Significant Change In Ejection Fraction Research Articles

Prediction of Cardiovascular Events and Structural and Functional Remodeling of the Heart in Patients With Severe Mitral Regurgitation of Various Genesis Underwent Transcatheter Mitral Valve Repair "Edge-To-Edge".

To search for predictors of adverse cardiovascular events after edge-to-edge transcatheter mitral valve repair (TMVR) in patients with severe mitral regurgitation (MR) of various origins with an assessment of structural and functional remodeling of the heart and left ventricular (LV) contractile function. The study included 73 patients (median age 71 [63; 80] years, 60.3% men) at a high surgical risk with severe MR of primary and secondary genesis, who underwent TMVR. The second-generation (58.9%) and fourth-generation (41.1%) clips were implanted. In addition to standard echocardiographic (EchoCG) indices, the parameters of left heart chamber longitudinal strain and LV myocardial function were assessed at baseline, on days 4-5, and at 6 and 12 months after the intervention. Also, the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) was assessed at baseline and on days 4-5 after TMVR. A significant decrease in MR was achieved during 12 months of follow-up. In the group with primary mitral regurgitation (PMR), MR decreased from 4.0 [3.4; 4.0] to 2.0 [1.5; 2.5] at one year of follow-up (p<0.001). In the group with secondary mitral regurgitation (SMR), MR decreased from 3.5 [3.0; 3.9] to 2.0 [2.0; 2.5] at 12 months of follow-up (p<0.001). This effect was associated with volumetric unloading of the left heart chambers evident as a significant decrease in the volumetric indices of the left chambers and an increase in the cardiac index. In the early postoperative period, the LV function was impaired as shown by decreases in the ejection fraction (EF), global longitudinal strain (GLS), LV myocardial function parameters, and an associated increase in NT-proBNP. By 12 months of follow-up, statistically significant improvements in global constructive work (GCW) and global work index (GWI) relative to baseline values were noted in both groups without significant changes in EF and LV GLS. A strong correlation was found between LV EF and GCW (r=0.812, p<0.001) and GWI (r=0.749, p<0.001). The overall survival was 89%, not differing between groups (p=0.72); the absence of hospitalization for decompensated heart failure (HF) was 79.5%, also without significant differences between the groups (p=0.78). According to multivariate regression analysis, the baseline GCW value was the strongest predictor of rehospitalization for decompensated HF (relative risk (RR) 0.997; 95% confidence interval (CI) 0.995-1.000; p=0.021) and the composite endpoint (CEP) (hospitalization for decompensated HF + all-cause mortality) (RR 0.998; 95% CI 0.996-1.000; p=0.033) in the cohort with PMR. In the group with SMR, the initial degree of MR was related with rehospitalization and the CEP (OR 12.252; 95% CI 2.125-70.651; p=0.005 and OR 16.098; 95% CI 2.944-88.044; p=0.001, respectively). The most significant predictor of overall mortality in the study population was the preoperative value of LV stroke volume (OR 0.824; 95% CI 0.750-0.906; p<0.001). Edge-to-edge TMVR exerts a positive effect on the prognosis and structural and functional remodeling of the heart in patients with PMR and SMR. Myocardial function indices may be useful in assessing the LV contractile function in patients with severe MR of various origins. Identification of predictors for adverse cardiovascular events, including with new EchoCG technologies, may contribute to better patient stratification.

Haemodynamic Forces: Emerging Markers of Ventricular Remodelling in Multiple Myeloma Cardiovascular Baseline Risk Assessment.

Multiple myeloma (MM) affects a population with a high prevalence of cardiovascular (CV) disease. These patients benefit from an accurate CV risk evaluation in order to choose the safest drug regimen. Haemodynamic forces (HDFs) analysis allows for the earlier detection of myocardial damage compared with standard markers; the role played by MM in HDFs alteration, with or without the influence of hypertension, is yet to be studied. Therefore, we aimed to identify differences in HDFs analysis in patients with MM, hypertension or both versus normotensive non-oncologic subjects. A total of 173 patients (MM hypertensive patients, MMHT; MM normotensive patients, MMNT; non-oncologic hypertensive patients, CoHT; and non-oncologic normotensive patients, CoNT) underwent transthoracic echocardiography for HDFs analysis and pulse wave velocity (PWV) assessment. Hypertensive patients (MMHT, CoHT) showed decreased ejection fraction (EF), global longitudinal strain (GLS) and HDFs values compared with CoNT, whereas ventricular mass (LVMi) and PWV increased. MMNT displayed a significant reduction in systolic HDFs (p < 0.006) and systolic ejection HDFs (p < 0.008) compared with CoNT, without significant change in EF, GLS, LVMi or PWV. In conclusion, MM leads to ventricular remodelling regardless of hypertension; HDFs application for MM patients could help detect early myocardial damage, especially in patients receiving cardiotoxic drugs.

Glucagon Receptor Antagonist for Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized. We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lepob/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts. In contrast to the post-transverse aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-transverse aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress. These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.

#1819 Cardio-fistular recirculation in patients with chronic heart failure and preserved ejection fraction

Abstract Background and Aims Cardio-fistular recirculation (CFR)—ratio of cardiac output (CO) to AVF volume blood flow (Qa)—is a well-known risk factor for death and cardiovascular adverse events. Currently, there are no clear limits for this index that definitely indicate AVF cardiotoxicity. In most cases, an interval score of &amp;lt;20%, 20-30%, or &amp;gt;30% is used to denote low, medium, and high risk, respectively. Typically, the assessment is performed on the interdialysiс day. HD sessions can cause significant hemodynamic changes, which may be important for patients with chronic heart failure (CFH) and preserved ejection fraction (EF), in whom the risk may be underestimated. The aim of this prospective cohort study is to evaluate changes in heart structure and CFR in patients with СFH and preserved EF before and after an HD session. Method The study included 20 stable adult HD patients who met the inclusion criteria: CHF with preserved EF (50%), NYHA I-II, Qa ≥1 l/min, CFR &amp;lt; 30%, interdialysiс weight gain &amp;lt; 5%, eKt/V &amp;gt; 1.2. Non-inclusion criteria: arrhythmias (except grade I AV block), NYHA III-IV, valvular disease (except mitral regurgitation I-II), intradialytic hypo/hypertension. All patients underwent transthoracic ECHO-CG with tissue Doppler on the third day after the last HD session (Monday/Tuesday), one hour before and 2 hours after the HD session. In addition, we measured AVF volume blood flow—brachial artery Qa. Results Patient Descriptive Statistics: M/F 8/12, mean age 52.2 (SD 11.2, range 41-67) years, HD vintage 49 (11.1, 33-72) months, BMI 28.2 (3.8, 22.9-36.0) kg/m2, interdialysiс weight gain 3.2 (0.8, 1.9-4.7) kg, relative interdialysiс weight gain 4.1% (0.8, 2.9-4.9). A significant trend in ECHO-CG parameters was observed, indicating a decrease in cardiac preload (Table 1). Although there were no significant changes in EF, a pronounced decrease in CO was noted with a relatively stable Qa value. As a result, 5 out of 20 patients had a CFR value of more than 30% after HD, which assigned them to a high-risk group. As shown in Fig. 1, even patients with pre-HD CFR values less than 25% were classified as high-risk. Patients were intentionally examined after a long interdialysiс interval because this HD session is associated with the greatest hemodynamic changes. Some publications suggest that the risk of death after long interdialysic interval is significantly higher than that after short interval. Increase in CFR after HD probably has a synergistic deleterious effect with other risk factors. The severity of this influence is determined by both the maximum achieved CFR values and the rate of CO recovery. Conclusion Some patients have a significant increase in CFR after HD. However, the prognostic value of this phenomenon remains unclear. In patients with significant CHF symptoms and normal or subnormal CFR on an interdialytic day, it is recommended to perform a post-HD examination. This can serve as a “stress test” to reveal any latent hemodynamic disadvantage caused by the AVF cardiotoxic effect.

CHANGES IN LEFT ATRIAL VOLUME DURING ECHOSTRESS IN PATIENTS UNDERGOING MITRAL VALVE PLASTIC CARDIAC SURGERY

Abstract Mitral Regurgitation (MR) is characterized by a high morbidity and mortality that often finds a solution only in the reparative surgical treatment, in particular in presence of myxomatous degeneration that cause the prolapse of one or both leaflets. This results in an increase in diastolic pressure that leads to a progressive dilation of the left atrium. The increase in Left Atrium Volume Index (LAVI) during stress test represents a negative prognostic factor in the clinical evolution of many pathologies, such as ischemic heart disease, hypertrophic cardiomyopathy, heart failure. An increase in peak/rest LAVI &amp;gt;6.8 ml/m2 correlates with a higher incidence of heart failure decompensation, reduced left ventricular contractile reserve (LVCR), pulmonary congestion. We evaluate the effect of MR reparative surgery on the changes of LAVI during stress–echo. We enrolled 19 patients, 11 females and 8 males, affected by MR candidate to cardiac surgery. We performed a physical stress–echo test by using the ABCDE protocol suggested by the Italian Society of Echocardiography and Cardiovascular Imaging (SIECVI), before and after 12 weeks from surgery. During each test, the changes in LAVI (ΔLAVI) expressed as peak/rest difference in ml/m2 was measured. In addition, the prognostic score deriving from the sum of the ABCDE criteria was calculated, such as the LVCR (C parameter of the score) that represents a parameter of the force deriving from the hemodynamic changes during the test. In all patients we observed a significant reduction in ΔLAVI (8.4+0.5 mL/m2 vs 9.7+0.7 mL/m2; p&amp;lt;0.0001). In addition, there was a significant reduction in the ABCDE prognostic score (from 4.19+0.43 to 3.48+0.37; p=0.002), secondary to the increase in the LVCR observed approximately 3 months after surgery (from 1.77 mmHg/ml to 2.44 mmHg/ml, p&amp;lt;0.0001), as well as a significant reduction in pulmonary congestion during stress (B parameter). There were no significant changes in ejection fraction, wall motion score index–WMSI (A parameter), coronary reserve (D parameter) and heart rate reserve (E parameter). These data demonstrate for the first time that mitral valve plastic surgery is able to reduce the ΔLAVI during stress echocardiography in patients with severe MR. The surgical procedure also resulted in both an improvement in the LVCR and a reduction in the degree of pulmonary congestion, that ultimately led to an improvement in the ABCDE prognostic score.

Effects of lung resection on heart structure and function: A tissue Doppler ultrasound survey of 43cases.

Changes in heart structure and function after lung resection in patients with lung cancer are challenging to manage. Therefore, a non-invasive and reliable measurement tool to gauge such changes is critical. The purpose of the present study was to compare cardiological changes before and after lung resection using tissue Doppler imaging (TDI). A total of 43 patients (19 men and 24 women) with primary non-small cell lung cancer (n=37) and metastatic cancer in the lungs (n=6) were enrolled in the study.nTDI was used to determine the thickness of the ascending aorta, the open size of the ascending valve, the anterior-oposterior diameters of the left atrium and left ventricle, and the thickness of the ventricular septum and right ventricle before and after lung resection. Left ventricular (LV) ejection fraction (EF), pulmonary valve flow rate, tricuspid annular or mitral leaflet tip early (E) peak/late (A) diastolic blood flow velocities, tricuspid regurgitation flow, the lateral mitral annulus early (e') diastolic velocity and mitral E/e' ratio were used to determine LV filling pressure. Results revealed no significant differences between male and female patients in terms of the open size of the ascending valve, the anterior-posterior diameter of the left ventricle and the mitral E/e' ratio. Significant differences were found in the width of the ascending aorta, anterior-posterior diameter of the left atrium, width of the LV septum and right ventricular (RV) diameter before and after lung resection. Finally, there were significantchanges in EF and tricuspid pressure. The results indicated that TDI was useful as a non-invasive method for assessing left and right heart function following lung resection. The LV and RV dimensions were affected, but LV filling pressure was preserved after lobectomy.

Effects of pericyte and smooth muscle specific knock-out of CXCL12 on cardiac function after myocardial ischemia in mice

Abstract Introduction Ischemic cardiomyopathy as a result of myocardial infarction represents one of the most common causes of heart failure (1). The C-X-C motif chemokine ligand 12 (CXCL12) and its receptor CXCR4 facilitate cardiac repair after myocardial ischemia (MI) and play fundamental roles in cardiovascular development (2). However, the cell- and tissue-specific actions of CXCL12 are poorly understood, limiting the introduction of targeted therapies. Here, we aimed to examine the role of pericyte and smooth muscle cell-specific CXCL12 expression on myocardial function after MI. Methods We generated a smooth muscle protein 22-alpha-Cre and a pericyte protein NG2-Cre driven mouse model to ablate CXCL12 specifically in smooth muscle cells (SM22-Cre x CXCL12flox/flox) and in pericytes (NG2-Cre x CXCL12flox/flox). Genotyping was performed using ear hole biopsy by PCR. Hearts were analysed morphologically by histology and immunofluorescence. Cardiac function and dimensions of the wall thicknesses and cardiac cavities were determined by echocardiography. Myocardial infarction was induced in the animals and cardiac function was further investigated 28 days after MI. Results In immunofluorescence, we found that CXCL12 is highly expressed in SM22+ smooth muscle cells and in cells surrounding arterial blood vessels (3). NG2-CXCL12-/- mice did not show increased mortality, they behaved inconspicuously and no obvious developmental defects could be detected. Echocardiographic analysis of cardiac function in NG2-Cre x CXCL12flox/flox mice without infarction showed no significant difference in left ventricular (LV) performance and no evidence of abnormal geometry of the ventricles compared with controls. Assessment of SM22-Cre x CXCL12flox/flox mice after MI revealed reduced ejection fraction (EF) (29.0%±9.7 vs. 40.0%±8.1; n=10; p=0.027) and stroke volume (SV) (19.0µl±3.3 vs. 32.7µl±10.3; n=10; p=0.002) compared to non-transgenic controls. In contrast NG2-Cre x CXCL12flox/flox mice showed no significant changes in EF (34.6%±11.4 vs. 40.0%±8.1; n=10; p=0.368) and SV (27.7µl±7.3 vs. 32.7µl±10.3; n=10; p=0.303). Conclusion Our findings suggest that pericyte specific CXCL12 plays no major role in cardiac development and function after MI. In contrast, KO of CXCL12 in smooth muscle seems to deteriorate cardiac function after ischemia.

Effect of vitamin D receptor genetic polymorphism on the clinical response to angiotensin converting enzyme inhibitors therapy among breast cancer patients with chemotherapy induced cardiomyopathy

Abstract Background Blockade of the renin-angiotensin-aldosterone system (RAAS) is the cornerstone treatment of chemotherapy induced cardiomyopathy (CIC) yet, variability in response to angiotensin converting enzyme inhibitors (ACEIs) acting on the RAAS is well-documented. Vitamin D was found to play a role in regulating RAAS. Previous studies revealed an inverse relationship between levels of vitamin D in serum and RAAS activation. Purpose The current study is primarily to evaluate the association between genetic variants in the vitamin D receptor (VDR) and clinical response to ACEIs among breast cancer patients receiving chemotherapy with CIC. Methods A total of 60 breast cancer patients with CIC (mean ejection fraction 30%) on β-blocker therapy were started on a ACEIs and followed for 6 months. Post-ACEIs-treatment changes in ejection fraction (EF) and serum potassium (K) were evaluated. We genotyped VDR gene polymorphisms including; ApaI (rs7975232), TaqI (rs731236), BsmI (rs1544410) and FokI (rs2228570) variants using TaqMan technique. Stepwise linear regression was performed to identify genetic and clinical factors associated with variability in ACEIs response, with adjustment for all potential confounding covariates. Results BsmI (rs1544410) (CT) heterozygous and TaqI (rs731236) (GA) genotypes had a significant increase in EF (12.8% and 10.8 %, respectively) and serum K (1.1 mEq/L and 0.91 mEq/L respectively); adjusted-p = 0.0001 and 0.004 for ∆EF and adjusted-p = 0.005 and 0.002 for ∆K. In contrast, (AA) homozygous carriers of the ApaI SNP (rs7975232) had a smaller increase in EF (∆EF = 1.2%) and K (∆K = 0.1 mEq/L) compared to (CA) (∆EF = 6.5%, ∆K = 0.73mEq/L) and (CC) (∆EF = 9%, ∆K = 0.9mEq/L) carriers; adjusted-p = 0.003 for ∆EF, adjusted-p = 0.004 for ∆K. Finally, for the FokI SNP (rs2228570), there was no significant change in EF and serum K level. Conclusion The results from this study highlight that BsmI (rs1544410) and TaqI (rs731236) are strong predictors of response to ACEIs therapy in chemotherapy-induced cardiomyopathy (CIC).

Abstract 13469: A Comprehensive Echocardiographic Assessment of Patients With Chronic Myeloid Leukemia on Dasatinib

Background: Dasatinib, a tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia (CML), is known to cause cardiotoxicities; however, little is known about the echocardiographic changes associated with this drug. Here we present a comprehensive echocardiographic assessment of patients with CML on dasatinib receiving care at a quaternary facility. Methods: We performed a retrospective cohort analysis on consecutive adult patients with CML receiving dasatinib between 2017-2022 who had a baseline and follow-up echocardiogram. Comprehensive clinical, laboratory and advanced echocardiographic data with speckle-tracking analyses (Tomtec Arena, Germany) were included. Results: Among 41 adult patients with CML (average age 64±16 years old, 39% female) who were prescribed with dasatinib (initial dose 100mg once daily), at baseline, 7 (17%) patients had heart failure with preserved ejection fraction (HFpEF), 11 (27%) coronary artery disease, and 3 (7%) pulmonary hypertension. There was a statistically significant increase in the indexed LV end-diastolic diameter and LV mass in pre- vs post-dasatinib echocardiograms; however, there was no significant change in ejection fraction or global longitudinal strain. There was no significant change in RV structure or function measures. There was a significant increase in LA volume index and decrease in lateral e’ velocity in pre- vs post-dasatinib echocardiograms. A trend towards declining LA reservoir strain post-dasatinib was noted. Ten (24%) patients had a progression in diastology grading after the initiation of dasatinib. Five out of 7 patients with HFpEF at baseline had progression in diastolic function post-dasatinib. Conclusions: Dasatinib was associated with significant changes in LV end-diastolic diameter, LV mass, LA volume, and diastolic parameters in patients with CML. These findings require further corroboration with a larger patient cohort and correlation with clinical outcomes.

Abstract 17975: Improvement in Exercise Capacity After Surgical Septal Myectomy in Obstructive Hypertrophic Cardiomyopathy Patients is Related to Peak Exercise Strain Rate and Mechanical Reserve

Background: Significant improvements in functional capacity are noted after septal myectomy in symptomatic patients with obstructive hypertrophic cardiomyopathy (oHCM). However, the underlying mechanism behind these improvements is unclear. Methods: Conventional and strain echocardiography, at rest and post-exercise, was performed pre-and post-septal myectomy in 59 OHCM patients (42 men; mean age 50±12years). Exercise capacity was expressed as metabolic equivalents (METs) after treadmill exercise testing. Global longitudinal peak systolic strain (S) and stain rate (SR) were measured at rest and peak-exercise. Results: After myectomy, outflow gradient decreased significantly (resting gradient: 69±43 to 13±8mmHg; provoked gradient: 141±50 to 40±21mmHg; both p&lt;0.001) with no significant change in ejection fraction (66±5% to 65±4%, p=NS). METs improved significantly (9.5±3.2 to 10.6±2.9, p=0.001). There was no significant change in S and SR at rest (S: -15.17±2.89% to -15.27±2.75%; SR:-0.95±0.18S-1 to -0.92±0.15S-1, both p=NS) or post-exercise (S: -17.06±3.63% to -16.68±2.79%; SR: -1.45±0.30S-1 to -1.52±0.28S-1, both p=NS). Mechanical reserve (MRES, change in systolic SR with exercise) increased significantly (55±30% to 67±32%, p=0.02). METs correlated significantly with exercise SR and MRES determined pre-myectomy (exercise SR: r=-0.41, p=0.003; MRES: r=0.33, p=0.017) and post-myectomy (exercise SR: r=-0.53, p&lt;0.001; MRES: r=0.51, p&lt;0.001). Improvement in METs was significantly correlated with changes in MRES (r=0.36, p=0.019). Multivariable linear regression confirmed an independent correlation between exercise SR and MRES with METs. Conclusions: Resting and peak exercise myocardial contractility (longitudinal S and SR) do not change significantly after septal myectomy. Post-myectomy MRES improves significantly and exercise capacity post-myectomy correlates significantly with pre- and post-myectomy functional status.

P44 IMPROVEMENT OF THE LEFT VENTRICULAR CONTRACTILE RESERVE IN PATIENTS UNDERGOING MITRAL VALVE PLASTIC CARDIAC SURGERY

Abstract Mitral Regurgitation (MR) is a clinical condition characterized by a high morbidity and mortality in severe or moderate forms complicated by hemodynamic instability, that often finds a solution only in the reparative surgical treatment. MR is often caused the presence of myxomatous degeneration that affects one or more structures of the valve apparatus, causing the prolapse of one or both leaflets. Surgical treatment can improve the hemodynamic parameters and consequently the prognosis of the patients, even though there is not still data concerning the myocardial contractile reserve. The aim of the study was to evaluate the effect of MR reparative surgery on the left ventricular contractile reserve during physical stress echocardiography. We enrolled 12 patients, 8 females and 4 males, affected by MR candidate to cardiac surgery. We performed a physical stress–echo test by using the ABCDE protocol suggested by the Italian Society of Echocardiography and Cardiovascular Imaging (SIECVI), before and after approximately 12 weeks from cardiac surgery. After each test, the prognostic score deriving from the sum of the ABCDE criteria was calculated; in addition, we measured the left ventricular contractile reserve (C parameter of the score) that represents a parameter of the force deriving from the hemodynamic changes during the test. In all patients we observed a significant improvement in the ABCDE prognostic score after cardiac surgery (3.89 + 0.43 vs 3.18 + 0.37; p = 0.002). There were no significant changes in ejection fraction, indexed left atrial volume, wall motion score index–WMSI (A parameter), coronary reserve (D parameter), and heart rate reserve (E parameter). The most relevant data concerns the increase in the left ventricular contractile reserve at 3 months after cardiac surgery (1.77 mmHg/ml vs 2.44 mmHg/ml, p&amp;lt;0.0001). Furthermore, a significant reduction in pulmonary congestion during stress was observed (B parameter). These data demonstrate for the first time that mitral valve plastic surgery is able to improve the left ventricular contractile reserve in patients with severe MR. Furthermore, the surgical procedure determined both a reduction in the degree of pulmonary congestion and an improvement in the ABCDE prognostic score during physical stress echocardiography.

Abstract P5-07-08: Evaluating the risk of cardiotoxicity associated with concurrent trastuzumab emtansine (TDM1) and radiation therapy in patients with early-stage HER2 positive breast cancer

Abstract BACKGROUND: HER2-positive breast cancers, which accounts for 20% of breast cancers, is associated with aggressive clinical behavior and inferior survival. The approval of HER2 targeted therapy has changed the landscape of this disease and has reduced disease recurrence by 50% and has improved survival by 33%. (1) However, cardiotoxicity is a well-recognized adverse event associated with HER2-targeted therapies. Adjuvant trastuzumab emtansine (TDM1) is the current standard of care for patients with residual breast cancer after neoadjuvant HER2-targeted therapy. TDM1 is associated with a risk of cardiotoxicity defined as a decline in left ventricular ejection fraction (LVEF). In a pooled analysis of data from seven metastatic breast cancer trials with TDM1, the incidence of cardiac events such as congestive heart failure (CHF), cardiac ischemia, cardiac arrhythmia or grade 1/2 LVEF drop was 3.37%. Adjuvant breast radiation (RT) is routinely offered for patients at high risk for recurrence. Breast RT is also associated with long-term increased risk of cardiac disease more than 10 years after RT. The HERA trial which studied use of adjuvant trastuzumab showed that rates of cardiotoxicity were higher in patients receiving concurrent RT with trastuzumab (left sided &amp;gt; right sided breast cancer) compared to those who did not receive adjuvant RT, although not statistically significant. In the multivariate analysis, no treatment or baseline cardiovascular risk factors were strongly correlated with LVEF, but radiation therapy showed a borderline correlation (adjusted HR, 1.258; 95% CI, 1.00-1.58; P = .049). The risk of cardiotoxicity with concurrent TDM1 and RT has not been well studied. With increasing use of TDM1 in the adjuvant setting, it is important to understand the cardiotoxic effects of combination therapy in early-stage breast cancer. METHODS: We undertook a review of our clinical database to identify patients who received adjuvant TDM1 with concurrent RT for Stage I-III breast cancer from 1/2020 to 01/2022. Clinical parameters including age, date of diagnosis, history of cardiac disorders, echocardiogram findings, radiation dose, final pathologic stage and molecular subtypes of cancer were extracted. All patients had ejection fraction to monitor cardiac fraction. Global longitudinal strain (GLS), which is a more sensitive and reproducible indicator of cardiac dysfunction than LVEF, was also collected, if available. RESULTS: Of 32 patients identified in our retrospective analysis, two patients (6%) developed a drop in ejection fraction post radiation. Median age of patients was 57y. Majority of the patients were Caucasian (44%) followed by Hispanic (28%). 19 (60%) patients had right sided breast cancers and 13(40%) patients had left sided cancers. The mean pre-radiation ejection fraction was 60% and post radiation was 61%. Using paired t-testing, there was no statically significant difference in ejection fraction after radiation (p=0.343). Comparative GLS measurements were available for 16 patients and there was no statical difference with concurrent radiation (p=0.18). All patients tolerated radiation with mostly grade 2 skin dermatitis except four patients who had grade 3 skin dermatitis. One patient had to discontinue radiation early given grade 3 skin dermatitis. CONCLUSION: This institutional review of 32 patients suggests that adjuvant TDM1 with concurrent RT did not result in a significant change in ejection fraction or GLS. Most patients tolerated radiation without significant skin toxicities. One of the limitations of the study is the small sample size. A larger study should look at more broader conclusions; however this data has strong clinical implications. Cardiac Parameters pre and post RT Citation Format: Faheem Farooq, Dillon Cason, Nisha Ohri, Shicha Kumar, Allison Grann, Anna Litvak, Shridar Ganesan, Bruce G. Haffty, Deborah Toppmeyer, Coral Omene, Mridula A. George. Evaluating the risk of cardiotoxicity associated with concurrent trastuzumab emtansine (TDM1) and radiation therapy in patients with early-stage HER2 positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-07-08.

Impact of exercise training on myocardial contractile functions assessed by cardiac magnetic resonance in post-myocardial infarction patients

BackgroundImprovement of functional capacity and mortality reduction in post-MI patients were found to be associated with regular exercise training. The cardiac magnetic resonance (CMR) is considered the most accurate non-invasive modality in quantitative assessment of left ventricular (LV) volumes and systolic functions. Our main objective was to investigate the impact of exercise training on LV systolic functions in patients post anterior MI using CMR. 32 patients on recommended medical treatment 4 week after having a successful primary PCI for an anterior MI were recruited, between May 2018 and May 2019. They were divided into two groups, training group (TG): 16 assigned to a 12 week exercise training program and control group (CG): 16 who received medical treatment without participating in the exercise training program. Treadmill exercise using modified Bruce protocol was done to TG before and after the training program in order to record the resting and maximum HR, metabolic equivalent (MET), and calculate HR reserve. CMR was performed for all patients 4 weeks after PCI and was repeated after completion of the study period to calculate ejection fraction (EF), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and wall motion score index (WMSI).Results100% were males. 6 patients from CG dropped during follow-up, no statistically significant difference between the two groups regarding age, BMI, smoking status, hypertension, diabetes mellitus and dyslipidemia. Using the CMR, the TG showed significant improvement in EF (36.6 ± 14.2% to 43.1 ± 12.4%; P < 0.001) and WMSI (2.03 ± 0.57 to 1.7 ± 0.49; P < 0.001), without statistically significant change in LV volumes. Regarding CG no significant changes in EF, WMSI, LV volumes were found. There was significant improvement in EF and WMSI change before and after study in TG vs. CG [6.5 (2.3–9.0) vs. − 2.0 (− 6.8 to 1.3), P value < 0.001] and [− 0.3 (− 0.5 to 0.1) vs. 0.1 (− 0.1 to − 0.5), P value 0.001] respectively.Conclusions12 weeks of exercise training program in post-MI patients have a favorable impact on LV global and regional systolic functions without adversely affecting LV remodeling (as assessed by CMR).

Preliminary Results With a Novel Expanded Polytetrafluoroethylene-based Pulmonary Valved Conduit

BackgroundA novel polymeric pulmonary valved conduit, resistant to calcification and structural valve deterioration, may provide a more durable therapy option for the pediatric population by preventing loss of right ventricular function and increasing freedom from valve-related reintervention and mortality. MethodsThis was a prospective, multicenter, single-arm study evaluating safety and performance of an investigational novel expanded polytetrafluoroethylene–based valve. Patients met study inclusion/exclusion criteria, had a signed informed consent, had pre- and postoperative evaluation via transthoracic echocardiography, and 6-month cardiac magnetic resonance imaging. ResultsSeventeen patients were enrolled from 3 sites. Median age was 12 years (range, 6-17 years) with 52.9% male. Body surface area ranged from 0.82 to 1.57 m2. There has been no mortality and 100% freedom from device related reinterventions. Baseline compared with 6-month cardiac magnetic resonance imaging (in 11 of 16 patients with available data) suggests favorable right ventricular remodeling (right ventricular end-diastolic volume, 123 ± 37 to 94 ± 25 mL/m2) with no significant change in ejection fraction. Through current follow-up, no patient has a right ventricular outflow tract gradient >20 mm Hg (mean, 11.2 ± 4.3 mm Hg). No evidence of worsening valvular insufficiency was observed throughout postoperative serial transthoracic echocardiogram evaluations. No pulmonary regurgitation above baseline (≤ mild) was observed. No patient developed endocarditis. No thrombus or calcification was identified. ConclusionsThis preliminary evaluation of a novel expanded polytetrafluoroethylene–based valved conduit suggests promising valve function with no thromboembolic or infectious complications, no valve related reinterventions, no valve-related adverse events or unexpected findings, improved right ventricular volumes, and encouraging hemodynamic performance through current follow-up.

Effect of surgical treatment on myocardial strain in patients with pheochromocytoma and paraganglioma: a mini-review and meta-analysis.

Information on systolic dysfunction, as assessed by left-ventricular (LV) mechanics, in patients with pheochromocytoma after surgical treatment is scanty. We performed a systematic meta-analysis of speckle tracking echocardiographic studies to provide an updated comprehensive information on this issue. The PubMed, OVID-MEDLINE, and Cochrane library databases were analyzed to search for articles published from the inception up to May 31st 2021. Studies were identified using MeSH terms and crossing the following search items: "myocardial strain" "left ventricular mechanics", "speckle tracking echocardiography", "systolic dysfunction", "pheochromocytoma", and "paraganglioma". A total of 92 surgically treated patients with pheochromocytoma/paraganglioma were included in 3 longitudinal studies. Successful surgical treatment was associated with a decrease in relative wall thickness (SMD -0.25 ± 0.10, CI -0.45/-0.05, p < 0.01) and an improvement in global longitudinal strain (SMD -0.45 ± 0.10, CI -0.66/-0.24, p < 0.0001). The favorable effects of treatment on LV geometry and mechanics were not accompanied by significant changes in ejection fraction (SMD -0.07 ± 0.10, CI -0.27/0.12, p = 0.44). This meta-analysis adds a new piece of evidence, suggesting that surgical treatment of patients with pheochromocytoma impacts favorably on LV geometry and LV mechanics, and, more importantly, the assessment of LV changes in this setting can no longer rely on conventional echocardiographic parameters such as ejection fraction.

Mutation of the Cardiac Sodium Channel Nav1.5 Leads to Sex Specific Arrhythmias

Introduction Cardiac Nav1.5 sodium channels, encoded by the SCN5A gene, are responsible for initiating the electrical action potential in the heart, resulting in coordinated muscular contraction. Channelopathies caused by mutations in Nav1.5 occur in 1/2500 individuals and lead to arrhythmic diseases, such as long QT syndrome, and cardiomyopathies1,2. Males with Nav1.5 mutations are at a higher risk for sudden cardiac arrest, indicative of an innate protection in females through an unknown mechanism. The gain of function Arg222Gln mutation affects the voltage sensing segment of Nav1.5, creating an aberrant pore leading to arrhythmia-inducing membrane ion leaks3. We sought to determine the sex-specific effects of this clinically relevant mutation, attempting to undercover the protective mechanisms present in females. Methods The Arg222Gln mutation was knocked into exon 6 of the mouse SCN5A gene to generate viable animals that phenocopy the human disease. Three-lead electrocardiograms (ECG) from adult male and female animals were recorded under anesthesia, including wild-type (WT) controls. Isoproterenol (β-adrenoreceptor agonist) was injected to examine electrophysiological changes under acute stress. Baseline echocardiograms were collected at four months and after 30 days of transverse aortic constriction (TAC). Differentially expressed genes from whole heart lysate were measured by chip-based analysis after TAC . Protein levels were quantified using Western blot and ELISA. Results ECG measurements revealed a prolonged QTc (0.064ms±0.006) and QRS interval (0.011ms±0.0003) in mutant males compared to WT males (0.036ms±0.008 and 0.0085ms±0.0004 respectively) (P<0.05). Mutant males had an observable sinus arrhythmia at baseline (RMSSD of beat to beat intervals of 4.60 vs 0.79 in WT males, P<0.05), whereas mutant and wild-type females had no evidence of adverse changes to the beating rhythm. The ejection fraction (EF) of mutant males decreased by 40%±9.9% 4 weeks post-TAC, whereas no significant changes in EF were observed in all other groups. We found that transcript and protein levels of pyruvate dehydrogenase kinase-4, which reduces pyruvate dehydrogenase (PDH) activity through phosphorylation, were 6-fold higher in mutant males compared to WT males (P<0.05), whereas no differences were observed between females. Despite this, phospho-PDH levels were lower and PDH activity higher in mutant males compared to WT males (P<0.01), with no differences between the female groups. Conclusion We found functional, electrophysiological, and metabolic enzyme abnormalities in male mice harboring the Arg222Gln Nav1.5 mutation. These differences did not exist in the female mutant mice. Our data illustrate a strong sex-specific phenotype, and suggest that metabolic alterations through increased PDH activity provide a protective mechanism against the arrhythmia and heart failure produced by Nav1.5-related cation leak. Further experiments will seek to determine if sex hormones alone can induce a protective effect in the context of the Arg222Gln mutation. 1Priori et al., NEJM, 2003 2Veerman et al., Gene, 2015 3Moreau et al., J Gen Physio, 2015

Effect of Bariatric Surgery on Natriuretic Peptide Levels: A Systematic Review and Meta-Analysis.

The effect of bariatric surgery on natriuretic peptide levels in patients with obesity is unclear. The purpose of this study was to conduct a systematic review and meta-analysis to determine the effect of bariatric surgery on B-type natriuretic peptide (BNP) and aminoterminal BNP (NT-proBNP) levels. MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched to February 2020. Primary outcomes included change in NT-proBNP or BNP levels following bariatric surgery and change in weight and body mass index. Secondary outcomes included change in blood pressure, echocardiographic findings, and heart failure symptoms. MINORS tool was used to assess quality of evidence. Twelve studies with 622 patients were included. Most patients underwent Roux-en-Y gastric bypass (RYGB) (70.5%). Mean absolute reduction in body mass index was 23%. NT-proBNP levels increased significantly from baseline at 6 months (mean difference [MD] 53.67 pg/mL; 95% confidence interval [CI], 28.72-78.61; P ≤ 0.001, I2 = 99%; 8 studies) and 12 months (MD 51.16 pg/mL; 95% CI, 20.46-81.86; P = 0.001, I2 = 99%; 8 studies) postbariatric surgery. BNP levels also increased significantly at 6 months (MD 17.57 pg/mL; 95% CI, 7.62-27.51; P < 0.001, I2 = 95%; 4 studies). Systolic and diastolic blood pressure decreased significantly 12 months after surgery. Studies measuring echocardiographic findings saw improvement in left ventricle mass and the E/A ratio, but no significant change in ejection fraction. Bariatric surgery is associated with increased natriuretic peptide levels in the absence of deteriorating cardiac function, and may be associated with improved cardiac and metabolic function after the procedure.

A two year echocardiographic follow-up of patients with chronic total occlusion treated with percutaneous coronary intervention or receiving only medical therapy

Abstract Background Percutaneous coronary intervention of chronic total occlusion (PCI CTO) can reduce angina and the need for bypass surgery, however, it is still not clear how it effects the myocardial function. Conventional echocardiography is subjective and experience-dependent while tissue Doppler imaging together with strain imaging provides a more objective assessment of myocardial contractility. Purpose Our aim was to access the effectiveness of percutaneous coronary intervention (PCI) along with optimal medical therapy (OMT) on myocardial function. Methods We compared two groups of patients. The first group of patients underwent PCI CTO with OMT while the second group of patients only received OMT (control group). The echocardiographic exam was performed before randomization and after 24 months of follow-up. Doppler time intervals- isovolumetric relaxation time (IVRT), isovolumetric contraction time (IVCT) and ejection time (ET) were measured from mitral inflow and left ventricular outflow Doppler tracings. Myocardial performance index (MPI) is equal to the sum of the IVRT and IVCT divided by the ET. Velocity of early mitral filling wave (E) was measured and divided by average peak early diastolic annular velocity (e'). Peak longitudinal strain was assessed in 17 left ventricular segments. Time intervals from start Q/R on electrocardiogram to peak negative strain during the cardiac cycle were assessed. Mechanical dispersion was defined as the standard deviation of this time interval from 17 left ventricular segments, reflecting myocardial contraction heterogeneity Results Comparing the groups at follow up, there was no significant change in ejection fraction (EF), diastolic function, and mechanical dispersion, however, there was improvement in GLS and MPI (Table 1). Conclusion Global longitudinal strain as a parameter of systolic function and Myocardial performance index as a parametar of global systolic and diastolic function are sensitive markers that can detect subtle improvement in myocardial function after recanalisation of CTO. Funding Acknowledgement Type of funding source: None

Effects of Vitamin D on Left Ventricular Ejection Fraction in Patients with Systolic Heart Failure: A Double-Blind Randomized Clinical Trial.

BackgroundHeart failure is a pathophysiologic state in which the cardiac output is not able to supply the body with enough oxygen and nutrients. The prevalence of heart failure has increased dramatically over the last decades. Vitamin D levels in patients with chronic heart failure are lower than healthy controls, and vitamin D deficiency has a direct relationship with mortality.ObjectivesThis study aimed to evaluate the effect of vitamin D on the improvement of left ventricular ejection fraction in patients with systolic heart failure.MethodsIn this case-control clinical trial, 142 patients with chronic systolic heart failure were identified. Based on the inclusion and exclusion criteria, 114 patients were enrolled in the study and randomly divided into two groups. One group (n = 58) received 50,000 units of vitamin D capsules weekly for eight weeks, and the patients in the other group (n = 56) received a placebo. After excluding 15 patients from the placebo group and 17 patients from the intervention group during the study, according to the exclusion criteria, 41 patients were evaluated in both groups for ejection fraction changes after two months.ResultsAccording to the results of this research, there were no statistically significant differences in the baseline parameters between the two studied groups. The intervention group consisted of 18 female and 23 male patients with a mean age of 61.68 ± 19.8 years. Moreover, the placebo group included 21 female and 20 male patients with a mean age of 62.12 ± 18.2 years. After a 2-month follow-up, the intervention group showed statistically significant changes in ejection fraction, end-diastolic volume, and heart failure class compared to the placebo group. Also, the serum level of albumin and vitamin D in the intervention group was significantly higher than the placebo group.ConclusionsThe results of this study show that vitamin D treatment can improve the ejection fraction and functional ability of patients with vitamin D deficiency. If more comprehensive studies support this hypothesis, vitamin D deficiency assessment and correction in patients with chronic heart failure may be recommended.

Ultrastructural and Echocardiographic Assessment of Chronic Doxorubicin-Induced Cardiotoxicity in Rats.

Doxorubicin (DOX) is one of the secondary metabolites of Streptomyces peucetius var. caesius. It is a common and effective chemotherapeutic agent used for the treatment of different diseases, including lymphoma, leukemia, breast cancer, and solid tumors. However, this medicine causes cardiotoxic side effects, which limit its clinical application. The present study examined the cardiomyopathy induced by DOX via echocardiography and transmission electron microscopy (TEM). The main objective was to evaluate the capacity of echocardiography and TEM as diagnostic tools for DOX-induced cardiotoxicity. Moreover, the correlation between intracellular and functional changes due to cardiotoxicity was assessed in a rat model. Cardiomyopathy was induced in rats by two cumulative doses of DOX. Group I received DOX 12 [i.e., 12 mg/kg, intraperitoneal (IP)] and group II received DOX 15 (i.e., 15 mg/kg, IP) in six equal doses over two weeks. Group III as the control (Ctrl) group received normal saline as a vehicle. Mortality during the study was only observed in the DOX 15 group. The echocardiographic assessments revealed significant changes in ejection fraction, fractional shortening, and heart rate in the groups which received DOX. In addition, severe cardiac arrhythmia was evident in DOX-treated groups. Remarkable adverse effects, such as moderately degenerated cells and inflated mitochondria were observed in the TEM analysis of rat hearts in the DOX groups. The present study indicated that rat models are suitable for investigating DOX-induced cardiomyopathy, especially at the dose of 12 mg/kg. Furthermore, echocardiography and TEM examinations were found to be valuable methods for the determination of cardiotoxicity in rats due to DOX.