Color Doppler Splay in Mitral Regurgitation: Hemodynamic Correlates and Outcomes in a Clinical Cohort.

BACKGROUND: Recently, an artifactual horizontal extension of the color Doppler signal was described in patients with mitral regurgitation (MR), called color Doppler splay (CDS). This side-lobe artifact was shown to be associated with concealed and significant MR. In the present study, the authors assessed the prognostic significance of CDS and its hemodynamic correlates. METHODS: Consecutive patients with primary and secondary MR underwent comprehensive transthoracic echocardiography. Machine settings were fixed for all patients. MR severity was assessed using an integrated approach, as advocated in current international guidelines. The presence of CDS and CDS width and duration were assessed. The outcome measures included the incidence of major adverse cardiac events (a composite of cardiovascular mortality, hospitalization for decompensated heart failure, mitral valve surgery, or percutaneous mitral intervention). RESULTS: One hundred twenty-seven of 469 patients (27%) with MR demonstrated CDS. The presence of CDS was associated with worse MR, and CDS width correlated with effective regurgitant orifice area, regurgitant volume, and vena contracta width. Mitral annular or leaflet calcification was inversely associated with the presence of CDS. Patients with CDS experienced worse event-free survival. For CDS width, a cutoff of >29 mm was identified as optimal regarding outcome prediction in our cohort and termed "severe CDS." In multivariate Cox regression, the presence of severe CDS was associated with adverse outcome, independent of MR etiology or severity and other clinical and echocardiographic predictors of outcome, and provided incremental prognostic value on top of these parameters. CONCLUSIONS: In patients with MR, the presence of CDS is associated with more severe MR and worse outcomes. Severe CDS provides incremental prognostic value on top of traditional MR metrics and should alert the echocardiographer that MR severity may be underestimated.

Propionyl-L-carnitine for intermittent claudication.

BACKGROUND: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis. Intermittent claudication is a symptomatic form of PAD that is characterized by pain in the lower limbs caused by chronic occlusive arterial disease. This pain develops in a limb during exercise and is relieved with rest. Propionyl-L-carnitine (PLC) is a drug that may alleviate the symptoms of PAD through a metabolic pathway, thereby improving exercise performance. OBJECTIVES: The objective of this review is to determine whether propionyl-L-carnitine is efficacious compared with placebo, other drugs, or other interventions used for treatment of intermittent claudication (e.g. exercise, endovascular intervention, surgery) in increasing pain-free and maximum walking distance for people with stable intermittent claudication, Fontaine stage II. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and the ClinicalTrials.gov trials register to July 7, 2021. We undertook reference checking and contact with study authors and pharmaceutical companies to identify additional unpublished and ongoing studies. SELECTION CRITERIA: Double-blind randomized controlled trials (RCTs) in people with intermittent claudication (Fontaine stage II) receiving PLC compared with placebo or another intervention. Outcomes included pain-free walking performance (initial claudication distance - ICD) and maximal walking performance (absolute claudication distance - ACD), analyzed by standardized treadmill exercise test, as well as ankle brachial index (ABI), quality of life, progression of disease, and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, and evaluated trials for risk of bias. We contacted study authors for additional information. We resolved any disagreements by consensus. We performed fixed-effect model meta-analyses with mean differences (MDs) and 95% confidence intervals (CIs). We graded the certainty of evidence according to GRADE. MAIN RESULTS: We included 12 studies in this review with a total number of 1423 randomized participants. A majority of the included studies assessed PLC versus placebo (11 studies, 1395 participants), and one study assessed PLC versus L-carnitine (1 study, 26 participants). We identified no RCTs that assessed PLC versus any other medication, exercise, endovascular intervention, or surgery. Participants received PLC 1 grams to 2 grams orally (9 studies) or intravenously (3 studies) per day or placebo. For the comparison PLC versus placebo, there was a high level of both clinical and statistical heterogeneity due to study size, participants coming from different countries and centres, the combination of participants with and without diabetes, and use of different treadmill protocols. We found a high proportion of drug company-backed studies. The overall certainty of the evidence was moderate. For PLC compared with placebo, improvement in maximal walking performance (ACD) was greater for PLC than for placebo, with a mean difference in absolute improvement of 50.86 meters (95% CI 50.34 to 51.38; 9 studies, 1121 participants), or a 26% relative improvement (95% CI 23% to 28%). Improvement in pain-free walking distance (ICD) was also greater for PLC than for placebo, with a mean difference in absolute improvement of 32.98 meters (95% CI 32.60 to 33.37; 9 studies, 1151 participants), or a 31% relative improvement (95% CI 28% to 34%). Improvement in ABI was greater for PLC than for placebo, with a mean difference in improvement of 0.09 (95% CI 0.08 to 0.09; 4 studies, 369 participants). Quality of life improvement was greater with PLC (MD 0.06, 95% CI 0.05 to 0.07; 1 study, 126 participants). Progression of disease and adverse events including nausea, gastric intolerance, and flu-like symptoms did not differ greatly between PLC and placebo. For the comparison of PLC with L-carnitine, the certainty of evidence was low because this included a single, very small, cross-over study. Mean improvement in ACD was slightly greater for PLC compared to L-carnitine, with a mean difference in absolute improvement of 20.00 meters (95% CI 0.47 to 39.53; 1 study, 14 participants) or a 16% relative improvement (95% CI 0.4% to 31.6%). We found no evidence of a clear difference in the ICD (absolute improvement 4.00 meters, 95% CI -9.86 to 17.86; 1 study, 14 participants); or a 3% relative improvement (95% CI -7.4% to 13.4%). None of the other outcomes of this review were reported in this study. AUTHORS' CONCLUSIONS: When PLC was compared with placebo, improvement in walking distance was mild to moderate and safety profiles were similar, with moderate overall certainty of evidence. Although In clinical practice, PLC might be considered as an alternative or an adjuvant to standard treatment when such therapies are found to be contraindicated or ineffective, we found no RCT evidence comparing PLC with standard treatment to directly support such use.

Average pixel intensity method for prediction of outcome in secondary mitral regurgitation.

BACKGROUND: Echocardiographic grading of secondary mitral regurgitation (SMR) severity is challenging and involves multiple guideline-recommended parameters. We previously introduced the average pixel intensity (API) method for grading SMR. In this study, the clinical outcome in SMR based on the API method for grading MR was compared with conventional grading methods. METHODS: 231 patients with systolic heart failure and reduced ejection fraction (ischaemic/non-ischaemic) and SMR were prospectively enrolled. MR was graded using all guideline-recommended parameters and the API method, which is based on the pixel intensity of the continuous wave Doppler signal. The primary outcome was MACE (major adverse cardiac event). RESULTS: The API method was applicable in 98% of patients with SMR (n=227). During a median follow-up of 24 months, 98 patients (43%) had a MACE (cardiovascular mortality (n=50, 22%), heart failure hospitalisation (n=44, 19%), mitral valve surgery (n=11, 5%), percutaneous mitral intervention (n=12, 5%), heart transplantation (n=5, 2%)). On log-rank test, the API method was highly significant in predicting clinical outcome. On multivariable Cox proportional hazard analysis, SMR grading with the API method was an independent predictor of clinical outcome (along with NYHA class and right ventricular systolic pressure; p<0.001), increasing the event risk by 9% per 10 au API rise (p=0.001). In the same multivariable analysis, proximal isovelocity surface area (PISA)-effective regurgitant orifice area or PISA-regurgitant volume were not independent predictors of events (p=0.18 and 0.26, respectively). CONCLUSION: SMR grading with the API method is an independent predictor of clinical outcome and provides prognostic information in addition to clinical and other echocardiographic variables.

The Average Pixel Intensity Method and Outcome of Mitral Regurgitation in Mitral Valve Prolapse.

BACKGROUND: Mitral regurgitation (MR) is a frequent consequence of mitral valve prolapse (MVP). However, the echocardiographic grading of MR is challenging, and the recommended grading parameters have several limitations. The authors developed a novel echocardiographic parameter to grade MR, the average pixel intensity (API) method, on the basis of pixel intensity analysis of the continuous-wave Doppler signal. METHODS: Transthoracic echocardiography was performed prospectively in consecutive patients with MVP (N = 149). MR was quantitatively assessed using the API method, vena contracta width, effective regurgitant orifice area, and regurgitant volume. The primary clinical events were cardiovascular mortality, mitral valve surgery, percutaneous mitral intervention, and heart failure hospitalization. RESULTS: The API method was feasible in 90% of all patients with MVP, which was significantly higher than vena contracta width, effective regurgitant orifice area, and regurgitant volume. During a median follow-up period of 17 months, 44 patients (32%) had major adverse cardiac events, and the majority of events occurred in the holosystolic MVP subgroup. The degree of MR severity by the API method was highly significant for the prediction of events. An API cutoff of 111 arbitrary units was defined as "severe" MR due to MVP, with overall superior sensitivity and specificity compared with cutoffs for established MR grading parameters. In patients who did not have major adverse cardiac events during the follow-up period (n = 92), no significant changes in measures of MR severity were found on follow-up echocardiography. CONCLUSIONS: The API method is predictive of clinical events and outcomes in MR due to MVP. Therefore, the API method may be considered for grading the severity of MR due to MVP in clinical practice.