Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3795_Библиотеки_им_академика_М_И_Перельмана

antibody against cadherin 11 is under evaluation in phase I clinical trials for rheumatoid arthritis [103]. Hopefully, after the safety results, new clinical trials evaluating if cadherin 11 block will affect CAVD progression will be performed.

understanding of the CAVD complexity from onset, progression, and treatment [108]. Recently, Schlotter et al. [109] presented the first “spatiotemporal multi-omics” mapping proteome and transcriptome of human CAVD. Differences at transcriptional and protein level were identified among non-diseased, fibrotic, and calcific stages of CAVD. Authors suggest that pathological process involved in CAVD may act in parallel to promote valvular fibrosis and calcification. Thanks to their experimental approach, the authors highlighted that structural matrix proteins, such as proline-arginine-rich end leucine-rich repeat protein (PRELP) and procollagen C-endopeptidase enhancer 2 (PCOLCE2), as well as secreted proteins, such as clusterin (CLU) and high-temperature requirement A serine peptidase 1 (HTRA1), con- tributed to the calcification propensity [109]. Hence, the identified molecular pathways and the associated proteins could represent novel therapeutic targets to halt CAVD progression.

vasodilator therapy differ with treatment type and duration [18] (Figure 1). With short-term treatment, reduced fiber shortening is associated with a decrease in preload that is countered by a reduction in afterload, to maintain a stable stroke volume. With long-term treatment, regression of hypertrophy is associated with a reduction in ventricular volume and wall stress. The diastolic pressure-volume curve shifts leftward, resulting in an improvement of preload reserve and a relatively preserved stroke volume [18]. Moreover, preload and afterload are interrelated: because peak systolic stress is substantially elevated in AR [19] afterload reduction enables such a volume-overload ventricle to perform more work merely by moving the workload relation to a more favorable and efficient operative load [18]. Thus, the primary goal of vasodilator therapy should focus on correction of this excessive afterload, which is predominant in AR. Therefore, vasodilators are particu- larly useful in patients with systolic hypertension [20, 21]. This reduction in afterload enables an increase in LVEF despite a decrease in preload. Other goals of this treatment are the reduction of venous congestion signs and the restoration of preload reserve.

single dose administration. Five trials with hydralazine have been published [29-33]. In the largest randomized, double-blind, placebo-controlled trial with hydralazine (average dose 216 mg/day given to 45 asymptomatic patients), Greenberg et al. [31] found a significant reduction in LV volumes (end-diastolic and end-systolic) and a small improvement of LVEF in hydralazine recipients. ACE inhibitors may increase LV emptying, resulting in a favorable systolic unloading effect [21]. However, only a few small studies have evaluated the use of ACE inhibitors in chronic AR, with equivocal results, possibly because plasma renin activity is not increased in this setting [20]. Whereas Wisenbaugh et al. [36] found no change in LV volume or LVEF in 23 patients given captopril 25 mg/day for 6 months, Schön [37] found a significant decrease in LV volume and increase in LVEF in 12 patients given quinapril 10–20 mg/day for 12 months. Banaszewski et al., [27] comparing 3 years’ treatment with captopril or nifedipine, found no change in LV end-systolic diameter or LVEF in either group, even though LV end-diastolic diameter was more reduced in captopril recipients. Moreover, several investigators have reported the effectiveness of ACE inhibitors in reducing not only LV volume overload but also LV hypertrophy [32, 36, 37]. Schön [37] demonstrated a 35% reduction in LV mass and a complete reversal of LV hypertrophy with quinapril 10-20 mg/day. Lin et al., [32] in a large randomized, double-blind trial comparing enalapril and hydralazine, found a significant reduction in LV volume and mass at 1 year in the enalapril group. Because of the physiological role of the cardiac renin-angiotensin system in normal growth of the left ventricle, the benefits of ACE inhibition are particularly interesting in reducing LV hypertrophy in growing children with LV overload [35, 38]. Calcium channel antagonists have also been used in chronic AR. After one year nifedipine 20mg twice daily reduced systolic and diastolic blood pressure, and produced an important reduction in LV volume and mass and a large increase in the LVEF in a randomized trial [34]. Nifedipine was superior to hydralazine in this trial; [34] reduction in LV volume and increase in LVEF at 1 year was greater with nifedipine, and there was a reduction in LV mass. In 16 patients with

69) or digoxin 0.25 mg/day (n = 74). The cause of AR was rheumatic heart disease in 61% of patients. Digoxin was chosen instead of placebo, even though its beneficial effect on AR was only based on a previously published 1-month trial [40]. The rate of progression to AVR was significantly lower in the nifedipine group at all evaluation times after the first year. No AVR occurred in the first two years in the nifedipine group. At the end of the 6-year follow-up, a

(5.8% per year) was similar to that previously reported for patients receiving no medical

therapy [5, 41]. Compared with the digoxin group, patients in the nifedipine group had lower LV end-diastolic and end-systolic volume indices and a higher LVEF. In all nifedipine recipients, the LVEF returned to normal values after AVR, whereas it remained abnormal in four patients (20%) treated with digoxin. This study supports the as- sumption that nifedipine is effective in delaying the need for surgery. It also suggests that use of vasodilators requires a careful follow-up to avoid masking of progressive myocardial dysfunction that would not recover despite AVR. To summarize, in chronic AR, an ACE inhibitor may be the most appropriate drug for patients with hypertension and/or LV dilatation, whereas nifedipine appears to be the best ‘evidence- based’ treatment for asymptomatic patients with severe AR and no LV dysfunction [20].

because they block compensatory tachycardia. In patients with disease of the aortic root, such as in Marfan disease, progressive enlargement of the aortic root is associated with AR and dissection. In such patients, the primary goal of a pharmacologic treatment is to limit aortic dilatation and avoid occurrence of aortic dissection. The only treatment proven to be effective is a prophylactic ↑-adrenergic blockade that reduces the progression of the aneurysmal dilatation [9]. In fact, Shores et al., [9] in a randomized trial in 70 patients with Marfan syndrome, found significantly lower aortic-root dimensions and a better survival rate in the propanolol group than in the control group. Recommended ↑-adrenoceptor antagonists are propanolol (mean dosage 212 α 68 mg/day) or atenolol (100 mg/day) [9, 10]. Although likely, this beneficial effect of ↑-adrenoceptor antagonists in patients with Marfan syndrome has not been proven in patients with bicuspid valve or dilatation of the ascending aorta not associated with Marfan syndrome. ↑-Adrenoceptor antagonist therapy may also be useful in patients with impaired LV function after AVR for AR. In these patients, ↑-adrenoceptor antagonist therapy is postulated to improve cardiac performance by reducing cardiac volume and mass [42]. Treatment with different ↑-adrenoceptor antagonists (atenolol 50 mg/day, carvedilol 10 mg/day, or bisoprolol 5mg/day) was associated with benefit in a retrospective study [42].