The functional integrity of the endothelium is essential for vascular health. In addition to maintaining a delicate balance between vasodilation and vasoconstriction, the endothelium has numerous other complex roles involved in the maintenance of vascular homeostasis. Chronic exposure to cardiovascular risk factors and oxidative stress results in an imbalance in these functions, creating an environment that favors reduced vasodilation and a proinflammatory and prothrombic state. The involvement of endothelial dysfunction in all stages of the cardiovascular continuum makes it an important target for treatment. One of the major endothelial-derived factors involved in the maintenance of endothelial function is nitric oxide (NO). Angiotensin-converting enzyme (ACE) inhibitors increase NO production both directly and indirectly by preventing production of angiotensin II (which diminishes NO production) and inhibiting the degradation of bradykinin (which stimulates local release of NO). Among the ACE inhibitors, perindopril appears to have the greatest effects on bradykinin and has demonstrated efficacy in a number of markers of endothelial dysfunction including arterial stiffness and progression of atherosclerosis. There is also strong evidence supporting the use of perindopril-based therapy for the treatment of hypertension and for reducing the risk of cardiovascular morbidity and mortality in a wide range of patients across the cardiovascular continuum.Funding: The journal’s Rapid Service Fee was funded by Servier.

Aims  To obtain the normal range for 2D echocardiographic (2DE) measurements of left ventricular (LV) layer-specific strain from a large group of healthy volunteers of both genders over a wide range of ages. Methods and results  A total of 287 (109 men, mean age: 46 ± 14 years) healthy subjects were enrolled at 22 collaborating institutions of the EACVI Normal Reference Ranges for Echocardiography (NORRE) study. Layer-specific strain was analysed from the apical two-, three-, and four-chamber views using 2DE software. The lowest values of layer-specific strain calculated as ±1.96 standard deviations from the mean were −15.0% in men and −15.6% in women for epicardial strain, −16.8% and −17.7% for mid-myocardial strain, and −18.7% and −19.9% for endocardial strain, respectively. Basal-epicardial and mid-myocardial strain decreased with age in women (epicardial; P = 0.008, mid-myocardial; P = 0.003) and correlated with age (epicardial; r = −0.20, P = 0.007, mid-myocardial; r = −0.21, P = 0.006, endocardial; r = −0.23, P = 0.002), whereas apical-epicardial, mid-myocardial strain increased with the age in women (epicardial; P = 0.006, mid-myocardial; P = 0.03) and correlated with age (epicardial; r = 0.16, P = 0.04). End/Epi ratio at the apex was higher than at the middle and basal levels of LV in men (apex; 1.6 ± 0.2, middle; 1.2 ± 0.1, base 1.1 ± 0.1) and women (apex; 1.6 ± 0.1, middle; 1.1 ± 0.1, base 1.2 ± 0.1). Conclusion  The NORRE study provides useful 2DE reference ranges for novel indices of layer-specific strain.

This study aimed to evaluate the modification of non-invasive myocardial work (MW) indices related to aortic stenosis (AS) stages of cardiac damage and their prognostic value. The echocardiographic and outcome data of 170 patients, with asymptomatic moderate-to-severe AS and left ventricular ejection fraction (LVEF) ≥50%, and 50 age- and sex-comparable healthy controls were analysed. Primary endpoints were the occurrence of all-cause and cardiovascular death. Increased values of the global work index (GWI), global constructive work (GCW), and global wasted work (GWW) were observed in AS patients compared to controls (GWI: 2528 ± 521 vs. 2005 ± 302 mmHg%, GCW: 2948 ± 598 vs. 2360 ± 353 mmHg%, p < 0.001; GWW: 139 ± 90 vs. 90 ± 49 mmHg%, p = 0.005), with no changes in the global work efficiency. When patients were stratified according to the stages of cardiac damage, the GWI showed lower values in Stage 3–4 as compared to Stage 0 and Stage 2 (p = 0.024). During a mean follow-up of 30 months, 27 patients died. In multivariable Cox-regression analysis, adjusted for confounders, GWI (HR: 0.998, CI: 0.997–1.000; p = 0.034) and GCW (HR:0.998, CI: 0.997–0.999; p = 0.003) were significantly associated with excess mortality. When used as categorical variables, a GWI £ 1951 mmHg% and a GCW £ 2475 mmHg% accurately predicted all-cause and cardiovascular death at 4-year follow-up. In conclusion, in asymptomatic patients with moderate-to-severe AS, reduced values of GWI and GCW are associated with increased mortality. Therefore, the evaluation of MW indices may allow for a better identification of asymptomatic patients with moderate to severe AS and preserved LVEF whom are at increased risk of worse prognosis during follow-up.

Most serotonergic neurons display a prominent medium-duration afterhyperpolarization (mAHP), which is mediated by small-conductance Ca(2+) -activated K(+) (SK) channels. Recent ex vivo and in vivo experiments have suggested that SK channel blockade increases the firing rate and/or bursting in these neurons. The purpose of this study was therefore to characterize the source of Ca(2+) which activates the mAHP channels in serotonergic neurons. In voltage-clamp experiments, an outward current was recorded at -60 mV after a depolarizing pulse to +100 mV. A supramaximal concentration of the SK channel blockers apamin or (-)-bicuculline methiodide blocked this outward current. This current was also sensitive to the broad Ca(2+) channel blocker Co(2+) and was partially blocked by both ω-conotoxin and mibefradil, which are blockers of N-type and T-type Ca(2+) channels, respectively. Neither blockers of other voltage-gated Ca(2+) channels nor DBHQ, an inhibitor of Ca(2+)-induced Ca(2+) release, had any effect on the SK current. In current-clamp experiments, mAHPs following action potentials were only blocked by ω-conotoxin and were unaffected by mibefradil. This was observed in slices from both juvenile and adult rats. Finally, when these neurons were induced to fire in an in vivo-like pacemaker rate, only ω-conotoxin was able to increase their firing rate (by ~30%), an effect identical to the one previously reported for apamin. Our results demonstrate that N-type Ca(2+) channels are the only source of Ca(2+) which activates the SK channels underlying the mAHP. T-type Ca(2+) channels may also activate SK channels under different circumstances.

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