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Abstract: Aortic regurgitation (AR) is a valvular disease characterized by retrograde blood flow from the aorta to the left ventricle. Various etiologies result in either an acute or chronic clinical presentation of AR and affect the severity of disease progression. Acute AR is a medical emergency caused by sudden increases in left ventricular volume. Immediate surgical intervention, vasoactive agents, and antibiotics are crucial for management. Chronic AR progresses gradually, leading to heart failure symptoms due to left ventricular remodeling. Diagnoses of both acute and chronic AR rely on electrocardiography, chest radiographs, and echocardiography. Cardiac magnetic resonance imaging may be incorporated in chronic AR diagnosis. Medical management of chronic AR aims to control hypertension and delay left ventricular dysfunction. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and potentially calcium-channel blockers are recommended for chronic AR. β-Blockers are cautioned against because of their potential negative effects. This article emphasizes the importance of early diagnosis and prompt surgical intervention in AR. This review provides a comprehensive overview of the pathophysiology and clinical manifestations of acute and chronic AR and a medication regimen for treating chronic AR in the adult population., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Aortic valve regurgitation (AR) is a volume-overload disease causing severe eccentric left ventricular (LV) hypertrophy and eventually heart failure. There is currently no approved drug to treat patients with AR. Many vasodilators including angiotensin-converting enzyme inhibitors have been evaluated in clinical trials, but although some results were promising, others were inconclusive. Overall, no drug has yet been able to improve clinical outcome in AR and the controversy remains. We have previously shown in an animal model that captopril (Cpt) reduced LV hypertrophy and protected LV systolic function, but we had not evaluated the clinical outcome. This protocol was designed to evaluate the effects of a long-term Cpt treatment on survival in the same animal model of severe aortic valve regurgitation., Methods and Results: Forty Wistar rats with AR were treated or untreated with Cpt (1 g/L in drinking water) for a period of 7 months to evaluate survival, myocardial remodeling, and function by echocardiography as well as myocardial metabolism by µ positron emission tomography scan. Survival was significantly improved in Cpt-treated animals with a survival benefit visible as soon as after 4 months of treatment. Cpt reduced LV dilatation and LV hypertrophy. It also significantly improved the myocardial metabolic profile by restoring the level of fatty acids metabolic enzymes and use., Conclusions: In a controlled animal model of pure severe aortic valve regurgitation, Cpt treatment reduced LV remodeling and LV hypertrophy and improved myocardial metabolic profile and survival. These results support the need to reevaluate the role of angiotensin-converting enzyme inhibitors in humans with AR in a large, carefully designed prospective clinical trial.

Background: Aortic regurgitation (AR) is a chronic disease for which there is currently no approved medical treatment. We previously reported in an animal model that β-blockade with metoprolol exerted beneficial effects on left ventricular remodeling and survival. Despite the recent publication of promising human data, β-blockade in chronic AR remains controversial. More data are needed to support this potentially new treatment strategy. We hypothesized that carvedilol might be another safe treatment option in chronic AR, considering its combined β-blocking and α-blocking effects and proven efficacy in patients with established heart failure., Methods and Results: The effects of a 6-month treatment with carvedilol 30 mg/kg/d orally were evaluated in adult Wistar rats with severe AR. Sham-operated and untreated AR animals were used as controls. Carvedilol treatment resulted in less left ventricular hypertrophy and dilatation. Ejection fraction was improved and filling pressures were reduced by carvedilol. β1-Receptor expression was also improved as well as myocardial capillary density. Those beneficial effects were noted despite the presence of drug-induced bradycardia., Conclusions: Carvedilol exerted protective effects against volume-overload cardiomyopathy in this model of aortic valve regurgitation with preserved ejection fraction. These results suggest a protective class effect of β-blockers. Combined with the recent publication of promising human data, our findings support the need to carefully design a prospective study in humans to evaluate the effects of β-blockers in chronic aortic valve regurgitation.

Background: At present, no medical therapy is known to affect the progression of rheumatic mitral stenosis (MS). We sought to assess the effect of statin treatment on long-term progression of MS in a large population., Methods and Results: From our 20-year database, we identified all patients with rheumatic MS with > or =2 echocardiographies > or =1 year apart. Exclusion criteria were previous intervention on the mitral valve, more than moderate aortic regurgitation, or symptoms at first examination. The study sample included 315 patients (mean age, 61+/-12 years; 224 women); 35 patients (11.1%) were treated with statins, and 280 (88.9%) were not. Mean follow-up period was 6.1+/-4.0 years (range, 1 to 20). The rate of decrease in mitral valve area was significantly lower in the statin group compared with the untreated group (0.027+/-0.056 versus 0.067+/-0.082 cm(2)/y; P=0.005). The annualized change in mean transmitral gradient was lower in statin-treated patients (0.20+/-0.59 versus 0.58+/-0.96 mm Hg/y; P=0.023). The prevalence of fast MS progression (annual change in mitral valve area >0.08 cm(2)) was significantly lower in the statin group (P=0.008). An increase in systolic pulmonary artery pressure of >10 mm Hg was found in 17% of patients in the statin group versus 40% of untreated patients (P=0.045)., Conclusions: Our study shows a significantly slower progression of rheumatic MS in patients treated with statins. These findings could have an important impact in the early medical therapy of patients with rheumatic heart disease.

Background: Past studies have suggested that the adrenergic system becomes abnormally activated in chronic volume overload, such as in severe aortic valve regurgitation (AR). However, the effectiveness of agents directed against this adrenergic activation has never been adequately tested in chronic AR. We therefore tested the effects of metoprolol treatment on the left ventricular (LV) function and remodeling in severe chronic AR in rats., Methods and Results: Severe AR was created in adult male Wistar rats by retrograde puncture of the aortic leaflets under echocardiographic guidance. Two weeks later, some animals received metoprolol treatment (25 mg/kg) orally for 24 weeks, and some were left untreated. LV dimensions, ejection fraction, and filling parameters were evaluated by echocardiography. Hearts were harvested at 1, 2, 14, and 180 days for the evaluation of hypertrophy, beta-adrenergic receptor status, and extracellular matrix remodeling. We found that metoprolol treatment prevented LV dilatation and preserved the ejection fraction and filling parameters compared with untreated animals. Metoprolol increased the expression of beta1-adrenoreceptor mRNA and reduced G protein receptor kinase 2 levels. Collagen I and III mRNA levels were reduced. Cardiac myocyte hypertrophy was also prevented., Conclusions: In our experimental model of severe AR, metoprolol treatment had a significant beneficial global effect on LV remodeling and function. These results suggest that the adrenergic system is important in the development of volume-overload cardiomyopathy in AR and that adrenergic-blocking agents may play a role in the treatment of this disease.

Objective: Angiotensin converting enzyme (ACE) inhibitors decrease preload and afterload and are therefore of potential value in valvular regurgitation. The present study was designed to assess the effects of treatment for 1 year with an ACE inhibitor on myocardial performance., Patients and Methods: Twenty-four patients with isolated moderate to severe chronic aortic regurgitation or mitral regurgitation who were free of coronary disease were studied before treatment (control) with the ACE inhibitor quinapril and were then followed for 1 year during quinapril therapy (10-20 mg/day)., Results: After 1 year of ACE inhibition, the regurgitant fraction fell by 27 and 42%, compared with control values, in the aortic and mitral regurgitation groups, respectively (P = 0.0001). The left ventricular end-diastolic volume was reduced from 150 +/- 33 to 128 +/- 30 ml/m2 in the aortic regurgitation group, and from 146 +/- 26 to 109 +/- 24 ml/m2 in the mitral regurgitation group (P = 0.0001 for each). End-systolic volume decreased from 55 +/- 27 to 44 +/- 28 ml/m2 in the aortic regurgitation group (P = 0.005) and from 63 +/- 43 to 47 +/- 29 ml/m2 in the mitral regurgitation group (P = 0.002). The left ventricular ejection fraction increased slightly at rest and during exercise in patients with aortic regurgitation, but showed no change in the mitral regurgitation patients after 1 year of quinapril treatment. Echocardiographic studies showed that after 1 year of therapy there was a decrease of about 10% in the left ventricular end-diastolic and end-systolic diameter in both patient groups. Moreover, the left ventricular mass was reduced by 35% in the aortic regurgitation group (P = 0.0001), and left ventricular hypertrophy, which was present in all patients, was reversed completely. In the mitral regurgitation group, a mass reduction of 15% was observed after 1 year of quinapril treatment, and the septal wall thickness, which indicated borderline hypertrophy, decreased to normal., Conclusion: These results demonstrate that long-term ACE inhibition in patients with valvular regurgitation reverses left ventricular dilation and reduces left ventricular mass and hypertrophy, thereby improving left ventricular function. Further, they suggest that ACE inhibition may have the potential to delay aortic or mitral valve replacement.

Aortic regurgitation (AR) was induced in rabbits by aortic valve puncture. Two years later, echocardiography [two-dimensional (2-D) and M-mode; Doppler] was used to monitor acute left ventricular (LV) effects of milrinone. At that time, two of eight AR survivors had hindlimb edema and/or ascites. Baseline LV diameter and wall thickness of AR rabbits was 125-145% for that of sham-operated subjects; mean stroke volume and total LV output (TLVO) were approximately 2.5 x normal; regurgitant fraction was 0.57; and effective (forward) cardiac output (CO) was normal. Basal LV fractional shortening (FS) and mean circumferential fiber shortening velocity (Vcf) were not significantly depressed. Milrinone (10 micrograms/kg/min. i.v.) decreased mean LV stroke volume and TLVO by 25-33% (p less than 0.05). However, forward CO was maintained as regurgitant stroke volume fell an average of 52%. Milrinone significantly reduced aortic mean reverse/mean forward blood flow velocity ratio (-16%) and LV end-diastolic (ED) chamber diameter (-7%), consistent with reduced regurgitation. Mean Vcf was 39% greater than that seen after saline infusion (p less than 0.05). Thus, milrinone promoted Vcf and maintained forward CO in rabbits with chronic compensated AR while appreciably reducing LV regurgitation, chamber size, and total output. These beneficial effects may reflect vasodilating and positive inotropic activities confirmed in normal rabbits.

We determined that the spontaneous changes in cardiac output (CO) over 12 hr in 21 patients with chronic severe aortic regurgitation averaged +/- 8.9% (p = .03). We then measured changes in CO over time after administering incremental doses of oral hydralazine (50, 100, 150, and 200 mg) every 12 hr and analyzed these changes by several methods. Changes over time of only + 14% were highly significant (p less than .001) when analyzed by t test, but were not significant by repeated-measures analysis of variance (ANOVA). When changes in CO were compared with internal control values (spontaneous changes over 12 hr), only changes of 20% or more were significant (p less than .05). Transient "peak effects" markedly overestimated the maximum effects after all doses. We then compared the incremental doses of hydralazine, given either every 8 or every 12 hr, with respect to (1) the hemodynamic changes induced, and (2) the relative incidence of acute side effects. Maximal increases in CO were similar when hydralazine was given every 8 hr (16 patients) and every 12 hr (21 patients), and ranged from + 14% after 50 mg to + 61% after 200 mg. After the 150 and 200 mg doses, marked sustained increases in CO were present at 8 hr and mild increases in CO were still present at 12 hr. Hydralazine every 8 hr was associated with side effects in 25% to 86% of patients, but when the drug was given every 12 hr it was associated with side effects in only 5% to 19% of patients (p less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the effects of afterload reduction in chronic severe aortic insufficiency by measuring the hemodynamic response to oral hydralazine in 10 consecutive patients. Hemodynamics were also measured during maximal exercise in eight of these patients. At rest, hydralazine reduced pulmonary artery wedge pressure from 14 to 9 mm Hg (p less than 0.01), and increased cardiac index by 70% and stroke volume index by 35% (both p less than 0.001). Before hydralazine, pulmonary artery wedge pressure exceeded 20 mm Hg in five patients during maximal exercise; with hydralazine, at identical levels of exercise, pulmonary artery wedge pressure remained below 20 mm Hg in all patients. For the group, hydralazine reduced pulmonary artery wedge pressure from 21 to 12 mm Hg (p less than 0.05) and increased cardiac index by 31% (p less than 0.05) during exercise; changes in stroke volume index were more variable and there was no significant increase for the group, although several patients increased stroke volume substantially and the overall increase was 34%. These data show that afterload reduction has beneficial effects on cardiac performance in chronic severe aortic insufficiency both at rest and during exercise. Hydralazine may be of use in such patients either in preparation for valve replacement or as interim therapy.

Although vasodilator drugs acutely reduce regurgitation and improve cardiac performance in aortic insufficiency, their long-term effects on left ventricular size and function are uncertain. Consequently, we performed a double-blinded, placebo-controlled trial using hydralazine in 80 minimally symptomatic patients who had clinically stable, moderate-to-severe aortic insufficiency. Patients randomized to hydralazine displayed a progressive reduction in left ventricular end-diastolic volume index (LVEDVI) measured by radionuclide angiography, the predetermined end point of the study. At 24 months, mean LVEDVI had been reduced by 30 +/- 38 ml/m2, an 18% reduction from baseline. In contrast, LVEDVI changed minimally in patients randomized to placebo, and the intergroup differences over time were statistically significant (p less than 0.03). The hydralazine group also experienced reductions in left ventricular end-systolic volume index and increases in ejection fraction that were significantly different (both p less than 0.01) from changes in placebo-treated patients. These findings show that long-term treatment with hydralazine reduces the volume overload in aortic insufficiency and suggest that such therapy may have a beneficial effect on the natural history of the disease.

A new cardioselective beta 1-adrenoceptor partial agonist, xamoterol, has been developed for the treatment of heart failure, especially that associated with ischemic heart disease. To investigate the hemodynamic effect of xamoterol in relation to sympathetic nervous activity, hemodynamic variables and plasma norepinephrine (NE) levels were measured at rest and during three graded bicycle exercise tests before and after a single intravenous dose of 0.15 mg/kg xamoterol in 10 patients with mild-to-moderate left ventricular dysfunction. Plasma NE increased with increasing grade of exercise and a linear correlation between plasma NE and heart rate was observed at four time points (at rest and three exercise levels) before and after xamoterol. After administration of xamoterol, the slope of the regression line of plasma NE-heart rate relation was significantly less steep than that before drug. Predose and postdose regression lines crossed at 440 pg/ml of plasma NE. Similar effects were observed on the plasma NE-cardiac index and plasma NE-systolic blood pressure relations (regression lines crossed at 380 and 530 pg/ml of plasma NE, respectively). Thus, xamoterol had a dual agonist-antagonist effect in relation to plasma NE, and the crossover point lay approximately between 400 pg/ml and 500 pg/ml. This level of plasma NE was achieved at a low exercise level and at a heart rate of about 100 beats/min. These results indicate that xamoterol has intrinsic sympathomimetic activity comparable to relatively low sympathetic activity (400 to 500 pg/ml of plasma NE) and therefore acts as a beta 1-agonist when sympathetic nervous activity is below this level and as an antagonist when sympathetic activity is above this level.

Nitroprusside was used to reduce afterload in 13 patients with isolated, severe aortic regurgitation. The drug significantly lowered mean aortic pressure, pulse pressure, left ventricular end-diastolic pressure and left ventricular volume. Total ventricular, or angiographic, cardiac index was generally unaffected, but forward cardiac index was improved significantly in 8 of 13 patients. Augmentation of forward cardiac index was seen in patients with subnormal resting forward cardiac index, in patients with decidedly elevated end-diastolic pressure, and in those with depressed resting ejection fractions. Regurgitant fraction fell with nitroprusside in six patients and remained unchanged in seven. Total stroke work index was diminished in all patients. These data show that afterload reduction in patients with severe aortic regurgitation may improve hemodynamics by reducing aortic regurgitation or by improving ventricular pump function. The lowered total stroke work, reduced ventricular size and improved forward cardiac index imply that afterload reduction may benefit left ventricular failure and delay progressive ventricular dysfunction in patients with aortic regurgitation.