaggerates Ang II-induced microvascular injury by modulating innate and adaptive immune responses.