Effectiveness of polypill for primary and secondary prevention of cardiovascular disease: a pragmatic cluster-randomised controlled trial (PolyPars).

BACKGROUND: We aimed to investigate the effectiveness of fixed-dose combination therapy (polypill) for primary and secondary prevention of major cardiovascular diseases in a typical rural setting. METHODS: The PolyPars Study is a two-arm pragmatic cluster-randomised trial nested within the PARS cohort study, including all residents aged over 50 years in the entire district in southern Iran. The 91 villages underwent random allocation into two arms: the control arm, encompassing 45 clusters, was subjected to non-pharmacological intervention (educational training on healthy lifestyle), whereas the intervention arm, comprising 46 clusters, received the non-pharmacological interventions in conjunction with a once-daily polypill tablet. This tablet comprised two antihypertensive agents, a statin and aspirin. The primary outcome was the first occurrence of major cardiovascular events defined as a composite of hospitalisation for acute coronary syndrome (non-fatal myocardial infarction and unstable angina), fatal myocardial infarction, non-fatal and fatal stroke, sudden death and heart failure. The Cox regression model, with shared frailty, was used to account for clustering effect. RESULTS: During December 2015-December 2016, a total of 4415 participants aged 50-75 years were recruited (2200 participants in the intervention arm and 2215 participants in the control arm). The overall median of follow-up duration was 4.6 years (interquartile interval 4.4-4.9). The achieved adherence rate to polypill in intervention arm was 86%. In the control group, 176 (8.0%) of 2215 participants developed primary outcome, compared with 88 (4.0%) of 2200 participants in the polypill group. We found substantial reduction in risk of primary outcome both in relative and absolute scales (HR 0.50, 95% CI 0.38 to 0.65; absolute risk reduction 4.0%, 95% CI 2.5% to 5.3%). No difference in serious adverse events was observed between the two groups. CONCLUSIONS: The fixed-dose combination therapy using polypill can safely halve the risk of major cardiovascular diseases at the population level. TRIAL REGISTRATION NUMBER: NCT03459560.

The evaluation of bariatric surgery effect on cardiac structure and function using transthoracic echocardiography: a cohort study.

BACKGROUND: Obesity is a pathology and a leading cause of death worldwide. Obesity can harm multiple organs, including the heart. In this study, we aim to investigate the effect of bariatric surgery and following weight loss on cardiac structure and functions using echocardiography parameters in patients with morbid obesity. METHODS: In this cohort study, 30 patients older than 18 with BMI > 40 or BMI > 35 and comorbidity between March 2020 to March 2021 were studied. The patients underwent transthoracic echocardiography before and after six months of the bariatric surgery. RESULTS: In total, 30 patients (28 women, 93.3%) with a mean age of 38.70 ± 9.19 were studied. Nine (30%) were diabetic, and 9 (30%) had hypertension. After six months of bariatric surgery, all physical measurements, including weight, Body mass index, and Body surface area, decreased significantly (p < 0.001). After bariatric surgery, all parameters regarding left ventricular morphology, including left ventricular mass, interventricular septal thickness, left ventricular posterior wall thickness, left ventricular end-systolic diameter, and left ventricular end-diastolic diameter, improved significantly (p < 0.001). Also, LVEF rose post-bariatric surgery (p < 0.001). TAPSE parameter indicating right ventricular function also improved (p < 0.001). Right ventricular diameter, left atrium volume, and mitral inflow E/e' decreased significantly (p < 0.001). CONCLUSION: Systolic and diastolic parameters refine significantly after bariatric surgery in patients with obesity. Bariatric surgery lead to significant cardiac structure and function improvement.

Global longitudinal strain for detection of cardiac iron overload in patients with thalassemia: a meta-analysis of observational studies with individual-level participant data.

BACKGROUND: Although cardiac magnetic resonance (CMR) is the most reliable tool for assessment of CIO in patients with thalassemia, it is not always readily available. Recent studies have explored the potential of GLS as an alternative for diagnosis of CIO. We aimed to investigate the efficacy of global longitudinal strain (GLS) for detection of cardiac iron level (CIO). METHODS: We searched SCOPUS, MEDLINE, and Embase to identify the studies which used GLS for assessment of CIO. We searched for individual participant data (IPD) in eligible studies to perform ROC curve analysis. CMR with a T2* cut-off value of 20 ms was considered as the gold standard. A meta-analysis was performed and the risk of bias was assessed using the JBI Checklist. RESULTS: A total of 14 studies with 789 thalassemia patients (310 and 430 with and without CIO respectively and 49 with undetermined condition) were considered eligible for meta-analysis. IPDs of 405 participants were available. GLS was significantly lower in patients with CIO (-17.5 ± 2.7%) compared to those without CIO (-19.9 ± 2.3%; WMD = 1.6%, 95% CI = [0.76-2.4], p = 0.001, I2 = 77.1%) and to normal population (-20.61 ± 2.26%; WMD = 2.2%, 95% CI = [0.91-3.5], p = 0.001, I2 = 83.9%). A GLS < -19.5% could predict CIO with 92.8% sensitivity and 34.63% specificity (AUC = 0.659, 95% CI = [0.6-0.72], p-value < 0.0001). A GLS value < -6% has 100% positive predictive and ≥ -24.5% has 100% negative predictive values for detection of CIO. CONCLUSIONS: According to our study, GLS is a strong predictor of CIO and when CMR is not available, it may be a useful screening method for identification of CIO in thalassemia patients.

Left ventricular thrombosis and endogenous endophthalmitis in the setting of COVID-19: A case report.

Aside from typical pneumonia, the coronavirus disease 2019 (COVID-19) has shown several extra-pulmonary manifestations. This study was done on a 66-year-old male patient who concomitantly had endogenous endophthalmitis and left ventricular thrombosis one month after being hospitalized due to COVID-19.

Sildenafil for Primary Prevention of Anthracycline-Induced Cardiac Toxicity: A Phase I/II Randomized Clinical Trial, SILDAT-TAHA6 Trial.

Background: Previous animal studies have shown a protective effect of 5-phosphodiesterase inhibitors on cancer therapeutics-related cardiac dysfunction (CTRCD) of anthracyclines. Aim: The aim of this study was to evaluate the clinical effect of sildenafil on the primary prevention of CTRCD in human. Materials and Methods: In this randomized double-blind clinical trial, the primary end point was efficacy in preventing the reduction of left ventricular ejection fraction (LVEF). The intervention group patients received sildenafil at a dose of 25 milligrams twice a day before starting the chemotherapeutic regimen, and the control group received placebo. All the patients at baseline and after the 6-month follow-up underwent 4D and speckle-tracking echocardiography and cardiac MRI, accompanied by hs-troponin I and NT-Pro-BNP measurement. Results: Sixty patients were enrolled in this study, and data from 52 patients (24 patients in the intervention group and 28 patients in the control group) were used in the final analysis. Our findings showed that in the intervention and control groups, LVEF was dropped from 61.28 ± 7.36 to 51.57 ± 7.67 (difference (D) = -9.71 ± 11.95, p=0.003) and from 57.9 ± 7.29 to 50.2 ± 7.02% (D = -7.7 ± 5.93; p=0.001), respectively (between-group difference = -2.01%, p=0.26). CTRCD was detected in 11 patients in the control group (42.8%) and 10 in the intervention group (41.6%, p=0.51). Conclusion: Consumption of sildenafil for primary prevention of anthracycline-induced cardiac toxicity seems to be unbeneficial. This trial is registered with IRCT20180506039554N1.

Alarm of non-communicable disease in Iran: Kavar cohort profile, baseline and 18-month follow up results from a prospective population-based study in urban area.

The PERSIAN Kavar cohort study (PKCS) aims to investigate the prevalence, trends, and relevant prognostic risk factors of non-communicable diseases in participants aged 35-70 years living in the urban area of Kavar County. Kavar County is located at the center of Fars province in the southwest of Iran. Overall, 5236 adults aged 35-70 years old were invited to participate in the PKCS. From whom, 4997 people comprising 2419 men and 2578 women met the inclusion criteria and were recruited in the study (participation rate: 95.4%). This study is aimed to follow participants for at least 10 years; it is designed to perform all procedures similar to the primary phase including biological sampling, laboratory tests, physical examinations, and collecting general, nutritional, and medical data at the 5th and 10th years of follow-up. In addition, participants are annually followed-up by phone to acquire data on the history of hospitalization, any major diagnosis or death. At the enrollment phase, trained interviewers were responsible for obtaining general, nutritional, and medical data utilizing a 482-item questionnaire. The results of the baseline phase of this study show that the overweight category was the most prevalent BMI category among the registered participants (n = 2005, 40.14%). Also, almost one-third of Kavar adult population suffered from metabolic syndrome at the baseline phase (n = 1664, 33.30%). The rate of eighteen-month follow-up response was 100% in the PKCS. Hypertension (n = 116, 2.32%), cardiovascular outcomes (n = 33, 0.66%), and diabetes (n = 32, 0.64%) were the most prevalent new-onset NCDs during eighteen months of follow-up in the participants.

Right ventricular free wall strain for detection of anthracycline induced cardiac toxicity.

Anthracycline agents are routinely used for treatment of many types of malignancy, while imposing the risk for cardiotoxicity (AT-CMP). Although the right ventricle (RV) is more susceptible to cardiotoxicity, most of the studies have focused on left ventricle (LV) function for monitoring AT-CMP. In this study, we have focused on RV function before and after chemotherapy using two-dimensional speckle tracking Echocardiography. In this prospective study, newly diagnosed and untreated cancerous patients without previous cardiovascular diseases were enrolled. For all patients, baseline echocardiography was performed before the initiation of the anthracycline regimen and after 6 months of follow up when the chemotherapy was stopped. Several parameters of LV and RV function were measured using 3D echocardiography and STE techniques. 60 patients were enrolled in the study. There was a significant decrease (P = 0.001) in RV fractional area change (53.57% ± 4.36 vs. 45.66% ± 6.19), RV Global longitudinal strain (GLS) (- 22.93% ± 1.95 vs. - 18.53 ± 2.75), and RV free wall strain (FWLS) (- 25.75% ± 3.01 VS. - 20.30 ± 3.78). There was a significant decline in LVEF (59.42 ± 6.36% vs. 51.1 ± 6.31%) and LV-GLS (- 21.1 ± 1.8% vs - 18.6 ± 2.6%) (both P = 0.001) as well. Among the parameters changed following chemotherapy, RV-FWLS was dropped to a pathological level in 25% of patients showing the highest potential for detection of anthracyclines effect on the myocardium. Anthracycline therapy can induce subclinical RV dysfunction. In this clinical setting, RV free wall strain shows a great ability to exhibit deleterious effects of anthracyclines on the myocardium. This finding needs to be confirmed in future and larger studies.

Correction: Effectiveness of Polypill for Prevention of Cardiovascular Disease (PolyPars): Protocol of a Randomized Controlled Trial.

This corrects the article "Effectiveness of polypill for prevention of cardiovascular disease (PolyPars): protocol of a randomized controlled trial" published on 2020: Volume 23, Issue 08, Pages 548-556. Correction to: Arch Iran Med. 2020;23(8):548-556. doi: 10.34172/aim.2020.58. In the original version of this article, the recruitment period was wrongly reported to last from December 2014 to December 2015 in abstract and methods sections of the article. This is corrected into "from December 2015 to December 2016" in the PDF and HTML versions of the article. Also the "PolyIran" is changed to "PolyPars" in the last paragraph of the discussion section in the PDF and HTML versions of the article.

Effectiveness of Polypill for Prevention of Cardiovascular Disease (PolyPars): Protocol of a Randomized Controlled Trial.

BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death in Iran. A fixed-dose combination therapy (polypill) was proposed as a cost-effective strategy for CVD prevention, especially in lower-resource settings. We conducted the PolyPars trial to assess the effectiveness and safety of polypill for prevention of CVD. METHODS: The PolyPars trial is a pragmatic cluster randomized controlled trial nested within the Pars Cohort Study. Participants were randomized to an intervention arm and a control arm. Participants in the control arm received minimal non-pharmacological care, while those in the intervention arm received polypill in addition to minimal care. The polypill comprises hydrochlorothiazide 12.5 mg, aspirin 81 mg, atorvastatin 20 mg, and either enalapril 5 mg or valsartan 40 mg. The primary outcome of the study is defined as the first occurrence of acute coronary syndrome (non-fatal myocardial infarction and unstable angina), fatal myocardial infarction, sudden cardiac death, new-onset heart failure, coronary artery revascularization procedures, transient ischemic attack, cerebrovascular accidents (fatal or non-fatal), and hospitalization due to any of the mentioned conditions. The secondary outcomes of the study include adverse events, compliance, non-cardiovascular mortality, changes in blood pressure, fasting blood sugar, and lipids after five years of follow-up. RESULTS: From December 2014 to December 2015, 4415 participants (91 clusters) were recruited. Of those, 2200 were in the polypill arm and 2215 in the minimal care arm. The study is ongoing. This trial was registered with ClinicalTrials.gov number NCT03459560. CONCLUSION: Polypill may be effective for primary prevention of CVDs in developing countries.

Fragmented QRS as an early predictor of left ventricular systolic dysfunction in healthy individuals: a nested case-control study in the era of speckle tracking echocardiography.

BACKGROUND: Several studies addressed the association between fragmented QRS (fQRS) on 12-lead EKG and left ventricular (LV) dysfunction in patients with a variety of cardiovascular disorders. We tested such association in healthy individuals. METHODS: Out of 500 healthy participants without -overt cardiovascular disease from the Shiraz Heart Study cohort, we identified 20 subjects with fQRS (cases) and 20 peers without fQRS (controls). Global LV longitudinal strain (GLS) was measured by speckle tracking echocardiography in the two groups. Comparison was made between case and control groups by using chi-square or independent sample t-test or ANOVA. RESULTS: Age, gender, ejection fraction, LV volume and dimensions did not differ between the case and the control groups. Overall, 14 subjects out of 40 had reduced GLS (≤20%) and 10 of them (25%) had fQRS. GLS was significantly lower in the group with fQRS than in the control group (19.9 ± 1.8 vs 21.4 ± 1.6; p = 0.009). CONCLUSIONS: Healthy subjects with fQRS present regional LV systolic dysfunction, assessed by GLS, in the presence of a normal ejection fraction. These data suggest that fQRS may be a promising tool to identify apparently healthy subjects with regional LV systolic dysfunction.

Global longitudinal strain as an Indicator of cardiac Iron overload in thalassemia patients.

BACKGROUND AND OBJECTIVE: Cardiac involvement due to iron overload is the most common cause of morbidity and mortality in patients with thalassemia, and many patients remain asymptomatic until the late stages. Therefore, early detection of heart problems in such patients at subclinical stages can improve the prognosis of these patients. We investigated the role of speckled tracking (SI) and tissue Doppler echocardiography (TDI) in early detection of iron overload in these patients. METHODS: 52 thalassemic patients who were receiving regular blood transfusion with normal global LV function were examined by two- and three-dimensional echocardiography. Cardiac MRI was done and T2* images were considered as the non-invasive gold standard for evaluating cardiac iron deposition. Serum ferritin level was assessed and the relationships between serum ferritin levels and echo finding with cardiac MRI T2* was investigated. RESULTS: No significant relationship was seen between serum ferritin levels and cardiac MRI T2*. Among the echocardiographic findings, septal systolic myocardial velocity (P = 0.002 and r = 0.43) and global strain (GLS) (P = 0.000 and r = 0.60) were significantly associated with T2*. A GLS < 19.5 could predict a T2* level below 20 by 82.14% sensitivity and 86.36% specificity (area under the curve = 0.87; p < 0.0001). CONCLUSION: While serum ferritin level and ejection fraction are not useful candidates, GLS may be used as a valuable marker to screen thalassemia patients for myocardial iron deposition, using a cut off value below - 19.5. This approach may facilitate the cardiac follow up, reduce the costs, and contribute to preventing deterioration of cardiac function in countries with limited availability of cardiac MRI.

Reduced myocardial reserve in cirrhotic patients: an evaluation by dobutamine stress speckle tracking and tissue Doppler imaging (TDI) echocardiography.

Introduction: Despite the normal systolic function at rest, cirrhotic patients often suffer from volume overload and symptoms of heart failure as they face stressful situations. This study investigated the myocardial reserve in cirrhotic patients at resting condition and peak stress by dobutamine speckle tracking echocardiography (STE) and tissue Doppler imaging (TDI). Methods: Twenty cirrhotic patients and 10 normal individuals aged 30-50 were selected randomly. For all of the participants, complete echocardiographic study of 2D, STE and TDI was done at rest and peak stress status with dobutamine. The following parameters were assessed: ejection fraction (EF), global longitudinal LV strain (GLS), strain rate in the septal basal segment and lateral wall and E' in the septal basal segment by color-coded method. Results: At baseline, EF was higher than 55% in both groups. GLS was higher (-22.6±2.4%) in the case group than the control group (-19.2±1.9%) at resting condition. After stress, it showed a greater increase (-22.5±1.7%) in the controls compared to cirrhotic patients (-22.6±3.3%; mean difference = 2.6 ± 2.03, P = 0.02). In cirrhotic patients, the average strain rate in the basal septal segment decreased after stress (-1.2 ± 0.3/s to-1.1 ± 0.3/s), but it increased in the control group (-1.1 ± 0.2/s to -1.8 ± 0.2/s). Conclusion: Despite the presence of normal resting systolic function in cirrhotic patients, there was insufficient increase or even a decrease in myocardial function with stress; this may indicate the absence of sufficient myocardial reserve in cirrhotic patients. These findings would help to explain the reason for occurrence of heart failure or hemodynamic changes in cirrhotic patients.

Assessment of Subclinical Myocardial Changes in Non-Alcoholic Fatty Liver Disease: A Case-Control Study Using Speckle Tracking Echocardiography.

BACKGROUND: Considering the association between cardiac abnormalities and non-alcoholic fatty liver disease (NAFLD), the present study aimed to evaluate the relationship between biopsy-proven NAFLD and functional echocardiographic parameters, including left ventricular (LV) global longitudinal strain (GLS) in asymptomatic individuals. METHODS: Thirty asymptomatic patients with liver biopsy-proven NAFLD and the same number with no evidence of fatty liver in ultrasonography were enrolled in the study as cases and controls, respectively. The measured echocardiographic parameters included LV ejection fraction (LVEF), LV end-systolic and end-diastolic dimensions (ESD, EDD), LV end-systolic and end-diastolic volumes (ESV, EDV), E/e' ratio (early-diastolic mitral inflow velocity/early-diastolic myocardial velocity), E/A ratio (early-diastolic mitral inflow velocity/late-diastolic mitral inflow velocity), and GLS. Data were analyzed using the SPSS statistical software (version 18.0) by performing the independent t test, Chi-square, and non-parametric Mann-Whitney U tests. P values <0.05 were considered statistically significant. RESULTS: A significant difference in ESD (32.1±1.4 mm vs. 34±1.8 mm), EDD (41.9±1.7 mm vs. 45.2±3.1 mm), and E/e' ratio (8.4±0.8 vs. 7.4±1.2) was detected among individuals with NAFLD compared with those without NAFLD (P<0.001 for the first two parameters and P=0.002 for the last one). GLS was also significantly lower in NAFLD patients than in controls, but within normal levels (19.3%±2.0 vs. 21.2%±1.4, P<0.001). CONCLUSION: The findings support the presence of subclinical cardiovascular structural and functional changes in patients affected by NAFLD. It also indicates that the use of GLS is more sensitive than LVEF for the detection of LV systolic dysfunction in NAFLD patients.

Incremental Value of Live/Real Time Three-Dimensional over Two-Dimensional Transesophageal Echocardiography in the Assessment of Atrial Septal Pouch.

An atrial septal pouch (ASP) results from partial fusion of the septum primum and the septum secundum, and depending on the site of fusion, the pouch can be left-sided (LASP) or right-sided (RASP). LASPs have been described in association with thrombi found in patients admitted with acute strokes, raising awareness of its potential cardioembolic role, especially in those with no other clearly identifiable embolic source. We retrospectively studied 39 patients in whom the presence of an ASP had been identified by three-dimensional transesophageal echocardiography (3DTEE) and who had a two-dimensional transesophageal echocardiogram (2DTEE) performed during the same clinical encounter. The incremental value provided by 3DTEE over 2DTEE included the detection of six ASPs not found by 2DTEE; the detection of two ASPs in the same subject (in four patients) not identified by 2DTEE; larger ASP measurements of length and height in over 80% of the cases; and measurement of the ASP width (elevational axis) for the calculation of the area of the ASP opening, because of its unique capability to view the pouch en face. In addition, the volume of ASP and of the echogenic masses contained in the ASP (four of 39 patients) could be calculated by 3DTEE, which is a superior parameter of size characterization when compared to individual dimensions. One of these patients who presented with ischemic stroke diagnosed by magnetic resonance imaging had a large (>2 cm) mass in a LASP, with echolucencies similar to those seen in thrombi and associated with clot lysis and resolution. This mass completely disappeared on anticoagulant therapy lending credence that it was most likely a thrombus. There was no history of stroke or any other type of embolic event in the other three patients with masses in ASP. In conclusion, this retrospective study highlights the incremental value of 3DTEE over 2DTEE in the comprehensive assessment and characterization of ASPs, which can aid in the clarification of their role in cryptogenic stroke patients.

Incremental value of live/real time three-dimensional transesophageal echocardiography over the two-dimensional technique in the assessment of primary cardiac malignant fibrous histiocytoma.

We describe a case of primary cardiac malignant fibrous histiocytoma where live/real time three-dimensional transesophageal echocardiography added incremental value to the two-dimensional modalities. Specifically, the three-dimensional technique allowed us to delineate the true extent and infiltration of the tumor, to identify characteristics of the tumor mass suggestive of its malignant nature, and to quantitatively assess the total tumor burden.

Coronary flow reserve, strain and strain rate imaging during pharmacological stress before and after percutaneous coronary intervention: comparison and correlation.

INTRODUCTION: Coronary flow reserve (CFR) could apply reliable information about the coronary circulation, and strain (S) and strain rate imaging (SRI) are able to quantify the left ventricular myocardial performance. The aim of this study was to assess myocardial performance in relation to the function of the coronary circulation before and after successful percutaneous coronary intervention (PCI) of the left anterior descending artery. MATERIAL AND METHOD: Fourteen patients (10 men, 4 women, mean age 53.2 ± 11.4 years) with severe left anterior descending stenosis who had a successful selective PCI were recruited into this study. CFR and myocardial deformity indices (S and SR) were recorded before and after percutaneous intervention, both at rest and during stress echo test. RESULTS: CFR, S, and SR increased after intervention significantly. There was significant correlation between CFR ratio and poststress systolic strain (SS) ratio and early diastolic strain rate (ESR) ratio (P < 0.05 and r > 0.6). Also CFR improvement had significant relationship with changes of poststress Systolic SR and poststress Systolic S (P < 0.05 and r > 0.6). Based on regression analysis the amount of change in CFR was independently associated with change in SS during stress and systolic SR. CONCLUSION: PCI improves CFR (a marker of coronary perfusion), strain, and strain rate (markers of regional cardiac wall deformation). The independent association between CFR improvement and poststress systolic strain and strain rate means that SRI parameters can independently predict CFR changes after PCI.

Echocardiographic evaluation of mitral geometry in functional mitral regurgitation.

OBJECTIVES: We sought to evaluate the geometric changes of the mitral leaflets, local and global LV remodeling in patients with left ventricular dysfunction and varying degrees of Functional mitral regurgitation (FMR). BACKGROUND: Functional mitral regurgitation (FMR) occurs as a consequence of systolic left ventricular (LV) dysfunction caused by ischemic or nonischemic cardiomyopathy. Mitral valve repair in ischemic MR is one of the most controversial topic in surgery and proper repairing requires an understanding of its mechanisms, as the exact mechanism of FMR are not well defined. METHODS: 136 consecutive patients mean age of 55 with systolic LV dysfunction and FMR underwent complete echocardiography and after assessing MR severity, LV volumes, Ejection Fraction, LV sphericity index, C-Septal distance, Mitral valve annulus, Interpapillary distance, Tenting distance and Tenting area were obtained. RESULTS: There was significant association between MR severity and echocardiogarphic indices (all p values < 0.001). Severe MR occurred more frequently in dilated cardiomyopathy (DCM) patients compared to ischemic patients, (p < 0.001). Based on the model, only Mitral valve tenting distance (TnD) (OR = 22.11, CI 95%: 14.18 - 36.86, p < 0.001) and Interpapillary muscle distance (IPMD), (OR = 6.53, CI 95%: 2.10 - 10.23, p = 0.001) had significant associations with MR severity.Mitral annular dimensions and area, C-septal distance and sphericity index, although greater in patients with severe regurgitation, did not significantly contribute to FMR severity. CONCLUSION: Degree of LV enlargement and dysfunction were not primary determinants of FMR severity, therefore local LV remodeling and mitral valve apparatus deformation are the strongest predictors of functional MR severity.