RNA binding protein IGF2BP2 expression is induced by stress in the heart and mediates dilated cardiomyopathy.

The IGF2BP family of RNA binding proteins consists of three paralogs that regulate intracellular RNA localization, RNA stability, and translational control. Although IGF2BP1 and 3 are oncofetal proteins, IGF2BP2 expression is maintained in many tissues, including the heart, into adulthood. IGF2BP2 is upregulated in cardiomyocytes during cardiac stress and remodeling and returns to normal levels in recovering hearts. We wondered whether IGF2BP2 might play an adaptive role during cardiac stress and recovery. Enhanced expression of an IGF2BP2 transgene in a conditional, inducible mouse line leads to dilated cardiomyopathy (DCM) and death within 3-4 weeks in newborn or adult hearts. Downregulation of the transgene after 2 weeks, however, rescues these mice, with complete recovery by 12 weeks. Hearts overexpressing IGF2BP2 downregulate sarcomeric and mitochondrial proteins and have fragmented mitochondria and elongated, thinner sarcomeres. IGF2BP2 is also upregulated in DCM or myocardial infarction patients. These results suggest that IGF2BP2 may be an attractive target for therapeutic intervention in cardiomyopathies.

The impact of aging on cardiac remodeling in chronic mitral regurgitation.

BACKGROUND: Chronic mitral regurgitation (MR) is a volume overload state that causes dilatation of the left sided cardiac chambers. The presence of significant dilatation is considered an indication for mitral valve intervention, however, aging may affect left ventricular (LV) remodeling independently of valvular disease. The objective of this study was to examine age-related changes in cardiac remodeling in a broad population of patients with chronic MR. METHODS: Consecutive subjects that underwent echocardiography examinations recorded in the echocardiography database of a university-affiliated laboratory were retrieved. Subjects were categorized into none/mild, moderate or severe MR. For purposes of analysis of differences with aging, the population was divided into groups above and below 70 years of age and standard echocardiographic measurements were compared between the groups. RESULTS: A total of 3492 subjects with at least moderate MR (mean age: 76 years, 52% female) were included in the study and compared to 18,250 subjects with none or mild MR. Older patients had significantly smaller LV end-diastolic diameters and volumes and significantly larger left atrial (LA) volumes when compared to the younger group. LA volume index increased in both age groups as MR severity increased, while LV end-diastolic volume increased with increasing MR only in the younger population. CONCLUSIONS: Cardiac remodeling in chronic MR is significantly influenced by age. Guideline based recommendations of timing of mitral valve interventions in asymptomatic MR patients, based on assessment of LA and LV remodeling, may need to take age into account.

Mitral Regurgitation Severity Assessment after Transcutaneous Edge-to-Edge Mitral Valve Repair: Recommended Integration versus Volumetric Assessment Guidelines.

Objectives: This article aims to evaluate the accuracy of the color-Doppler-based technique to evaluate residual mitral regurgitation post TEER. Background: The evaluation of residual mitral regurgitation (MR) post-mitral transcutaneous edge-to-edge repair (mitral TEER) is a critical determinant in patients' outcomes. The common methods used today, based on the integration of color flow Doppler parameters, may be misleading because of the multiple jets and high velocities created by the TEER devices. Methods: Patients undergoing TEER at Hadassah hospital were recruited between 2015 and 2019. Post-procedural MR was evaluated using the integrated qualitative approach as recommended by the guidelines. In addition, the MR volume for each patient was calculated by subtracting the forward stroke volume (calculated by multiplying the LVOT area with the velocity time integral of the LVOT systolic flow) from the total stroke volume (calculated by the biplane Simpson method of discs). We compared the two methods for concordance. Results: Overall, 112 cases were enrolled. In 55.4% of cases, the volumetric residual MR was milder than the MR severity assessed by the guidelines' recommended method. In 25.1%, the MR severity was similar in both methods. In 16.2%, the MR severity was worse when calculated using the volumetric method (pValue < 0.001, Kappameasure of agreement = 0.053). The lower residual MR degree using the volumetric approach was mostly observed in patients classified as "moderate" by the integrated approach. Conclusions: MR severity after TEER is often overestimated by the guideline-recommended integrative method when compared with a volumetric method. Alternative methods should be considered to assess the MR severity after mitral TEER.

Outcomes following transcatheter repair in patients with functional mitral regurgitation not receiving guideline directed medical therapy in Israel.

BACKGROUND: Transcatheter edge to edge repair (TEER) improves prognosis in patients with functional mitral regurgitation (FMR) receiving guideline directed medical therapy (GDMT). Many patients with FMR do not receive GDMT and the utility of TEER in this population remains unclear. METHODS: We retrospectively studied patients undergoing TEER. Clinical, echocardiographic and procedural variables were recorded. GDMT was defined as use of RAAS inhibitors and MRAs unless GFR was under 30 as well as beta blockers. The primary endpoint of the study was one year mortality. RESULTS: 168 patients (mean age 71.3 ± 9.3; 66% males) with FMR who underwent TEER were included of whom 116 (69%) received GDMT at the time of TEER and 52 (31%) did not. There were no significant demographic or clinical differences between the groups. There were no significant differences in procedural success and complications between groups. One year mortality was identical in the two groups (15% vs. 15%; RR 1.06, CI 0.43-2.63, P = 0.90). CONCLUSIONS: Our findings suggest that procedural success and one year mortality following TEER was not significantly different in HFREF patients with FMR with or without GDMT. Larger, prospective studies are necessary to define the benefit of TEER in this population.

Acute Reduction in Left Ventricular Function Following Transcatheter Mitral Edge-to-Edge Repair.

Background Little is known about the impact of transcatheter mitral valve edge-to-edge repair on changes in left ventricular ejection fraction (LVEF) and the effect of an acute reduction in LVEF on prognosis. We aimed to assess changes in LVEF after transcatheter mitral valve edge-to-edge repair for both primary and secondary mitral regurgitation (PMR and SMR, respectively), identify rates and predictors of LVEF reduction, and estimate its impact on prognosis. Methods and Results In this international multicenter registry, patients with both PMR and SMR undergoing transcatheter mitral valve edge-to-edge repair were included. We assessed rates of acute LVEF reduction (LVEFR), defined as an acute relative decrease of >15% in LVEF, its impact on all-cause mortality, major adverse cardiac event (composite end point of all-cause death, mitral valve surgery, and residual mitral regurgitation grade ≥2), and LVEF at 12 months, as well as predictors for LVEFR. Of 2534 patients included (727 with PMR, and 1807 with SMR), 469 (18.5%) developed LVEFR. Patients with PMR were older (79.0±9.2 versus 71.8±8.9 years; P<0.001) and had higher mean LVEF (54.8±14.0% versus 32.7±10.4%; P<0.001) at baseline. After 6 to 12 months (median, 9.9 months; interquartile range, 7.8-11.9 months), LVEF was significantly lower in patients with PMR (53.0% versus 56.0%; P<0.001) but not in patients with SMR. The 1-year mortality was higher in patients with PMR with LVEFR (16.9% versus 9.7%; P<0.001) but not in those with SMR (P=0.236). LVEF at baseline (odds ratio, 1.03 [95% CI, 1.01-1.05]; P=0.002) was predictive of LVEFR for patients with PMR, but not those with SMR (P=0.092). Conclusions Reduction in LVEF is not uncommon after transcatheter mitral valve edge-to-edge repair and is correlated with worsened prognosis in patients with PMR but not patients with SMR. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT05311163.

Prognostic Impact of Nutritional Status After Transcatheter Edge-to-Edge Mitral Valve Repair: The MIVNUT Registry.

Background Malnutrition is associated with poor prognosis in several cardiovascular diseases. However, its prognostic impact in patients undergoing transcatheter edge-to-edge mitral valve repair (TEER) is not well known. This study sought to assess the prevalence, clinical associations, and prognostic consequences of malnutrition in patients undergoing TEER. Methods and Results A total of 892 patients undergoing TEER from the international MIVNUT (Mitral Valve Repair and Nutritional Status) registry were studied. Malnutrition status was assessed with the Controlling Nutritional Status score. The association of nutritional status with mortality was analyzed with multivariable Cox regression models, whereas the association with heart failure admission was assessed by Fine-Gray models, with death as a competing risk. According to the Controlling Nutritional Status score, 74.4% of patients with TEER had any degree of malnutrition at the time of TEER (75.1% in patients with body mass index <25 kg/m2, 72.1% in those with body mass index ≥25 kg/m2). However, only 20% had moderate-severe malnutrition. TEER was successful in most of patients (94.2%). During a median follow-up of 1.6 years (interquartile range, 0.6-3.0), 267 (29.9%) patients died and 256 patients (28.7%) were admitted for heart failure after TEER. Compared with normal nutritional status moderate-severe malnutrition resulted a strong predictor of mortality (adjusted hazard ratio [HR], 2.1 [95% CI, 1.1-2.4]; P<0.001) and heart failure admission (adjusted subdistribution HR, 1.6 [95% CI, 1.1-2.4]; P=0.015). Conclusions Malnutrition is common among patients submitted to TEER, and moderate-severe malnutrition is strongly associated with increased mortality and heart failure readmission. Assessment of nutritional status in these patients may help to improve risk stratification.

Giant Intracardiac Lipoma: A Case Report and the Role of Multimodality Cardiac Imaging.

Cardiac lipomas, especially ones originating from the left ventricle, are extremely rare. They may be asymptomatic or may present with various non-specific symptoms. Herein, we report a case of a giant lipoma of the left ventricle, with frequent ventricular premature beats on electrocardiogram. An echocardiogram demonstrated a large hyperechoic mass occupying a significant portion of the left ventricle. We further describe the diagnostic workup utilizing multimodality cardiac imaging and treatment options. Cardiac MRI demonstrated fat suppression, and cardiac CT showed a homogenous low-attenuation mass suggesting lipomatous matter. The mass was subsequently surgically removed for pathology examination in order to rule out liposarcoma. Histopathology demonstrated mature adipocytes, entrapped myocytes with hypertrophy, and interstitial fibrosis foci confirming the diagnosis of lipoma.

Pitfalls of Echocardiographic Image Perception: How to Overcome Them?

In recent years, the significant development of echocardiography systems has led to a sharp improvement in echocardiographic images' quality. In parallel with this, computerized technologies are also going far forward, which today make it possible to ensure a high level of transmission, storage, and display of echocardiography studies. Despite this, many cardiologists are not familiar with modern computerized technologies' new possibilities and continue to use the old standards. That is why many echocardiography laboratories with the best echocardiography systems work following the old minimalist approach. In this paper, we will look at some of the most common mistakes that result from the improper transmission, storage, and demonstration of echocardiography studies, and describe possible ways to overcome these problems.

Structural and Functional Support by Left Atrial Appendage Transplant to the Left Ventricle after a Myocardial Infarction.

The left atrial appendage (LAA) of the adult heart has been shown to contain cardiac and myeloid progenitor cells. The resident myeloid progenitor population expresses an array of pro-regenerative paracrine factors. Cardiac constructs have been shown to inhibit deleterious remodeling of the heart using physical support. Due to these aspects, LAA holds promise as a regenerative transplant. LAAs from adult mT/mG mice were transplanted to the recipient 129X1-SvJ mice simultaneously as myocardial infarction (MI) was performed. A decellularized LAA patch was implanted in the control group. Two weeks after MI, the LAA patch had integrated to the ventricular wall, and migrated cells were seen in the MI area. The cells had two main phenotypes: small F4/80+ cells and large troponin C+ cells. After follow-up at 8 weeks, the LAA patch remained viable, and the functional status of the heart improved. Cardiac echo demonstrated that, after 6 weeks, the mice in the LAA-patch-treated group showed an increasing and statistically significant improvement in cardiac performance when compared to the MI and MI + decellularized patch controls. Physical patch-support (LAA and decellularized LAA patch) had an equal effect on the inhibition of deleterious remodeling, but only the LAA patch inhibited the hypertrophic response. Our study demonstrates that the LAA transplantation has the potential for use as a treatment for myocardial infarction. This method can putatively combine cell therapy (regenerative effect) and physical support (inhibition of deleterious remodeling).

Percutaneous Mitral Valve Repair in Cancer Patients with Heart Failure and Severe Mitral Regurgitation.

BACKGROUND: Cancer patients with heart failure (HF) and severe mitral regurgitation (MR) are often considered to be at risk for surgical mitral valve repair/replacement. Severe MR inducing symptomatic HF may prevent delivery of potentially cardiotoxic chemotherapy and complicate fluid management with other cancer treatments. OBJECTIVES: To evaluate the outcome of percutaneous mitral valve repair (PMVR) in oncology patients with HF and significant MR. METHODS: Our study comprised 145 patients who underwent PMVR, MitraClip, at Hadassah Medical Center between August 2015 and September 2019, including 28 patients who had active or history of cancer. Data from 28 cancer patients were compared to 117 no-cancer patients from the cohort. RESULTS: There was no significant difference in the mean age of cancer patients and no-cancer patients (76 vs. 80 years, P = 0.16); 67% of the patients had secondary (functional) MR. Among cancer patients, 21 had solid tumor and 7 had hematologic malignancies. Nine patients (32%) had active malignancy at the time of PMVR. The mean short-term risk score of the patients was similar in the two groups, as were both 30-day and 1-year mortality rates (7% vs. 4%, P = 0.52) and (29% vs. 16%, P = 0.13), respectively. CONCLUSIONS: PMVR in cancer patients is associated with similar 30-day and 1-year survival rate compared with patients without cancer. PMVR should be considered for cancer patients presenting with HF and severe MR and despite their malignancy. This approach may allow cancer patients to safely receive planned oncological treatment.

A Score to Assess Mortality After Percutaneous Mitral Valve Repair.

BACKGROUND: Risk stratification for transcatheter edge-to-edge mitral valve repair (TEER) is paramount in the decision-making process for treating severe mitral regurgitation (MR). OBJECTIVES: This study sought to create and validate a user-friendly score (MitraScore) to predict the risk of mortality in patients undergoing TEER. METHODS: The derivation cohort was based on a multicentric international registry that included 1,119 patients referred for TEER between 2012 and 2020. Score discrimination was assessed using Harrell's c-statistic, and the calibration was evaluated with the Gronnesby and Borgan goodness-of-fit test. An external validation was carried out in 725 patients from the GIOTTO registry. RESULTS: After multivariate analysis, we identified 8 independent predictors of mortality during the follow-up (2.1 ± 1.8 years): age ≥75 years, anemia, glomerular filtrate rate <60 mL/min/1.73 m2, left ventricular ejection fraction <40%, peripheral artery disease, chronic obstructive pulmonary disease, high diuretic dose, and no therapy with renin-angiotensin system inhibitors. The MitraScore was derived by assigning 1 point to each independent predictor. The c-statistic was 0.70. Per each point of the MitraScore, the relative risk of mortality increased by 55% (HR: 1.55; 95% CI: 1.44-1.67; P < 0.001). The discrimination and calibration for mortality prediction was better than those of EuroSCORE II (c-statistic 0.61) or Society of Thoracic Surgeons score (c-statistic 0.57). The MitraScore maintained adequate performance in the validation cohort (c-statistic 0.66). The score was also predictive for heart failure rehospitalization and was correlated with the probability of clinical improvement. CONCLUSIONS: The MitraScore is a simple prediction algorithm for the prediction of follow-up mortality in patients treated with TEER.

Native aortic valve Staphylococcus warneri endocarditis after COVID-19 infection: a case report and a review of literature.

We report a case of Staphylococcus warneri native valve endocarditis in an immunocompetent healthy adult, without known risk factors for infective endocarditis, two months following COVID-19 infection, who recovered with conservative treatment. Additionally, we reviewed previous cases of native valve endocarditis caused by Staphylococcus warneri and summarized the main clinical implications.

Conservative, surgical, and percutaneous treatment for mitral regurgitation shortly after acute myocardial infarction.

AIMS: Severe mitral regurgitation (MR) following acute myocardial infarction (MI) is associated with high mortality rates and has inconclusive recommendations in clinical guidelines. We aimed to report the international experience of patients with secondary MR following acute MI and compare the outcomes of those treated conservatively, surgically, and percutaneously. METHODS AND RESULTS: Retrospective international registry of consecutive patients with at least moderate-to-severe MR following MI treated in 21 centres in North America, Europe, and the Middle East. The registry included patients treated conservatively and those having surgical mitral valve repair or replacement (SMVR) or percutaneous mitral valve repair (PMVR) using edge-to-edge repair. The primary endpoint was in-hospital mortality. A total of 471 patients were included (43% female, age 73 ± 11 years): 205 underwent interventions, of whom 106 were SMVR and 99 PMVR. Patients who underwent mitral valve intervention were in a worse clinical state (Killip class ≥3 in 60% vs. 43%, P < 0.01), but yet had lower in-hospital and 1-year mortality compared with those treated conservatively [11% vs. 27%, P < 0.01 and 16% vs. 35%, P < 0.01; adjusted hazard ratio (HR) 0.28, 95% confidence interval (CI) 0.18-0.46, P < 0.01]. Surgical mitral valve repair or replacement was performed earlier than PMVR [median of 12 days from MI date (interquartile range 5-19) vs. 19 days (10-40), P < 0.01]. The immediate procedural success did not differ between SMVR and PMVR (92% vs. 93%, P = 0.53). However, in-hospital and 1-year mortality rates were significantly higher in SMVR than in PMVR (16% vs. 6%, P = 0.03 and 31% vs. 17%, P = 0.04; adjusted HR 3.75, 95% CI 1.55-9.07, P < 0.01). CONCLUSIONS: Early intervention may mitigate the poor prognosis associated with conservative therapy in patients with post-MI MR. Percutaneous mitral valve repair can serve as an alternative for surgery in reducing MR for high-risk patients.

Percutaneous Mitral Valve Repair in Patients with Severe Mitral Regurgitation and Acute Decompensated Heart Failure.

The role of percutaneous mitral valve repair (PMVr) in management of high-risk patients with severe mitral regurgitation (MR) and acute decompensated heart failure (ADHF) is undetermined. We screened all patients who underwent PMVr between October 2015 and March 2020. We evaluated immediate, 30-day, and 1-year outcomes in patients who underwent PMVr during hospitalization due to ADHF as compared to elective patients. From a cohort of 237 patients, we identified 46 patients (19.4%) with severe MR of either functional or degenerative etiology who underwent PMVr during index hospitalization due to ADHF, including 17 (37%) critically ill patients. Patients' mean age was 75.2 ± 9.8 years, 56% were males. There were no differences in background history between ADHF and elective patients. Patients with ADHF were at higher risk for surgery, reflected in higher mean EuroSCORE II, compared with elective patients. After PMVr, we observed higher 30-day mortality rate in ADHF patients as compared to the elective group (10.9% vs. 3.1%, respectively, p = 0.042). One-year mortality rate was similar between the groups (21.7% vs. 17.9%, p = 0.493). Clinical and echocardiographic follow-up showed improvement of NYHA functional class and sPAP reduction in both groups ((54 ± 15 mmHg to 50 ±15 in the elective group (p = 0.02), 58 ± 13 mmHg to 52 ± 12 in the ADHF group (p = 0.02)). PMVr could be an alternative option for treatment of patients with severe MR and ADHF.

Diabetes induces remodeling of the left atrial appendage independently of atrial fibrillation in a rodent model of type-2 diabetes.

BACKGROUND: Diabetic patients have an increased predisposition to thromboembolic events, in most cases originating from thrombi in the left atrial appendage (LAA). Remodeling of the LAA, which predisposes to thrombi formation, has been previously described in diabetic patients with atrial fibrillation, but whether remodeling of the LAA occurs in diabetics also in the absence of atrial fibrillation is unknown. To investigate the contribution of diabetes, as opposed to atrial fibrillation, to remodeling of the LAA, we went from humans to the animal model. METHODS: We studied by echocardiography the structure and function of the heart over multiple time points during the evolution of diabetes in the Cohen diabetic sensitive rat (CDs/y) provided diabetogenic diet over a period of 4 months; CDs/y provided regular diet and the Cohen diabetic resistant (CDr/y), which do not develop diabetes, served as controls. All animals were in sinus rhythm throughout the study period. RESULTS: Compared to controls, CDs/y developed during the evolution of diabetes a greater heart mass, larger left atrial diameter, wider LAA orifice, increased LAA depth, greater end-diastolic and end-systolic diameter, and lower E/A ratio-all indicative of remodeling of the LAA and left atrium (LA), as well as the development of left ventricular diastolic dysfunction. To investigate the pathophysiology involved, we studied the histology of the hearts at the end of the study. We found in diabetic CDs/y, but not in any of the other groups, abundance of glycogen granules in the atrial appendages , atria  and ventricles, which may be of significance as glycogen granules have previously been associated with cell and organ dysfunction in the diabetic heart. CONCLUSIONS: We conclude that our rodent model of diabetes, which was in sinus rhythm, reproduced structural and functional alterations previously observed in hearts of human diabetics with atrial fibrillation. Remodeling of the LAA and of the LA in our model was unrelated to atrial fibrillation and associated with accumulation of glycogen granules. We suggest that myocardial accumulation of glycogen granules is related to the development of diabetes and may play a pathophysiological role in remodeling of the LAA and LA, which predisposes to atrial fibrillation, thromboembolic events and left ventricular diastolic dysfunction in the diabetic heart.

Safety and Feasibility of MitraClip Implantation in Patients with Acute Mitral Regurgitation after Recent Myocardial Infarction and Severe Left Ventricle Dysfunction.

Patients with severe mitral regurgitation (MR) after myocardial infarction (MI) have an increased risk of mortality. Transcatheter mitral valve repair may therefore be a suitable therapy. However, data on clinical outcomes of patients in an acute setting are scarce, especially those with reduced left ventricle (LV) dysfunction. We conducted a multinational, collaborative data analysis from 21 centers for patients who were, within 90 days of acute MI, treated with MitraClip due to severe MR. The cohort was divided according to median left ventricle ejection fraction (LVEF)-35%. Included in the study were 105 patients. The mean age was 71 ± 10 years. Patients in the LVEF < 35% group were younger but with comparable Euroscore II, multivessel coronary artery disease, prior MI and coronary artery bypass graft surgery. Procedure time was comparable and acute success rate was high in both groups (94% vs. 90%, p = 0.728). MR grade was significantly reduced in both groups along with an immediate reduction in left atrial V-wave, pulmonary artery pressure and improvement in New York Heart Association (NYHA) class. In-hospital and 1-year mortality rates were not significantly different between the two groups (11% vs. 7%, p = 0.51 and 19% vs. 12%, p = 0.49) and neither was the 3-month re-hospitalization rate. In conclusion, MitraClip intervention in patients with acute severe functional mitral regurgitation (FMR) due to a recent MI in an acute setting is safe and feasible. Even patients with severe LV dysfunction may benefit from transcatheter mitral valve intervention and should not be excluded.