scholarly journals Impact of Sacubitril/Valsartan on Clinical and Echocardiographic Parameters in Heart Failure Patients With Reduced Ejection Fraction: Data From a Real Life 2-year Follow-Up Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Giuseppe Armentaro ◽  
Graziella D’Arrigo ◽  
Marcello Magurno ◽  
Alfredo F. Toscani ◽  
Valentino Condoleo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Real Life ◽  
Functional Class ◽  
Left Ventricular Ejection ◽  
Reduced Ejection Fraction ◽  
Repeated Observations ◽  
Nyha Functional Class ◽  
Echocardiographic Parameters

Heart failure (HF) represents a widespread health problem characterized by high morbidity and mortality. Sacubitril/Valsartan (sac/val) has improved clinical prognosis in patients affected by HF with reduced ejection fraction (HFrEF). The aim of this study was to evaluate the effectiveness and durability of sac/val treatment on the clinical, hemodynamic and echocardiographic parameters, in real-life consecutive HFrEF outpatients, evaluated up to 2-years of follow-up. We collected 300 repeated observations over time in 60 patients suffering of HFrEF and symptomatic despite optimal drug therapy. Patients with left ventricular ejection fraction (LVEF) <35 and II-III NYHA functional class were considered. All patients underwent to clinical-instrumental and laboratory determinations and Minnesota Living with HF Questionnaire (MLHFQ) every 6 months until 24 months to evaluate possible clinical benefits and adverse events. During a 2-year follow-up period and through a 6-monthly control of the study variables both clinical, hemodynamic, biochemical and echocardiographic parameters significantly improved, in particular cardiac index (CI), both atrial and ventricular volumes and global longitudinal strain (GLS). Furthermore, there was a reduction of NT-proBNP levels and betterment of renal function and NYHA functional class, demonstrating the efficacy and durability of sac/val treatment. In a multiple linear mixed model the longitudinal evolutions of CI were associated to concomitant changes of GLS and E/e’ ratio. Our study, contemplating the collection of 300 repeated observations in 60 patients, provides a complete and detailed demonstration of sac/val effects, showing effectiveness, safety and effect durability of the treatment every 6 months up to 2-years of follow-up with significant improvement of several clinical, hemodynamic and echocardiographic parameters in HFrEF outpatients.

scholarly journals Effect of Empagliflozin on the Clinical Stability of Patients with Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial

Circulation ◽  
2020 ◽  
Author(s):  
Milton Packer ◽  
Stefan D. Anker ◽  
Javed Butler ◽  
Gerasimos S. Filippatos ◽  
João Pedro Ferreira ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Functional Class ◽  
Hazard Ratio ◽  
Double Blind ◽  
Reduced Ejection Fraction ◽  
Risk Of Death ◽  
Nyha Functional Class ◽  
Patients With Heart Failure

Background: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but additional data are needed about the effect of the drug on inpatient and outpatient events that reflect worsening heart failure. Methods: We randomly assigned 3730 patients with class II-IV heart failure with an ejection fraction of ≤40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to recommended treatments for heart failure, for a median of 16 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite endpoints. Results: Empagliflozin reduced the combined risk of death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (415 vs 519 patients; empagliflozin vs placebo, respectively; hazard ratio 0.76, 95% CI: 0.67-0.87), P <0.0001. This benefit reached statistical significance at 12 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (hazard ratio 0.67, 95% CI 0.50-0.90, P=0.008) and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (hazard ratio 0.64, 95% CI: 0.47-0.87, P=0.005). As compared with placebo, fewer patients in the empagliflozin group reported intensification of diuretics (297 vs 414), hazard ratio 0.67, 95% CI: 0.56-0.78, P<0.0001. Additionally, patients assigned to empagliflozin were 20-40% more likely to experience an improvement in NYHA functional class and were 20-40% less likely to experience worsening of NYHA functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up. The risk of any inpatient or outpatient worsening heart failure event in the placebo group was high (48.1 per 100 patient-years of follow-up), and it was reduced by empagliflozin (hazard ratio 0.70, 95% CI: 0.63-0.78), P<0.0001. Conclusions: In patients with heart failure and a reduced ejection fraction, empagliflozin reduced the risk and total number of inpatient and outpatient worsening heart failure events, with benefits seen early after initiation of treatment and sustained for the duration of double-blind therapy. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT03057977

Catheter ablation of atrial fibrillation benefits the patients with heart failure and preserved ejection fraction as well as those with heart failure and reduced ejection fraction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Yamauchi ◽  
I Morishima ◽  
Y Morita ◽  
K Takagi ◽  
H Nagai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Catheter Ablation ◽  
Ejection Fraction ◽  
Cardiac Function ◽  
Functional Class ◽  
Reverse Remodeling ◽  
Reduced Ejection Fraction ◽  
Nyha Functional Class ◽  
Patients With Heart Failure

Abstract Background Although catheter ablation of atrial fibrillation (AF) has recently been shown to improve the cardiac function and even mortality in patients with heart failure (HF) and reduced ejection fraction (HFrEF), few studies have examined the outcomes of AF catheter ablation in patients with HF with preserved ejection fraction (HFpEF). Purpose To verify the impact of AF catheter ablation on the cardiac function and HF status in patients with HFpEF. Methods We studied 306 patients with HF who had a history of an HF hospitalization and/or preprocedural serum BNP levels &gt;100pg/ml (age, 68.9±8.2 years old; male, 66.3%; non-paroxysmal AF, 63.1%, left atrial diameter [LAD], 42.5±6.3 mm; left ventricular ejection fraction [LVEF], 60.6±12.0%) out of 596 consecutive patients who underwent pulmonary vein isolation-based catheter ablation of AF. The patients with an LVEF ≥50% were defined as having HFpEF (n=262; age, 69.0±8.2 years old; male, 64.5%; non-paroxysmal AF, 61.8%, LAD, 42.1±5.9 mm; left LVEF, 64.0±8.2%) and the remaining patients with an LVEF &lt;50% were defined as having HFrEF (n=44, age, 67.9±8.7 years old; male, 77.0%; non-paroxysmal AF, 70.5%, LAD, 44.9±8.2 mm; LVEF, 40.1±10.2%). The patients received periodic follow-ups for 12 months after the catheter ablation. The cardiac function parameters including the echocardiographic findings and HF functional status of the patients were compared between baseline and 12 months, stratified by the HF subgroup. Results AF recurred in 60 patients with HFpEF (22.9%) and in 14 with HFrEF (31.8%) during the 12 month follow-up (p=0.27), however, sinus rhythm was maintained at 12 months in most of the patients (253 patients with HFpEF [96.6%] and 42 patients with HFrEF [95.5%]) (p=0.71). Figure 1 compares the changes in the cardiac function parameters and NYHA functional class from baseline to the 12-month follow-up stratified by the HF subgroup. Both the patients with HFpEF and HFrEF had significant improvements in the serum BNP levels, chest thorax ratio, and LVEF determined by echocardiography. LA reverse remodeling as shown by a significant reduction in the LAD was observed in both HF subgroups, however, the E/E', an index of the LV diastolic function, did not significantly change in either of the subgroups. Similar to the patients with HFrEF, an improvement in the NYHA functional class was seen in those with HFpEF. Conclusions Catheter ablation of AF may benefit patients with HFpEF as well as those with HFrEF. Sinus rhythm maintenance achieved by AF catheter ablation in patients with HFpEF may lead to LA reverse remodeling and a better LV systolic function, thereby improving the NYHA functional class. It is unclear whether changes in the LV diastolic function may contribute to this favorable process. Funding Acknowledgement Type of funding source: None

scholarly journals Use of Free-Living Step Count Monitoring for Heart Failure Functional Classification: Validation Study (Preprint)

2018 ◽  
Author(s):  
Jonathan-F. Baril ◽  
Simon Bromberg ◽  
Yasbanoo Moayedi ◽  
Babak Taati ◽  
Cedric Manlhiot ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pilot Study ◽  
Ejection Fraction ◽  
Functional Class ◽  
Step Count ◽  
Functional Classification ◽  
Free Living ◽  
Reduced Ejection Fraction ◽  
Nyha Functional Class ◽  
Daily Total

BACKGROUND The New York Heart Association (NYHA) functional classification system has poor inter-rater reproducibility. A previously published pilot study showed a statistically significant difference between the daily step counts of heart failure (with reduced ejection fraction) patients classified as NYHA functional class II and III as measured by wrist-worn activity monitors. However, the study’s small sample size severely limits scientific confidence in the generalizability of this finding to a larger heart failure (HF) population. OBJECTIVE This study aimed to validate the pilot study on a larger sample of patients with HF with reduced ejection fraction (HFrEF) and attempt to characterize the step count distribution to gain insight into a more objective method of assessing NYHA functional class. METHODS We repeated the analysis performed during the pilot study on an independently recorded dataset comprising a total of 50 patients with HFrEF (35 NYHA II and 15 NYHA III) patients. Participants were monitored for step count with a Fitbit Flex for a period of 2 weeks in a free-living environment. RESULTS Comparing group medians, patients exhibiting NYHA class III symptoms had significantly lower recorded 2-week mean daily total step count (3541 vs 5729 [steps], P=.04), lower 2-week maximum daily total step count (10,792 vs 5904 [steps], P=.03), lower 2-week recorded mean daily mean step count (4.0 vs 2.5 [steps/minute], P=.04,), and lower 2-week mean and 2-week maximum daily per minute step count maximums (88.1 vs 96.1 and 111.0 vs 123.0 [steps/minute]; P=.02 and .004, respectively). CONCLUSIONS Patients with NYHA II and III symptoms differed significantly by various aggregate measures of free-living step count including the (1) mean and (2) maximum daily total step count as well as by the (3) mean of daily mean step count and by the (4) mean and (5) maximum of the daily per minute step count maximum. These findings affirm that the degree of exercise intolerance of NYHA II and III patients as a group is quantifiable in a replicable manner. This is a novel and promising finding that suggests the existence of a possible, completely objective measure of assessing HF functional class, something which would be a great boon in the continuing quest to improve patient outcomes for this burdensome and costly disease.

Left Ventricular Ejection Fraction Recovery in Patients with Heart Failure and Reduced Ejection Fraction Treated with Sacubitril/Valsartan

Cardiology ◽  
2020 ◽  
Vol 145 (5) ◽  
pp. 275-282 ◽  
Author(s):  
Pablo Díez-Villanueva ◽  
Lourdes Vicent ◽  
Francisco de la Cuerda ◽  
Alberto Esteban-Fernández ◽  
Manuel Gómez-Bueno ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular Ejection Fraction ◽  
Ejection Fraction ◽  
Left Ventricular ◽  
Functional Class ◽  
Ventricular Ejection ◽  
Cardiac Resynchronization ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

Background: A significant number of heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF) experience ventricular function recovery during follow-up. We studied the variables associated with LVEF recovery in patients treated with sacubitril/valsartan (SV) in clinical practice. Methods: We analyzed data from a prospective and multicenter registry including 249 HF outpatients with reduced LVEF who started SV between October 2016 and March 2017. The patients were classified into 2 groups according to LVEF at the end of follow-up (>35%: group R, or ≤35%: group NR). Results: After a mean follow-up of 7 ± 0.1 months, 62 patients (24.8%) had LVEF >35%. They were older (71.3 ± 10.8 vs. 67.5 ± 12.1 years, p = 0.025), and suffered more often from hypertension (83.9 vs. 73.8%, p = 0.096) and higher blood pressure before and after SV (both, p < 0.01). They took more often high doses of beta-blockers (30.6 vs. 27.8%, p = 0.002), with a smaller proportion undergoing cardiac resynchronization therapy (14.8 vs. 29.0%, p = 0.028) and fewer implanted cardioverter defibrillators (ICD; 32.8 vs. 67.9%, p < 0.001), this being the only predictive variable of NR in the multivariate analysis (OR 0.26, 95% CI 0.13–0.47, p < 0.0001). At the end of follow-up, the mean LVEF in group R was 41.9 ± 8.1% (vs. 26.3 ± 4.7% in group NR, p < 0.001), with an improvement compared with the initial LVEF of 14.6 ± 10.8% (vs. 0.8 ± 4.5% in group NR, p < 0.0001). Functional class improved in both groups, mainly in group R (p = 0.035), with fewer visits to the emergency department (11.5 vs. 21.6%, p = 0.07). Conclusions: In patients with LVEF ≤35% treated with SV, not carrying an ICD was independently associated with LVEF recovery, which was related to greater improvement in functional class.

scholarly journals Renal effects of Sacubitril/Valsartan in heart failure with reduced ejection fraction: a real life 1-year follow-up study

2019 ◽  
Vol 14 (8) ◽  
pp. 1287-1297 ◽  
Author(s):  
Francesco Spannella ◽  
Marco Marini ◽  
Federico Giulietti ◽  
Giulia Rosettani ◽  
Matteo Francioni ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Real Life ◽  
Renal Effects ◽  
Reduced Ejection Fraction ◽  
Follow Up Study

scholarly journals Sacubitril/Valsartan Improves Autonomic Function and Cardiopulmonary Parameters in Patients with Heart Failure with Reduced Ejection Fraction

2020 ◽  
Vol 9 (6) ◽  
pp. 1897 ◽  
Author(s):  
Francesco Giallauria ◽  
Giuseppe Vitale ◽  
Mario Pacileo ◽  
Anna Di Lorenzo ◽  
Alessandro Oliviero ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Autonomic Function ◽  
Left Ventricular ◽  
Exercise Stress ◽  
Left Ventricular Ejection ◽  
Peak Exercise ◽  
Ventricular Ejection Fraction ◽  
Reduced Ejection Fraction

Background: Heart rate recovery (HRR) is a marker of vagal tone, which is a powerful predictor of mortality in patients with cardiovascular disease. Sacubitril/valsartan (S/V) is a treatment for heart failure with reduced ejection fraction (HFrEF), which impressively impacts cardiovascular outcome. This study aims at evaluating the effects of S/V on HRR and its correlation with cardiopulmonary indexes in HFrEF patients. Methods: Patients with HFrEF admitted to outpatients’ services were screened out for study inclusion. S/V was administered according to guidelines. Up-titration was performed every 4 weeks when tolerated. All patients underwent laboratory measurements, Doppler-echocardiography, and cardiopulmonary exercise stress testing (CPET) at baseline and at 12-month follow-up. Results: Study population consisted of 134 HFrEF patients (87% male, mean age 57.9 ± 9.6 years). At 12-month follow-up, significant improvement in left ventricular ejection fraction (from 28% ± 5.8% to 31.8% ± 7.3%, p < 0.0001), peak exercise oxygen consumption (VO2peak) (from 15.3 ± 3.7 to 17.8 ± 4.2 mL/kg/min, p < 0.0001), the slope of increase in ventilation over carbon dioxide output (VE/VCO2 slope )(from 33.4 ± 6.2 to 30.3 ± 6.5, p < 0.0001), and HRR (from 11.4 ± 9.5 to 17.4 ± 15.1 bpm, p = 0.004) was observed. Changes in HRR were significantly correlated to changes in VE/VCO2slope (r = −0.330; p = 0.003). After adjusting for potential confounding factors, multivariate analysis showed that changes in HRR were significantly associated to changes in VE/VCO2slope (Beta (B) = −0.975, standard error (SE) = 0.364, standardized Beta coefficient (Bstd) = −0.304, p = 0.009). S/V showed significant reduction in exercise oscillatory ventilation (EOV) detection at CPET (28 EOV detected at baseline CPET vs. 9 EOV detected at 12-month follow-up, p < 0.001). HRR at baseline CPET was a significant predictor of EOV at 12-month follow-up (B = −2.065, SE = 0.354, p < 0.001). Conclusions: In HFrEF patients, S/V therapy improves autonomic function, functional capacity, and ventilation. Whether these findings might translate into beneficial effects on prognosis and outcome remains to be elucidated.

scholarly journals Head-to-head comparison of NT-proBNP and soluble ST2 for long-term prognosis of patients with hypertrophic cardiomyopathy

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
G Cediel Calderon ◽  
H Resta ◽  
P Codina ◽  
E Santiago-Vacas ◽  
M Domingo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Hypertrophic Cardiomyopathy ◽  
Primary Endpoint ◽  
Left Ventricular ◽  
Functional Class ◽  
Left Ventricular Ejection ◽  
Nyha Functional Class ◽  
C Statistic

Abstract Background N-terminal pro-brain natriuretic peptide (NT-proBNP) predicts mortality and the development of heart failure (HF) in hypertrophic cardiomyopathy (HCM), however, evidence regarding soluble interleukin-1 receptor-like 1 (ST2) in this population is lacking. Purpose To assess the ST2 and NT-proBNP significance for risk stratification of patients with HCM during long-term follow-up. Methods We prospectively enrolled a cohort of consecutive patients with HCM admitted to an ambulatory HF Unit in a Tertiary University Hospital. All patients had clinical and echocardiographic evaluation and measurement of NT-proBNP and ST2 at inclusion. The primary endpoint was the composite of all-cause death or HF-related hospitalization. Results 103 patients were enrolled, 68% (n=70) males with a median (IQR) age of 60 (50–71) years. The median (IQR) of ST2 was 31.5 (IQR: 24.5 – 40.7) pg/mL. During a median follow-up of 2.5 years, 17 patients had the primary endpoint. Both, NT-proBNP and ST2 (both log-transformed) were associated with the primary endpoint in the univariable analyses (p&lt;0.01). However, after adjustment by age, sex, NYHA functional class and left ventricular ejection fraction (LVEF), this association remained statistically significant only for ST2 (HR: 4.62, 95% CI 1.80–11.87, p=0.001 vs HR: 1.57, 95% CI 0.97–2.54, p=0.068 for NT-proBNP). The addition of ST2 to a clinical model (age, sex, NYHA functional class and LVEF) increased the Harrel's C statistic from 0.70 to 0.76, while the addition of NT-proBNP increase this C-statistic only to 0.73. Conclusions ST2 appears to be a valuable biomarker for the prediction of death and heart failure related hospitalization in patients with HCM, outperforming the prognostic value of NT-proBNP. Future research should delve into this association. FUNDunding Acknowledgement Type of funding sources: None.

scholarly journals Improvement in Left Ventricular Ejection Fraction in Outpatients With Heart Failure With Reduced Ejection Fraction

2020 ◽  
Vol 13 (7) ◽  
Author(s):  
Adam D. DeVore ◽  
Anne S. Hellkamp ◽  
Laine Thomas ◽  
Nancy M. Albert ◽  
Javed Butler ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Clinical Decision Making ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Factors Associated ◽  
Patients With Heart Failure

Background: Among patients with heart failure (HF) with reduced ejection fraction (EF), improvements in left ventricular EF (LVEF) are associated with better outcomes and remain an important treatment goal. Patient factors associated with LVEF improvement in routine clinical practice have not been clearly defined. Methods: CHAMP-HF (Change the Management of Patients with Heart Failure) is a prospective registry of outpatients with HF with reduced EF. Assessments of LVEF are recorded when performed for routine care. We analyzed patients with both baseline and ≥1 follow-up LVEF assessments to describe factors associated with LVEF improvement. Results: In CHAMP-HF, 2623 patients had a baseline and follow-up LVEF assessment. The median age was 67 (interquartile range, 58–75) years, 40% had an ischemic cardiomyopathy, and median HF duration was 2.8 years (0.7–6.8). Median LVEF was 30% (23–35), and median change on follow-up was 4% (−2 to −13); 19% of patients had a decrease in LVEF, 31% had no change, 49% had a ≥5% increase, and 34% had a ≥10% increase. In a multivariable model, the following factors were associated with ≥5% LVEF increase: shorter HF duration (odds ratio [OR], 1.21 [95% CI, 1.17–1.25]), no implantable cardioverter defibrillator (OR, 1.46 [95% CI, 1.34–1.55]), lower LVEF (OR, 1.15 [95% CI, 1.10–1.19]), nonischemic cardiomyopathy (OR, 1.24 [95% CI, 1.09–1.36]), and no coronary disease (OR, 1.20 [95% CI, 1.03–1.35]). Conclusions: In a large cohort of outpatients with chronic HF with reduced EF, improvements in LVEF were common. Common baseline cardiac characteristics identified a population that was more likely to respond over time. These data may inform clinical decision making and should be the basis for future research on myocardial recovery.

scholarly journals P974 Sacubitril/valsartan is well tolerated in patients with heart failure and a history of cancer

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
M K Frey ◽  
E Han ◽  
H Arfsten ◽  
N Pavo ◽  
M Huelsmann ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cancer Patients ◽  
Functional Class ◽  
Reduced Ejection Fraction ◽  
Non Hodgkin Lymphoma ◽  
Patients With Heart Failure ◽  
History Of ◽  
History Of Cancer

Abstract Introduction Sacubitril/valsartan has been shown to significantly reduce cardiovascular mortality and hospitalisations due to heart failure in patients with reduced ejection fraction when compared to enalapril. Until now, sacubitril/valsartan has not been evaluated in patients with a history of cancer, as these patients were excluded from the pivotal trial, PARADIGM-HF. The aim of the current study was to assess tolerability of sacubitril/valsartan in patients with a history of cancer. Methods We retrospectively enrolled all patients at our heart failure out-patient unit who fulfilled the indication criteria to receive sacubitril/valsartan and had a history of cancer. Fifteen patients receiving sacubitril/valsartan had a diagnosis of histologically confirmed cancer: 26.7% breast cancer (n = 4), 13.3% osteosarcoma (n = 2), 13.3% colorectal cancer (n = 2), 13.3% renal cell carcinoma (n = 2), 6.7% non-Hodgkin lymphoma (n = 1), 6.7% lung cancer (n = 1), 6.7% prostate cancer (n = 1), 6.7% bladder carcinoma and 6.7% myeoloproliferative syndrome (n = 1). Surgery due to cancer was performed in 80% of patients (n = 12), 26.7% previously received chemotherapy (n = 6) and 40% radiation therapy (n = 4). Results Sacubitril/valsartan was withdrawn in 2 patients (13.3%) because of dizziness and pruritus respectively. After a mean follow-up of 13 ±8 months, NYHA functional class improved significantly (mean -0.5, p = 0.001), ejection fraction as assassed by echocardiography increased (mean +6.8%, p = 0.018) and NT-proBNP was significantly decreased (mean -1552pg/ml, p = 0.026). There was no significant change in creatinine levels (+0.046 mg/dl, p = 0.564 ). Conclusions In this pilot study we were able to show that sacubitril/valsartan is generally well tolerated in patients with a history of cancer. Patients with cardiotoxicity induced heart failure can be treated and uptitrated with sacubitril/valsartan to usual dosages similarly as in other causes of heart failure. Larger studies are needed to confirm these findings in cancer patients with cardiotoxicity.

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