Role of Early Left Atrial Functional Decline in Predicting Cardiotoxicity in HER2 Positive Breast Cancer Patients Treated With Trastuzumab.

Trastuzumab is widely used in HER2 breast cancer. However, it may cause left ventricular (LV) dysfunction. A decrease in LV global longitudinal strain (GLS) has been previously demonstrated to be a good predictor of subsequent cancer therapy related dysfunction (CTRCD). Left atrial morphological remodeling during Trastuzumab therapy has also been shown. The aim of this study is exploring the relationship between early changes in left atrial function and the development of Trastuzumab-induced cardiotoxicity. Consecutive patients with diagnosis of HER2+non-metastatic breast cancer treated with Trastuzumab were prospectively enrolled. A clinical, conventional, and advanced echocardiographic assessment was performed at baseline and every three months, until a one-year follow-up was reached. One-hundred-sixteen patients completed the 12 months follow-up, 10 (9%) cases of CTRCD were observed, all after the sixth month. GLS and LVEF significantly decreased in the CTRCD group at 6 months of follow-up, with an earlier (3 months) significant worsening in left atrial morpho-functional parameters. Systolic blood pressure, early peak atrial longitudinal strain (PALS), peak atrial contraction (PACS) and left atrial volume (LAVI) changes resulted independent predictors of CTRCD at multivariable logistic regression analysis. Moreover, early changes in PALS and PACS resulted good predictors of CTRCD development (AUC 0.85; p = 0.008, p < 0.001 and 0.77; p = 0.008, respectively). This prospective study emphasizes that the decline in PALS and PACS among trastuzumab-treated patients could possibly increase the accuracy in identifying future CTRCD in non-metastatic HER2 breast cancer cases, adding predictive value to conventional echocardiographic assessment.

Outpatient tricuspid regurgitation in the community: Clinical context and outcome.

BACKGROUND AND AIMS: Epidemiology of tricuspid regurgitation (TR) is poorly known and its burden in the community is challenging to define. We aimed to evaluate the prevalence of TR in a geographically defined area and its outcome, in particular overall survival and hospitalization, considering different clinical contexts. METHODS: We retrospectively analyzed consecutive outpatients referred between 2006 and 2013 for echocardiography and clinical evaluation. Patients with at least moderate TR were included and five different clinical settings were defined: concomitant significant left-sided valvular heart disease (LVHD-TR), heart failure (HF-TR), previous open-heart valvular surgery (postop-TR), pulmonary hypertension (PHTN-TR) and isolated TR (isolated-TR). Primary endpoint was a composite outcome of all-cause mortality or first hospitalization for HF. RESULTS: Of 6797 consecutive patients with a clinical visit and echocardiograms performed in routine practice in a geographically defined community, moderate or severe TR was found in 4.8% of patients (327) . During median follow-up of 6.1 years, TR severity was a determinant of event-free survival. Analyzed for each clinical subset, eight-year event-free survival was 87 ± 7% for postop-TR subgroup, 75 ± 7% for isolated-TR, 67 ± 6% for PHTN-TR, 58 ± 6% for LHVD -TR and 52 ± 11% for HF-TR. CONCLUSION: Moderate or more TR is a notable finding in the community and has impact on event-free survival in all clinical settings, with the worst outcomes when associated with relevant left-sided valvular heart disease and HF.

Atrial Strain Assessment for the Early Detection of Cancer Therapy-Related Cardiac Dysfunction in Breast Cancer Women (The STRANO STUDY: Atrial Strain in Cardio-Oncology).

Left ventricular global longitudinal strain (GLS) has an important role in the diagnosis of cancer therapy-related cardiac dysfunction (CTRCD). Little is known about the role of atrial function in diagnosing CTRCD. The aim of our study was to assess the impact of anti-cancer drugs on atrial function measured by speckle-tracking echocardiography in breast cancer women. A prospective multicenter study was conducted enrolling 169 breast cancer women treated with anthracyclines. A cardiological evaluation including an electrocardiogram and echocardiogram with an analysis of GLS, left atrial (LA) strain, and LA stiffness (LASi) was performed at baseline (T0), 3 (T1), and 6 months (T2) after starting chemotherapy. The patients were divided into two groups: patients with asymptomatic mild cardiotoxicity at T1 (with a relative reduction in GLS > 15%; Group 1) and those without (Group 2). We did not find a significant change in left ventricular ejection fraction (LVEF) at T1 and T2; we found a significant change in GLS (p-value < 0.0001) in the peak atrial longitudinal strain (PALS) and in LASi (p-value < 0.0001). Impairment of atrial function was greater in Group 1 compared to Group 2. A PALS variation > 20.8% identified patients who were most likely to develop asymptomatic mild cardiotoxicity [AUC 0.62; CI (0.51-0.73) p = 0.06, sensitivity 45%, specificity 69.5%]. Conclusions: PALS and LASi significantly change during chemotherapy in association with GLS. Atrial strain is an additional parameter that could be measured together with GLS to detect cardiotoxicity early.

Mitral regurgitation and dyspnoea: the expanding role of mitral effective regurgitant orifice among un-selected patients.

AIMS: Mitral regurgitation is frequent in the general population and among suspected heart failure patients; however, to what extent it contributes to dyspnoea is unclear. We hypothesized mitral regurgitation to have a role in determining dyspnoea in unselected ambulatory patients. METHODS: Consecutive outpatients referred for echocardiography were retrospectively screened and included. We excluded patients with mitral stenosis or prosthesis, congenital heart disease, cardiac surgery (previous 6 months) and atrial fibrillation. Patients were classified into four dyspnoea grades based on how they perceived their disability. We assessed mitral regurgitation severity through the effective regurgitant orifice area (ERO). RESULTS: One hundred and fifty-four patients (58% men; age 67 ±â€Š14 years; mean ejection fraction 54 ±â€Š12%) formed the study population; 76 (49%) classified asymptomatic (grade I), 63 (41%) dyspnoea grade II and 15 (10%) grade III; none was in grade IV. Mitral regurgitation was present in 102 patients (66%): primary in 14 (14%) and secondary in 88 (86%); among grades I, II and III patients, mitral regurgitation was present in 35 (46%; ERO 0.05 ±â€Š0.10 cm), 52 (82%; ERO 0.10 ±â€Š0.13 cm) and 15 (100%; ERO 0.20 ±â€Š0.11 cm) patients, respectively (P < 0.0001). After adjusting for clinical (age, hypertension, ischemic heart disease, chronic kidney injury, chronic pulmonary disease) and echocardiographic confounders (ejection fraction, E/e'), ERO remained associated with symptoms presence (grade I versus II - III; P = 0.01 and P = 0.03, respectively). CONCLUSION: Among unselected heterogeneous ambulatory patients, mitral ERO was associated with the presence of dyspnoea and could therefore help in identifying symptomatic patients and in clinical characterization of patients with perceived dyspnoea.

Role of Speckle Tracking Echocardiography in the Evaluation of Breast Cancer Patients Undergoing Chemotherapy: Review and Meta-analysis of the Literature.

Diagnosis and management of Cancer therapeutics-related cardiac dysfunction is of crucial importance in breast cancer (BC) patients. The role of advanced echocardiographic techniques, such as deformation imaging, in the diagnosis and characterization of patients receiving cancer therapy has so far involved relatively small studies in the research setting. Therefore, we conducted a meta-analysis and systematic review of observational studies evaluating myocardial changes during chemotherapy detected through conventional echocardiographic parameters, such as 2D left ventricular ejection fraction (2D LVEF), and 2D Speckle tracking echocardiography (STE). The literature search retrieved 487 research works, articles, of which 17 were found to be pertinent with this topic. After full article review, 16 studies were considered suitable for the present analysis. Two separate analyses, one for the anthracyclines-based therapeutic regimen and one for the trastuzumab based therapeutic regimen, were performed. A significant reduction in 2D LVEF and 2D STE parameters during cancer therapy was found in both the investigations. Peak systolic global longitudinal strain demonstrated to be the most consistent 2D STE parameter in detecting early myocardial changes among all the studies. Thus, we confirmed the role of 2D STE for the early detection of myocardial damage, suggesting its crucial role in monitoring BC patients and eventually driving the introduction of cardioprotective treatment.

Usefulness of Left Atrial Remodeling in Predicting CardiacToxicity During Trastuzumab Therapy for Breast Cancer.

Trastuzumab is a key therapy for patients with human epidermal growth factor receptor 2 positive breast cancer (BC). However, it may cause left ventricular dysfunction, resulting in withdrawal of therapy. Left atrium (LA) enlargement has proven to cue subclinical ventricular dysfunction in various clinical setting. Aim of the study was to investigate the association between LA volume index (LAVI) change over time and the development of Cancer Therapeutics Related Cardiac Dysfunction (CTRCD). Consecutive human epidermal growth factor receptor 2 positive BC patients were retrospectively included. Transthoracic echocardiography was performed before starting Trastuzumab and at every 3 up to 12 months. LA volume was measured using the modified Simpson's rule and indexed for body surface area. Ninety patients formed the study population. All patients had a complete 12 months follow-up. Mean baseline LAVI was 27 ± 8 ml/m2 and it was dilated (≥34 ml/m2) in 10 patients (11%). During follow-up, CTRCD occurred in 19 (21%) patients and there was modest LAVI enlargement, with a mean increase of 3 ± 2 ml/m2 (p = 0.0002 vs. baseline). LAVI dilation was significantly higher in patients with CTRCD (average increase at the time of CTRCD vs. baseline: 7 ± 6 ml/m2, p = 0.008), versus patients without CTRCD (average increase at 12 months of follow-up 2±1, p = 0.02), p for comparison = 0.004. LAVI dilatation over time predicted CTRCD independently from baseline LAVI values and the presence of systemic arterial hypertension (OR for 5 ml/m2 dilation was 1.56 [95%CI 1.09 to 2.37], p = 0.01). Trastuzumab related CTRCD is associated with significant LAVI morphological remodeling in BC patients.

Left atrial volume in patients with HER2-positive breast cancer: One step further to predict trastuzumab-related cardiotoxicity.

BACKGROUND: Trastuzumab (TZ) therapy requires careful monitoring of left ventricular (LV) ejection fraction (LVEF) because it can be potentially cardiotoxic. However, LVEF is an imperfect parameter and there is a need to find other variables to predict cardiac dysfunction early. Left atrium (LA) enlargement has proven to be a powerful predictor of adverse outcomes in several disease entities. HYPOTHESIS: Baseline LA volume enlargement might predict TZ-related LV dysfunction. METHODS: HER2-positive breast cancer patients receiving TZ and undergoing transthoracic echocardiography at baseline and at follow-up every 3 months were retrospectively recruited. One-hundred sixty-two patients formed the study population. RESULTS: Baseline LAVI was dilated in 14 patients (8.6%). Mean follow-up was 14 ± 4 months. Cardiotoxicity occurred in 24 patients (14.8%). LAVI was an independent predictor of TZ-induced LV dysfunction in a clinical model, after adjustment for age and hypertension (odds ratio per 5-mL/m2 LAVI increase: 1.34, 95% confidence interval: 1.03-1.82, P = 0.03); and in a hemodynamic model, including ventricular sizes and systolic blood pressure level (odds ratio per 5-mL/m2 LAVI increase: 1.34, 95% confidence interval: 1.01-1.81, P = 0.04). The predicted probability of developing cardiotoxicity increased progressively, in parallel with LAVI values. CONCLUSIONS: Baseline LA dilatation emerges as a condition associated with the development of cardiotoxicity in HER2-positive breast cancer patients treated with TZ.

Left ventricular end-diastolic volume as early indicator of trastuzumab-related cardiotoxicity in HER2+ breast cancer patients: results from a single-center retrospective study.

BACKGROUND: Adjuvant trastuzumab therapy increases survival rates in patients with early HER2-positive breast cancer, although it can be potentially cardiotoxic. The aim of this study was to evaluate the prevalence of left ventricular (LV) systolic dysfunction; and the relationship between the presence of cardiovascular risk factors, cardiac therapy and/or echocardiographic parameters of systolic function at baseline and the development of cardiotoxicity in such patients. METHODS: A total of 227 patients were retrospectively reviewed. Cardiotoxicity was defined as a decrease in LV ejection fraction (EF) below 50% or an absolute decrease of >10 points below the baseline value or any indication of heart failure. Each patient underwent echocardiography at baseline and at follow-up every three months. RESULTS: The prevalence of cardiotoxicity was 17.6% (15.4% asymptomatic, 2.2% symptomatic). Patients developing LV dysfunction presented hypertension (P=0.041) and diabetes (P=0.01) and used cardiac therapy at baseline more frequently. Smoke habit, age >50 and use of angiotensin-converting enzyme (ACE)-inhibitors, were independent predictors of cardiac damage. Furthermore, patients with LV dysfunction showed baseline LV end-diastolic volume (EDV) higher than those who did not and baseline EDV (OR=1.02; 95% CI: 1.00-1.04; P=0.027) independently predicted cardiotoxicity with 58 mL/m2 as best cut-off point (AUC=0.65, 95% CI: 0.55-0.75]). CONCLUSIONS: The prevalence of trastuzumab-related cardiotoxicity in patients with HER2-positive early breast cancer is relatively frequent, although asymptomatic in most cases. Baseline EDV resulted as independent predictor of cardiotoxicity suggesting that EDV may be more reliable than LVEF to identify patients at higher risk of developing cardiac damage.

Nonalcoholic Fatty Liver Disease Is Associated With Ventricular Arrhythmias in Patients With Type 2 Diabetes Referred for Clinically Indicated 24-Hour Holter Monitoring.

OBJECTIVE: Recent studies have suggested that nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of heart rate-corrected QT interval prolongation and atrial fibrillation in patients with type 2 diabetes. Currently, no data exist regarding the relationship between NAFLD and ventricular arrhythmias in this patient population. RESEARCH DESIGN AND METHODS: We retrospectively analyzed the data of 330 outpatients with type 2 diabetes without preexisting atrial fibrillation, end-stage renal disease, or known liver diseases who had undergone 24-h Holter monitoring for clinical reasons between 2013 and 2015. Ventricular arrhythmias were defined as the presence of nonsustained ventricular tachycardia (VT), >30 premature ventricular complexes (PVCs) per hour, or both. NAFLD was diagnosed by ultrasonography. RESULTS: Compared with patients without NAFLD, those with NAFLD (n = 238, 72%) had a significantly higher prevalence of >30 PVCs/h (19.3% vs. 6.5%, P < 0.005), nonsustained VT (14.7% vs. 4.3%, P < 0.005), or both (27.3% vs. 9.8%, P < 0.001). NAFLD was associated with a 3.5-fold increased risk of ventricular arrhythmias (unadjusted odds ratio [OR] 3.47 [95% CI 1.65-7.30], P < 0.001). This association remained significant even after adjusting for age, sex, BMI, smoking, hypertension, ischemic heart disease, valvular heart disease, chronic kidney disease, chronic obstructive pulmonary disease, serum γ-glutamyltransferase levels, medication use, and left ventricular ejection fraction (adjusted OR 3.01 [95% CI 1.26-7.17], P = 0.013). CONCLUSIONS: This is the first observational study to show that NAFLD is independently associated with an increased risk of prevalent ventricular arrhythmias in patients with type 2 diabetes.

Nonalcoholic Fatty Liver Disease Is Independently Associated with Early Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes.

Accumulating evidence suggests that nonalcoholic fatty liver disease (NAFLD) is associated with left ventricular diastolic dysfunction (LVDD) in nondiabetic individuals. To date, there are very limited data on this topic in patients with type 2 diabetes and it remains uncertain whether NAFLD is independently associated with the presence of LVDD in this patient population. We performed a liver ultrasonography and trans-thoracic echocardiography (with speckle-tracking strain analysis) in 222 (156 men and 66 women) consecutive type 2 diabetic outpatients with no previous history of ischemic heart disease, chronic heart failure, valvular diseases and known hepatic diseases. Binary logistic regression analysis was used to examine the association between NAFLD and the presence/severity of LVDD graded according to the current criteria of the American Society of Echocardiography, and to identify the variables that were independently associated with LVDD, which was included as the dependent variable. Patients with ultrasound-diagnosed NAFLD (n = 158; 71.2% of total) were more likely to be female, overweight/obese, and had longer diabetes duration, higher hemoglobin A1c and lower estimated glomerular filtration rate (eGFR) than those without NAFLD. Notably, they also had a remarkably greater prevalence of mild and/or moderate LVDD compared with those without NAFLD (71% vs. 33%; P<0.001). Age, hypertension, smoking, medication use, E/A ratio, LV volumes and mass were comparable between the two groups of patients. NAFLD was associated with a three-fold increased odds of mild and/or moderate LVDD after adjusting for age, sex, body mass index, hypertension, diabetes duration, hemoglobin A1c, eGFR, LV mass index and ejection fraction (adjusted-odds ratio 3.08, 95%CI 1.5-6.4, P = 0.003). In conclusion, NAFLD is independently associated with early LVDD in type 2 diabetic patients with preserved systolic function.

Heart valve calcification in patients with type 2 diabetes and nonalcoholic fatty liver disease.

PURPOSE: Aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are two powerful predictors of adverse cardiovascular outcomes in patients with type 2 diabetes, but the etiology of valvular calcification is uncertain. Nonalcoholic fatty liver disease (NAFLD) is an emerging cardiovascular risk factor and is very common in type 2 diabetes, but whether NAFLD is associated with valvular calcification in this group of patients is presently unknown. METHODS: We undertook a cross-sectional study of 247 consecutive type 2 diabetic outpatients with no previous history of heart failure, valvular heart diseases (aortic stenosis, mitral stenosis, moderate or severe aortic and mitral regurgitation) or hepatic diseases. Presence of MAC and AVS was detected by echocardiography. NAFLD was diagnosed by ultrasonography. RESULTS: Overall, 139 (56.3%) patients had no heart valve calcification (HVC-0), 65 (26.3%) patients had one valve affected (HVC-1) and 43 (17.4%) patients had both valves affected (HVC-2). 175 (70.8%) patients had NAFLD and the prevalence of this disease markedly increased in patients with HVC-2 compared with either HVC-1 or HVC-0 (86.1% vs. 83.1% vs. 60.4%, respectively; p < 0.001). NAFLD was significantly associated with AVS and/or MAC (unadjusted-odds ratio 3.51, 95% CI 1.89-6.51, p < 0.001). Adjustments for age, sex, waist circumference, smoking, blood pressure, hemoglobin A1c, LDL-cholesterol, kidney function parameters, medication use and echocardiographic variables did not appreciably weaken this association (adjusted-odds ratio 2.70, 95% CI 1.23-7.38, p < 0.01). CONCLUSIONS: Our results show that NAFLD is an independent predictor of cardiac calcification in both the aortic and mitral valves in patients with type 2 diabetes.