Aortic Regurgitation: Review of Current Management.

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. ß-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.

Detection of soluble suppression of tumorigenicity 2 and N-terminal B-type natriuretic peptide in a rat model of aortic regurgitation: differential responses to omecamtiv mecarbil.

OBJECTIVES: Both N-terminal fragment of B-type natriuretic peptide (NT-proBNP) and soluble isoform of ST2 (sST2) have been identified as biomarkers of heart failure. We evaluated the plasma levels of NT-proBNP and sST2 in a rat model of severe aortic valve regurgitation (AR) and correlated these findings with echocardiographic measurements. We also examined the impact of omecamtiv mecarbil (OM) on these parameters. METHODS: The plasma levels of NT-proBNP and sST2 were measured in 18 rats both before and 2 months after surgical induction of AR, and at these same time points, in six rats assigned to a sham-procedure control group. Plasma biomarkers were then measured again after infusion of OM or placebo in rats with AR (n=8 and 10, respectively) and OM alone in the sham control rats (n=6). Echocardiographic measurements were collected before and 2 months after induction of AR. RESULTS: Our results revealed increased levels of plasma NT-proBNP (219 ± 34 pg/mL vs. 429 ± 374 pg/mL; p<0.001) in rats with AR at day 7 after infusion of placebo, whereas plasma levels of sST2 were higher in this cohort after infusion of either OM or placebo. We identified a significant positive correlation between plasma sST2 with posterior wall thickness in diastole (r=0.34, p<0.05) and total body weight (r=0.45, p<0.01) in rats with surgically induced AR. CONCLUSIONS: Because sST2 increased markedly, whereas NT-proBNP remained unchanged, when OM was administered, we hypothesize that sST2 has a distinct capability to detect deleterious effects of passive muscle tension, not reliably assessed by NT-proBNP, in the setting of AR.

The myosin activator omecamtiv mecarbil improves wall stress in a rat model of chronic aortic regurgitation.

In patients with chronic aortic regurgitation (AR), excessive preload and afterload increase left ventricle wall stress, leading to left ventricular systolic dysfunction. Thus, the objective of the present study was to evaluate the effects of the myosin activator omecamtiv mecarbil (OM) on left ventricle wall stress in an experimental rat model of severe chronic AR. Forty adult male Wistar rats were randomized into two experimental groups: induction of AR (acute phase) by retrograde puncture (n = 34) or a sham intervention (n = 6). Rats that survived the acute phase (n = 18) were randomized into an OM group (n = 8) or a placebo group (n = 10). Equal volumes of OM (1.2 mg/kg/h) or placebo (0.9% NaCl) were continuously infused into the femoral vein over 30 min. OM significantly decreased end-systolic and end-diastolic and maximum wall stress in this experimental rat model of chronic severe AR (p < 0.001) and increased systolic performance assessed by fractional shortening and left ventricle end-systolic diameter; both p < 0.05). These effects were correlated with decreased indices of global cardiac function (cardiac output and stroke volume; p < 0.05) but were not inferior to baseline pump indices. Infusion with placebo did not affect global cardiac function but decreased end-systolic wall stress (p < 0.05) and increased systolic performance (all p < 0.001). In the sham-operated (control) group, OM decreased diastolic wall stress (p < 0.05). Based on these results, OM had a favorable effect on left ventricle wall stress in an experimental rat model of severe chronic AR.

Interaction Between Sacubitril and Valsartan in Preventing Heart Failure Induced by Aortic Valve Insufficiency in Rats.

BACKGROUND: Synergistic interactions between neprilysin inhibition (NEPi) with sacubitril and angiotensin receptor type1 blockade (ARB) with valsartan have been implicated in improvement of left ventricular (LV) contractility, relaxation, exercise tolerance, and fibrosis in preexisting heart failure (HF) induced by aortic valve insufficiency (AVI). It is not known whether this pharmacologic synergy can prevent cardiovascular pathology in a similar AVI model. Our aim was to investigate the pharmacology of sacubitril/valsartan in an experimental setting with therapy beginning immediately after creation of AVI. METHODS: HF was induced through partial disruption of the aortic valve in rats. Therapy began 3 hours after valve disruption and lasted 8 weeks. Sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), sacubitril (31 mg/kg), or vehicle were administered daily via oral gavage (N=8 in each group). Hemodynamic assessments were conducted using Millar technology, and an exercise tolerance test was conducted using a rodent treadmill. RESULTS: Only sacubitril/valsartan increased total arterial compliance and ejection fraction (EF). Therapies with sacubitril/valsartan and valsartan similarly improved load-dependent (dP/dtmax) and load independent indices (Ees) of LV contractility, and exercise tolerance, whereas sacubitril did not. None of the therapies improved LV relaxation (dP/dtmin), whereas all reduced myocardial fibrosis. CONCLUSIONS: 1) The synergistic interaction between NEPi and ARB in early therapy with sacubitril/valsartan leads to increased total arterial compliance and EF. 2) Improvement in indices of LV contractility, and exercise tolerance with sacubitril/valsartan is likely because of ARB effect of valsartan. 3) All three therapies provided antifibrotic effects, suggesting both ARB and NEPi are capable of reducing myocardial fibrosis.

Effects of the cardiac myosin activator Omecamtiv-mecarbil on severe chronic aortic regurgitation in Wistar rats.

BACKGROUND: Aortic regurgitation (AR) is a valvular disease that can lead to systolic heart failure. Treatment options besides cardiac surgery are limited and consequently severe AR is associated with higher mortality and morbidity when not operated. In this investigation, we examined the effects of a novel cardiac myosin activator, Omecamtiv-mecarbil (OM), in rats with chronic severe AR. METHODS: AR was created by retrograde puncture of the aortic valve leaflets in 20 adults Wistar rats. 12 animals survived the acute AR phase and were randomized 2 months thereafter into OM (n = 7) or placebo groups (n = 5). Two rats underwent a sham operation and served as controls. Equal volumes of OM or placebo (NaCl 0.9%) were perfused in the femoral vein by continuous infusion (1.2 mg/kg/hour) during 30 min. Doppler-echocardiography was performed before and at the end of the infusion periods. RESULTS: OM increased indices of global cardiac function (cardiac output, stroke volume), and increased systolic performance (fractional shortening, ejection fraction, left ventricular end systolic diameter) (all p < 0.05). These effects concurred with decreases in indices of LV preload (left atrial size, left ventricular end diastolic diameter) as well in the aortic pre-ejection period / left ventricular ejection time ratio (all p < 0.05). The severity score of the regurgitant AR jet did not change. Placebo infusion did not affect these parameters. CONCLUSION: The cardiac myosin activator OM exerts favorable hemodynamic effects in rats with experimental chronic AR.

Warfarin-related nephropathy with acute kidney injury in a patient with immunoglobulin A nephropathy.

A 55-year-old man with Marfan syndrome taking warfarin for anticoagulant therapy after aortic valve replacement developed acute kidney injury (serum creatinine level of 9.01 mg/dL) and gross macrohematuria. Renal biopsy showed red cell casts in the renal tubules, glomerular crescent formation in the glomeruli with immunoglobulin A deposition, and global sclerosis. Based on these findings, the patient was diagnosed with warfarin-related nephropathy with acute kidney injury characterized by immunoglobulin A nephropathy with crescents. The warfarin was withdrawn, and his hematuria and renal function improved without immunosuppressive agents.

Problems in anticoagulation of a patient with antibiotic treatment for endocarditis: interaction of rifampicin and vitamin K antagonists.

The cytochrome P450 is a superfamily of isoenzymes that are responsible for the metabolism of many drugs. Significant changes in pharmacokinetics and drug interactions may be due to induction of hepatic cytochrome P450 enzymes. Rifampicin is a common inducer of CYP3A4. We report a case of a 57-year-old woman who was suspected for endocarditis and therefore treated with rifampicin. Due to previous mechanical aortic valve replacement, she also received phenprocoumon for anticoagulation. Although continuing anticoagulant therapy, antibiotic coadministration led to normal international normalised ratio (INR) level. Fifteen days after the treatment with rifampicin ended, INR returned to therapeutic level.

Aortic Regurgitation Presenting with Recurrent Detachment of a Prosthetic Valve, as the First Presenting Symptom of Cardiovascular Behçet's Disease.

A 33-year-old man with severe aortic regurgitation underwent initial aortic valve replacement (AVR). During the 2 years after AVR, 3 reoperations for prosthetic valve detachment were required. During hospitalization, he had no typical clinical findings, with the exception of a persistent inflammatory reaction; a pseudo-aneurysm around the Bentall graft developed 27 days after the 4th operation. This unique clinical course suggested the possibility of Behçet's disease. In the 8 years of follow-up after the administration of prednisolone, the pseudo-aneurysm did not become enlarged and the detachment of the prosthetic valve was not observed. We herein present a case of cardiovascular Behçet's disease, with a review of the literature.

Comparison of effects of losartan and metoprolol on left ventricular and aortic function at rest and during exercise in chronic aortic regurgitation.

Aortic regurgitation (AR) increases the hemodynamic load on both the left ventricle (LV) and the aorta. Vasodilators and beta-blockers both reduce systemic blood pressure, but their relative effects on the LV and aortic function and aortic regurgitant fraction in chronic AR are uncertain. We aimed to compare short-term effects of losartan and metoprolol on LV and aortic function in asymptomatic patients with chronic moderate to severe AR, both at rest and during exercise, using cardiac magnetic resonance (CMR) imaging. 17 chronic AR patients were randomized to 4-6 weeks losartan followed by metoprolol, or vice versa, in a cross-over design. Aortic regurgitant fraction, aortic distensibility, pulse wave velocity and LV function were assessed at rest and after moderate exercise stress (29 ± 7 W, heart rate increase 25 ± 6 bpm) using CMR. Chronic AR patients on metoprolol had a significantly lower mean heart rate, cardiac power index and rate-pressure product, than on losartan (all p < 0.01). However, aortic regurgitant fraction was greater on metoprolol compared to losartan (by 7 ± 11%, p = 0.02). Metoprolol was also associated with a greater reduction in aortic distensibility during exercise than losartan (- 2.4 ± 1.5 × 10-3 vs - 1.7 ± 2.1 × 10-3 mmHg-1 respectively, p = 0.04). End-diastolic volume index was higher on metoprolol than losartan at exercise (difference 6.6 ± 7.8 ml/m2, p < 0.01), as was end-systolic volume index (difference 4.0 ± 5.2 ml/m2, p < 0.01). Losartan and metoprolol have significantly different short-term effects on aortic regurgitation and LV and aortic function in chronic AR. Further research is required to determine the long-term clinical significance of these changes.

Preliminary investigation of orally administered benazepril in horses with left-sided valvular regurgitation.

BACKGROUND: Despite the paucity of data available, orally administered angiotensin-converting enzyme (ACE) inhibitors are empirically used in horses with valvular regurgitation. OBJECTIVE: Evaluate the echocardiographic and hormonal changes in response to oral benazepril in horses with left-sided valvular regurgitation. STUDY DESIGN: Prospective, randomised double-blind, placebo-controlled trial. METHODS: Horses with mitral valve (MR) and/or aortic valve regurgitation (AR) received oral benazepril (n = 6) at a dosage of 1 mg/kg q 12 h or a placebo (n = 5) for 28 days. Echocardiography was performed before drug administration and after 28 days of treatment. Plasma renin activity, serum ACE activity, angiotensin II concentration, aldosterone concentration and biochemical variables were measured before drug administration and after 7 and 28 days of treatment. RESULTS: Relative to baseline, horses treated with benazepril had statistically significant reduction in left ventricular internal diameter in systole (mean difference between groups = -0.97 cm; 95% CI = -1.5 to -0.43 cm), aortic sinus diameter (-0.31 cm; -0.54 to -0.07 cm), and percentage of the aortic annulus diameter occupied by the base of the AR jet (-17.05%; -31.17 to -2.93%) compared with horses receiving a placebo. In addition, horses treated with benazepril had a significantly greater increase in cardiac output (11.95 L/min; 1.17-22.73 L/min) and fractional shortening (7.59%; 3.3-11.88%) compared with horses receiving a placebo. Despite profound serum ACE inhibition, renin activity and concentrations of angiotensin II and aldosterone were not significantly different between treatment groups or among time points. MAIN LIMITATIONS: Very small sample size and short treatment period. CONCLUSIONS: Treatment with oral benazepril resulted in statistically significant echocardiographic changes that might indicate reduced cardiac afterload in horses with left-sided valvular regurgitation. Additional studies with a larger sample size will be necessary to determine if administration of benazepril is beneficial in horses with valvular regurgitation. The Summary is available in Spanish - see Supporting Information.

Reversibility of Cardiac Function Predicts Outcome After Transcatheter Aortic Valve Replacement in Patients With Severe Aortic Stenosis.

BACKGROUND: Reversibility of left ventricular (LV) dysfunction in high-risk aortic stenosis patient and its impact on survival after transcatheter aortic valve replacement (TAVR) are unclear. We aimed to evaluate longitudinal changes of LV structure and function after TAVR and their impact on survival. METHODS AND RESULTS: We studied 209 patients with aortic stenosis who underwent TAVR from May 2006 to December 2012. Echocardiograms were used to calculate LV end-diastolic volume index (LVEDVi), LV ejection fraction, LV mass index (LVMi), and global longitudinal strain before, immediately (<10 days), late (1-3 months), and yearly after TAVR. During a median follow-up of 1345 days, 118 patients died, with 26 dying within 1 year. Global longitudinal strain, LVEDVi, LV ejection fraction, and LVMi improved during follow-up. In patients who died during the first year, death was preceded by LVEDVi and LVMi increase. Multivariable longitudinal data analysis showed that aortic regurgitation at baseline, aortic regurgitation at 30 days, and initial LVEDVi were independent predictors of subsequent LVEDVi. In a joint analysis of longitudinal and survival data, baseline Society of Thoracic Surgeons score was predictive of survival, with no additive effect of longitudinal changes in LVEDVi, LVMi, global longitudinal strain, or LV ejection fraction. Presence of aortic regurgitation at 1 month after TAVR was the only predictor of 1-year survival. CONCLUSIONS: LV reverse remodeling was observed after TAVR, whereas lack of LVEDVi and LVMi improvement was observed in patients who died during the first year after TAVR. Post-TAVR, aortic regurgitation blocks reverse remodeling and is associated with poor 1-year survival after TAVR.

Impact of valvular heart disease on oral anticoagulant therapy in non-valvular atrial fibrillation: results from the RAMSES study.

The definition of non-valvular atrial fibrillation (NVAF) is controversial. We aimed to assess the impact of valvular heart disease on stroke prevention strategies in NVAF patients. The RAMSES study was a multicenter and cross-sectional study conducted on NVAF patients (ClinicalTrials.gov identifier NCT02344901). The study population was divided into patients with significant valvular disease (SVD) and non-significant valvular disease (NSVD), whether they had at least one moderate valvular disease or not. Patients with a mechanical prosthetic valve and mitral stenosis were excluded. Baseline characteristics and oral anticoagulant (OAC) therapies were compared. In 5987 patients with NVAF, there were 3929 (66%) NSVD and 2058 (34%) SVD patients. The predominant valvular disease was mitral regurgitation (58.1%), followed by aortic regurgitation (24.1%) and aortic stenosis (17.8%). Patients with SVD had higher CHA2DS2VASc [3.0 (2.0; 4.0) vs. 4.0 (2.0; 5.0), p < 0.001] and HAS-BLED [2.0 (1.0; 2.0) vs. 2.0 (1.0; 2.0), p = 0.004] scores compared to patients with NSVD. Overall, 2763 (71.2%) of NSVD and 1515 (73.8%) of SVD patients were on OAC therapy (p = 0.035). When the patients with SVD were analyzed separately, the mean CHA2DS2VASc and HAS-BLED scores were higher in patients with mitral regurgitation compared to patients with aortic regurgitation and aortic stenosis [4.0 (3.0; 5.0), 3.0 (2.0; 4.0), 3.0 (2.0; 4.0) p < 0.001 and 2.0 (1.0; 3.0), 1.0 (1.0; 2.0), 1.0 (0.0; 2.0) p < 0.001, respectively]. In patients with SVD, 65.7% of mitral regurgitation, 82.6% of aortic regurgitation and 88.0% of aortic stenosis patients were on OAC therapy. One out of three NVAF patients had at least one moderate valvular heart disease with the predominance of mitral regurgitation. Patients with SVD were at greater risk of stroke and bleeding compared to patients with NSVD. Although patients with mitral regurgitation should be given more aggressive anticoagulant therapy due to their higher risk of stroke, they are undertreated compared to patients with aortic valve diseases.

Effects of lorcaserin on pre-existing valvulopathy: A pooled analysis of phase 3 trials.

OBJECTIVE: To evaluate the effects of lorcaserin in patients with pre-existing Food and Drug Administration (FDA)-defined valvulopathy. METHODS: This is a pooled, post hoc analysis of three Phase 3 studies. BLOOM and BLOSSOM patients were 18 to 65 years of age without diabetes and with a body mass index (BMI) of 27 to 29.9 kg/m2 and ≥1 weight-related comorbidity or a BMI of 30 to 45 kg/m2 . BLOOM-DM patients had a BMI of 27 to 45 kg/m2 and type 2 diabetes. Patients were treated with placebo, lorcaserin 10 mg once daily, or lorcaserin 10 mg twice daily. Serial echocardiographs were obtained at baseline and every 6 months. RESULTS: Included patients (N = 169) had FDA-defined valvulopathy at baseline and a week 52 echocardiogram. At week 52, 35.5% and 52.7% of patients experienced changes from baseline in aortic and mitral regurgitation, respectively. Numerically greater proportions of patients taking lorcaserin versus placebo had decreases in aortic (33.0% vs. 28.3%) or mitral (41.3% vs. 36.7%) regurgitation. Fewer patients taking lorcaserin versus placebo had increases in aortic (2.8% vs. 6.7%) or mitral (8.3% vs. 21.7%) regurgitation. No adverse event-related discontinuation was due to a valve problem. CONCLUSIONS: These data suggest that lorcaserin does not adversely affect valvular disease in patients with pre-existing FDA-defined valvulopathy.

Non-prescription proton-pump inhibitors for self-treating frequent heartburn: the role of the Canadian pharmacist

Heartburn and acid regurgitation are the cardinal symptoms of gastroesophageal reflux and occur commonly in the Canadian population. Multiple non-prescription treatment options are available for managing these symptoms, including antacids, alginates, histamine-H2 receptor antagonists (H2RAs), and proton-pump inhibitors (PPIs). As a result, pharmacists are ideally positioned to recommend appropriate treatment options based upon an individual’s needs and presenting symptoms, prior treatment response, comorbid medical conditions, and other relevant factors. Individuals who experience mild heartburn and/or have symptoms that occur predictably in response to known precipitating factors can manage their symptoms by avoiding known triggers and using on-demand antacids and/or alginates or lower-dose non-prescription H2RAs (e.g. ranitidine 150 mg). For those with moderate symptoms, lifestyle changes, in conjunction with higher-dose non-prescription H2RAs, may be effective. However, for individuals with moderate-to-severe symptoms that occur frequently (i.e. ≥2 days/week), the non-prescription (Schedule II) PPI omeprazole 20 mg should be considered. The pharmacist can provide important support by inquiring about the frequency and severity of symptoms, identifying an appropriate treatment option, and recognizing other potential causes of symptoms, as well as alarm features and atypical symptoms that would necessitate referral to a physician. After recommending an appropriate treatment, the pharmacist can provide instructions for its correct use. Additionally, the pharmacist should inquire about recurrences, respond to questions about adverse events, provide monitoring parameters, and counsel on when referral to a physician is warranted. Pharmacists are an essential resource for individuals experiencing heartburn; they play a crucial role in helping individuals make informed self-care decisions and educating them to ensure that therapy is used in an optimal, safe, and effective manner (AU)

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Long-Term Survival on Medical Therapy Alone after Blunt-Trauma Aortic Regurgitation: Report of a New Case with Summary of 95 Others.

Aortic regurgitation resulting from blunt chest trauma has been reported only 95 times, to our knowledge. The noncoronary and right coronary cusps are the cardiac structures most often injured. Although the aortic leaflets can appear to be undamaged after nonpenetrating trauma, they can have pathologic abnormalities and insufficient function. Some cases of posttraumatic aortic regurgitation progress slowly. Aortic valve replacement is the optimal treatment. We present the case of a then-62-year-old man who has lived more than 5 years after blunt-trauma aortic regurgitation. His is the only case of long-term survival on medical therapy alone among the 96 cases summarized in this report.