Cardiovascular dysfunction induced by combined exposure to nicotine inhalation and high-fat diet.

Smoking and high-fat diet (HFD) consumption are two modifiable risk factors for cardiovascular (CV) diseases, and individuals who are overweight or obese due to unhealthy diet are more likely to use tobacco products. In this study, we aim to investigate the combined effects of nicotine (the addictive component of all tobacco products) and HFD on CV health, which are poorly understood. C57BL/6N male mice were placed on either HFD (60 kcal% fat) or regular diet (22 kcal% fat) and exposed to air or nicotine vapor for 10-12 wk. CV function was monitored by echocardiography and radiotelemetry, with left ventricular (LV) catheterization and aortic ring vasoreactivity assays performed at end point. Mice on HFD exhibited increased heart rate and impaired parasympathetic tone, whereas nicotine exposure increased sympathetic vascular tone as evidenced by increased blood pressure (BP) response to ganglionic blockade. Although neither nicotine nor HFD alone or in combination significantly altered BP, nicotine exposure disrupted circadian BP regulation with reduced BP dipping. LV catheterization revealed that combined exposure to nicotine and HFD led to LV diastolic dysfunction with increased LV end-diastolic pressure (LVEDP). Moreover, combined exposure resulted in increased inhibitory phosphorylation of endothelial nitric oxide synthase and greater impairment of endothelium-dependent vasodilation. Finally, a small cohort of C57BL/6N females with combined exposure exhibited similar increases in LVEDP, indicating that both sexes are susceptible to the combined effect of nicotine and HFD. In summary, combined exposure to nicotine and HFD leads to greater CV harm, including both additive and new-onset CV dysfunction.NEW & NOTEWORTHY Nicotine product usage and high-fat diet consumption are two modifiable risk factors for cardiovascular diseases. Here, we demonstrate that in mice, combined exposure to inhaled nicotine and high-fat diet results in unique cardiovascular consequences compared with either treatment alone, including left ventricular diastolic dysfunction, dysregulation of blood pressure, autonomic dysfunction, and greater impairment of endothelium-dependent vasorelaxation. These findings indicate that individuals who consume both nicotine products and high-fat diet have distinctive cardiovascular risks.

Dapagliflozin pharmacokinetics is similar between patients with heart failure with reduced ejection fraction and patients with type 2 diabetes mellitus.

Dapagliflozin was recently approved for use in adults with chronic heart failure with reduced ejection fraction (HFrEF) with/without type 2 diabetes mellitus (T2DM). The objectives of this analysis were to characterize dapagliflozin pharmacokinetics in patients with HFrEF and to compare dapagliflozin systemic exposure between adults with HFrEF with/without T2DM and adults with T2DM. A nonlinear mixed-effects modelling approach was applied; the population-pharmacokinetic model was developed using 9735 dapagliflozin plasma concentrations from 2744 patients. The final two-compartmental model adequately described the observed dapagliflozin concentrations, with a similar estimated apparent clearance compared with a previous estimate in patients with T2DM without HF and in healthy subjects (23.0 [95% CI: 22.6-23.9] L/h vs. 22.9 [95% CI: 22.1-23.7] L/h). The model-predicted median area under the dapagliflozin concentration-time profile was ≤1.2-fold higher in patients with HFrEF vs. those with T2DM without HFrEF, which is not considered clinically relevant. Dapagliflozin exposure was similar between patients with HFrEF with/without T2DM and T2DM patients without HFrEF.

Cardiovascular magnetic resonance characterization of myocardial tissue injury in a miniature swine model of cancer therapy-related cardiovascular toxicity.

BACKGROUND: Left ventricular ejection fraction (LVEF) is the most commonly clinically used imaging parameter for assessing cancer therapy-related cardiac dysfunction (CTRCD). However, LVEF declines may occur late, after substantial injury. This study sought to investigate cardiovascular magnetic resonance (CMR) imaging markers of subclinical cardiac injury in a miniature swine model. METHODS: Female Yucatan miniature swine (n = 14) received doxorubicin (2 mg/kg) every 3 weeks for 4 cycles. CMR, including cine, tissue characterization via T1 and T2 mapping, and late gadolinium enhancement (LGE) were performed on the same day as doxorubicin administration and 3 weeks after the final chemotherapy cycle. In addition, magnetic resonance spectroscopy (MRS) was performed during the 3 weeks after the final chemotherapy in 7 pigs. A single CMR and MRS exam were also performed in 3 Yucatan miniature swine that were age- and weight-matched to the final imaging exam of the doxorubicin-treated swine to serve as controls. CTRCD was defined as histological early morphologic changes, including cytoplasmic vacuolization and myofibrillar loss of myocytes, based on post-mortem analysis of humanely euthanized pigs after the final CMR exam. RESULTS: Of 13 swine completing 5 serial CMR scans, 10 (77%) had histological evidence of CTRCD. Three animals had neither histological evidence nor changes in LVEF from baseline. No absolute LVEF <40% or LGE was observed. Native T1, extracellular volume (ECV), and T2 at 12 weeks were significantly higher in swine with CTRCD than those without CTRCD (1178 ms vs. 1134 ms, p = 0.002, 27.4% vs. 24.5%, p = 0.03, and 38.1 ms vs. 36.4 ms, p = 0.02, respectively). There were no significant changes in strain parameters. The temporal trajectories in native T1, ECV, and T2 in swine with CTRCD showed similar and statistically significant increases. At the same time, there were no differences in their temporal changes between those with and without CTRCD. MRS myocardial triglyceride content substantially differed among controls, swine with and without CTRCD (0.89%, 0.30%, 0.54%, respectively, analysis of variance, p = 0.01), and associated with the severity of histological findings and incidence of vacuolated cardiomyocytes. CONCLUSION: Serial CMR imaging alone has a limited ability to detect histologic CTRCD beyond LVEF. Integrating MRS myocardial triglyceride content may be useful for detection of early potential CTRCD.

A systematic review and meta-analysis of human population studies on the association between exposure to toxic environmental chemicals and left ventricular dysfunction (LVD).

BACKGROUND: Exposure to environmental chemicals has been associated with an elevated risk of heart failure (HF). However, the impact on early markers of HF, such as left ventricular dysfunction (LVD), remains limited. OBJECTIVE: To establish a foundation of evidence regarding early HF markers and their association with environmental pollutants, a systematic review and meta-analysis was conducted. METHODS: The search, conducted on October 13th, 2023, encompassed PubMed, Embase, and Web of Science without filters, focusing on observational studies reporting myocardial geometrical, structural, or functional alterations in individuals without a history of heart disease. This included the general adult population, workers, young people, and the elderly. The risk of bias was assessed using the ROBINS-I tool at both study and item levels. RESULTS: The systematic review included 17 studies involving 43.358 individuals exposed to air pollution and 2038 exposed to heavy metals. Approximately 41% of the effect measures of associations reported significant abnormalities in myocardial structure or function. The metanalyses by pollutants categories indicated positive associations between LV systolic and diastolic abnormalities and exposure to PM2.5 [-0.069 (-0.104, -0.033); -0.044 (-0.062, -0.025)] and PM10 [-0.055 (-0.087, -0.022); -0.030 (-0.050, -0.010)] and NO2 [-0.042 (-0.071, -0.013); -0.021 (-0.037, -0.004)], as well as positive associations between lead exposure and LV systolic abnormalities [-0.033 (-0.051, -0.016)]. CONCLUSIONS: Existing evidence shows that specific early markers of HF may be associated with exposure to chemical pollutants. It is recommended to include such endpoints in new longitudinal and case-control studies to confirm further risk associations. These studies should consider co-exposures, account for vulnerable groups, and identify cardiotoxic compounds that may require regulation. When examining the link between myocardial abnormalities and environmental exposure, it is also advisable to explore the supportive use of Adverse Outcome Pathway (AOP) approaches to confirm a causal relationship.

Left atrial reservoir longitudinal strain and its incremental value to the left ventricular global longitudinal strain in predicting anthracycline-induced cardiotoxicity.

BACKGROUND: Left ventricular global longitudinal strain (LVGLS) has been recommended by current guidelines for diagnosing anthracycline-induced cardiotoxicity. However, little is known about the early changes in left atrial (LA) morphology and function in this population. Our study aimed to evaluate the potential usefulness of LA indices and their incremental value to LVGLS with three-dimensional echocardiography (3DE) in the early detection of subclinical cardiotoxicity in patients with lymphoma receiving anthracycline. METHODS: A total of 80 patients with diffuse large B-cell lymphoma who received six cycles of anthracycline-based treatment were enrolled. Echocardiography was performed at baseline (T0), after four cycles (T1), and after the completion of six cycles of chemotherapy (T2). Left ventricular ejection fraction (LVEF), LVGLS, LA volumes, LA emptying fraction (LAEF), LA active emptying fraction (LAAEF), and LA reservoir longitudinal strain (LASr) were quantified with 3DE. Left atrioventricular global longitudinal strain (LAVGLS) was calculated as the sum of peak LASr and the absolute value of peak LVGLS (LAVGLS = LASr+|LVGLS|). LV cardiotoxicity was defined as a new LVEF reduction by ≥10 percentage points to an LVEF of ≤50%. RESULTS: Fourteen (17.5%) patients developed LV cardiotoxicity at T2. LA volumes, LAEF, and LAAEF remained stable over time. Impairment of LASr (28.35 ± 5.03 vs. 25.04 ± 4.10, p < .001), LVGLS (-22.77 ± 2.45 vs. -20.44 ± 2.62, p < .001), and LAVGLS (51.12 ± 5.63 vs. 45.61 ± 5.22, p < .001) was observed by the end of the fourth cycle of chemotherapy (T1). Statistically significant declines in LVEF (61.30 ± 4.73 vs. 57.08 ± 5.83, p < .001) were only observed at T2. The relative decrease in LASr (ΔLASr), LVGLS (ΔLVGLS), and LAVGLS (ΔLAVGLS) from T0 to T1 were predictors of LV cardiotoxicity. A ΔLASr of >19.75% (sensitivity, 71.4%; specificity, 87.9%; area under the curve (AUC), .842; p < .001), a ΔLVGLS of >13.19% (sensitivity, 78.6%; specificity, 74.2%; AUC, .763; p < .001), and a ΔLAVGLS of >16.80% (sensitivity, 78.6%; specificity, 93.9%; AUC, .905; p < .001) predicted subsequent LV cardiotoxicity at T2, with the AUC of ΔLAVGLS significantly larger than that of ΔLVGLS (.905 vs. .763, p = .027). Compared to ΔLVGLS, ΔLAVGLS showed improved specificity (93.9% vs. 74.2%, p = .002) and maintained sensitivity in predicting LV cardiotoxicity. CONCLUSIONS: LASr could predict anthracycline-induced LV cardiotoxicity with excellent diagnostic performance. Incorporating LASr into LVGLS (LAVGLS) led to a significantly improved specificity and maintained sensitivity in predicting LV cardiotoxicity.

[Cardiac Dysfunction and Arterial Hypertension as Manifestations of Cardiovasculotoxicity of iVEGF-Containing Chemotherapy. Clinical Case].

Significant advances in timely diagnosis and modern antitumor therapy have led to a considerable increase in the survival rate of cancer patients. On the other hand, the incidence of cardiovascular (CV) diseases and their complications is increasingly growing, including due to side effects of anticancer drugs. CV complications are the most common cause of non-oncological death of cancer patients. The development of polychemotherapy-induced arterial hypertension (AH) is closely associated with the use of certain groups of drugs, for example, inhibitors of vascular endothelial growth factor (iVEGF). Such AH is generally dose-dependent and reversible after interruption or termination of treatment. However, systemic AH, regardless of its genesis, is one of the key risk factors for many CV events (myocardial infarction, stroke, heart failure, arrhythmias) and kidney disease. Therefore, thorough blood pressure monitoring and its timely and adequate correction if needed are indicated when using certain groups of chemotherapy drugs. This article describes a clinical follow-up of a patient with induced AH associated with the iVEGF antitumor therapy for advanced uterine cancer with a rapid development of left ventricular myocardial dysfunction.

Heart failure related to contemporary breast cancer treatment.

ABSTRACT: This article addresses cardiotoxicity in patients with breast cancer who are treated with anthracyclines and/or anti-human epidermal growth factor 2 (HER2) therapy, namely doxorubicin and trastuzumab. Development of concise clinical guidelines for chemotherapy-induced heart failure is ongoing. Through identification of specific risk factors and clinical predictors of cardiotoxicity, clinicians are able to better understand and define effective monitoring strategies and optimize patient care. Close cardiac monitoring is recommended for patients throughout treatment with anthracyclines and anti-HER2 therapy. Pretreatment risk assessment with echocardiography and evaluation of cardiovascular risk factors aid in predicting the development of left ventricular (LV) dysfunction. Further clinical trials are needed to increase understanding and optimize treatment guidelines for LV dysfunction in patients taking anthracyclines or anti-HER2 therapy.

Three-Year Outcomes Following Permissive Cardiotoxicity in Patients on Trastuzumab.

INTRODUCTION: Cardiotoxicity, manifest by reduced left ventricular ejection fraction (LVEF), is the most common reason for the premature discontinuation of trastuzumab. While permissive cardiotoxicity (where mild cardiotoxicity is accepted to enable ongoing trastuzumab) has been shown feasible, the longer-term outcomes are unknown. We aimed to study the intermediate-term clinical outcomes of patients who underwent permissive cardiotoxicity. MATERIALS AND METHODS: We performed a retrospective cohort study of patients referred to the cardio-oncology service at McMaster University from 2016 to 2021 for LV dysfunction following trastuzumab administration. RESULTS: Fifty-one patients underwent permissive cardiotoxicity. The median (25th-75th percentile) follow-up time from cardiotoxicity onset was 3 years (1.3-4 years). Forty-seven (92%) patients completed trastuzumab; 3 (6%) developed severe LV dysfunction or clinical heart failure (HF) while on trastuzumab and prematurely discontinued therapy. One discontinued trastuzumab by patient choice. At final follow-up after therapy completion, 7 (14%) patients still had mild cardiotoxicity, including 2 who had clinical heart failure and stopped trastuzumab early. Among those with recovered LV function, 50% had normalized LVEF or GLS by 6 and 3 months, respectively, after initial cardiotoxicity. There was no difference in characteristics between those who did or did not recover their LV function. CONCLUSIONS: Among patients exposed to permissive trastuzumab cardiotoxicity for HER2-positive breast cancer, 6% were unable to complete planned trastuzumab due to severe LV dysfunction or clinical HF. Although most patients recover their LV function after trastuzumab discontinuation or completion, 14% still have persistent cardiotoxicity by 3-year follow-up.

Cardiac and obstetric outcomes of pregnancies for women after cardiotoxic therapy in childhood: a single center observational study.

BACKGROUND: Childhood cancer survivors (CCS) are at increased risk of cardiomyopathy during pregnancy if they have prior cardiotoxic exposure. Currently, there is no consensus on the necessity, timing and modality of cardiac monitoring during and after pregnancy. Therefore, we examined cardiac function using contemporary echocardiographic parameters during pregnancy in CCS with cardiotoxic treatment exposure, and we observed obstetric outcomes in CCS, including in women without previous cardiotoxic treatment exposure. METHOD: A single-center retrospective cohort study was conducted among 39 women enrolled in our institution's cancer survivorship outpatient clinic. Information on potential cardiotoxic exposure in childhood, cancer diagnosis and outcomes of all pregnancies were collected through interviews and review of health records. Echocardiographic exams before and during pregnancy were retrospectively analyzed for left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) if available. The primary outcomes were (i) left ventricular dysfunction (LVD) during pregnancy, defined as LVEF < 50% or a decline of ≥ 10% in LVEF below normal (< 54%), and (ii) symptomatic heart failure (HF). Rate of obstetric and fetal complications was compared to the general population through the national perinatal registry (PERINED). RESULTS: All pregnancies (91) of 39 women were included in this study. The most common malignancy was leukemia (N = 17, 43.6%). In 22 patients, echocardiograms were retrospectively analyzed. LVEFbaseline was 55.4 ± 1.2% and pre-existing subnormal LVEF was common (7/22, 31.8/%). The minimum value of LVEF during pregnancy was 3.8% lower than baseline (p = 0.002). LVD occurred in 9/22 (40.9%) patients and HF was not observed. When GLS was normal at baseline (< -18.0%; N = 12), none of the women developed LVD. Nine of out ten women with abnormal GLS at baseline developed LVD later in pregnancy. In our cohort, the obstetric outcomes seemed comparable with the general population unless patients underwent abdominal irradiation (N = 5), where high rates of preterm birth (only 5/18 born at term) and miscarriage (6/18 pregnancies) were observed. CONCLUSION: Our study suggests that women with prior cardiotoxic treatment have a low risk of LVD during pregnancy if GLS at baseline was normal. Pregnancy outcomes are similar to the healthy population except when patients underwent abdominal irradiation.

Low incidence of cardiotoxicity in patients with non-Hodgkin lymphoma receiving EPOCH after prior anthracycline exposure.

OBJECTIVE: To describe the incidence of cardiotoxicity in patients with anthracycline exposure who subsequently receive EPOCH for non-Hodgkin lymphoma (NHL). METHODS: We conducted a retrospective cohort study of adults with anthracycline exposure who subsequently received EPOCH for NHL at Memorial Sloan Kettering Cancer Center. The primary outcome was cumulative incidence of arrhythmia, heart failure (HF), left ventricular (LV) dysfunction, or cardiac death. RESULTS: Among 140 patients, most had diffuse large B-cell lymphoma. Inclusive of EPOCH, median cumulative doxorubicin-equivalent dose was 364 mg/m2 ; exposure was 400 mg/m2 or higher in 41%. With median 36-month follow-up, 23 cardiac events were noted in 20 patients. Cumulative incidence of cardiac events at 60 months was 15% (95% confidence interval [CI]: 9%-21%). When limited to LV dysfunction/HF, cumulative incidence at 60 months was 7% (95% CI: 3%-13%), with most events occurring after the first year. Univariate analysis indicated only history of cardiac disease and dyslipidemia to be associated with cardiotoxicity; no other risk factors, including cumulative anthracycline dose, were identified. CONCLUSIONS: In this retrospective cohort, representing the largest experience in this setting with extended follow-up, cumulative incidence of cardiac events was low. Rates of LV dysfunction or HF were particularly low, suggesting infusional administration may mitigate risk despite prior exposure.

Effects of Sacubitril-Valsartan in Patients With Various Types of Heart Failure: A Meta-analysis.

ABSTRACT: We performed a meta-analysis investigating the efficacy and adverse effects of sacubitril-valsartan in various types of heart failure including more recent studies and a larger sample size. We conducted an electronic search through Cochrane, Web of Science, PubMed, and Embase. Included studies were randomized controlled trials analyzing the efficacy of sacubitril-valsartan compared with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) in patients with heart failure. Fourteen trials were included. Pooled estimates were analyzed using RevMan 5.4.1. The odds ratio (OR) of hospitalization from worsening heart failure that compared sacubitril-valsartan with control was 0.70 (95% CI, 0.51-0.97; P = 0.03) in patients with heart failure with reduced ejection fraction (HFrEF) with a relative risk reduction (RRR) of 24.3% and absolute risk reduction (ARR) of 3.4%. In patients with heart failure with midrange (HFmEF) and preserved (HFpEF) ejection fraction, the OR was 0.80 (95% CI, 0.71-0.90; P = 0.0001) with RRR of 14.5% and ARR of 3.3%. There was a significant reduction in cardiovascular deaths (OR = 0.79; 95% CI, 0.70-0.89; P = <0.0001) and all-cause mortality (OR = 0.84; 95% CI, 0.75-0.94; P = 0.002) in patients with HFrEF, with no significant differences in patients with HFmEF and HFpEF. Hospitalization rate was significantly reduced in patients taking sacubitril-valsartan across all analyzed cohorts. Sacubitril-valsartan significantly reduced the risk of all-cause mortality and cardiovascular death in patients with HFrEF but not in patients with HFmEF/HFpEF. These findings support sacubitril-valsartan use in reducing hospitalization of patients with HFmEF and HFpEF. More studies should be performed to further analyze the efficacy of sacubitril-valsartan in patients with HFmEF/HFpEF.

Early detection of cancer therapy cardiotoxicity by radionuclide angiography: An update.

Cancer therapy-induced cardiotoxicity is an emerging clinical and healthcare issue. Myocardial dysfunction and heart failure are mostly responsible for increased cardiovascular mortality in cancer disease survivors. Several imaging surveillance techniques have been proposed for early diagnosis of cancer therapy-induced cardiac dysfunction. Our aim was to provide an update of radionuclide angiography applications in this field. Radionuclide angiography is widely used to assess left ventricular ejection fraction (LVEF) throughout cancer treatment, especially in patients with limited acoustic window. Additional prognostic data may be provided by phase analysis and diastolic function evaluation. Low LVEF and high approximate entropy at baseline seem to be predictors for cancer therapy-induced cardiac dysfunction. A decrease in peak filling rate and/or an increase in time to peak filling rate may be observed in patients undergoing anthracycline and/or trastuzumab administration. Diastolic function impairment may precede or not LVEF decrease. In conclusion, recent studies have provided novel insights into the possible role of radionuclide angiography in the early detection of cancer therapy cardiotoxicity. While interpreting the results of a radionuclide angiography examination, an integrated approach combining the evaluation of LVEF, LV diastolic function, and phase analysis may be useful to improve risk stratification of cancer patients treated with cardiotoxic agents.

Effects of switching from sacubitril/valsartan to valsartan alone on plasma levels of natriuretic peptides and myocardial remodeling in heart failure with reduced ejection fraction.

BACKGROUND: We examined the effect of switching from angiotensin receptor-neprilysin inhibitor (ARNI) to angiotensin-receptor blocker (ARB) on plasma levels of natriuretic peptides and myocardial remodeling. METHODS: This is a prospective study that included 11 patients with heart failure (HF) treated with ARNI. The patients were divided into two groups: 5 patients who continued treatment with sacubitril/valsartan 194/206 mg/day (ARNI-continue group) and 6 patients who were switched to valsartan 160 mg/day (ARB-switch group). The primary endpoint was percent change (%Change) in plasma A-, B-, and N-terminal pro-B-type natriuretic peptide (ANP, BNP, and NT-proBNP) levels from the baseline to week 24. The secondary endpoint was the change in echocardiographic parameters related to myocardial remodeling from the baseline to week 24. RESULTS: ANP levels in the ARB-switch group significantly decreased (from 1155.7 ± 592.6 pg/mL to 231.6 ± 233.8 pg/mL, p = 0.035), whereas those in the ARNI-continue group were not significant (p = 0.180). The %Change of decrease in ANP levels was significantly greater in the ARB-switch group than the ARNI-continue group (- 76.9% vs. -9.1%, p = 0.009). BNP levels were not significantly different between the baseline and week 24 in both groups. NT-proBNP levels in the ARB-switch group increased from 1185.3 ± 835.6 pg/mL to 1515.2 ± 1213.5 pg/mL, although the changes were not statistically significant (p = 0.345). The %Change of increase in NT-proBNP levels was significantly greater in the ARB-switch group than the ARNI-continue group (57.9% vs. 17.3%, p = 0.016). In the ARB-switch group, there was a significant increase in left ventricular (LV) end-systolic volume (from 41.3 ± 24.1 mL/m2 to 71.4 ± 8.8 mL/m2, p = 0.043) and LV peak-systolic wall stress (from 187.0 ± 42.7 × 103 dynes/cm2 to 279.7 ± 34.1 × 103 dynes/cm2, p = 0.012) from the baseline to week 24 and a trend toward a decrease in LV ejection fraction (p = 0.080). In the ARNI-continue group, no differences in echocardiographic parameters were observed from the baseline to week 24. CONCLUSION: Switching from ARNI to ARB may worsen HF due to returning to myocardial remodeling induced by a sustained decline in ANP levels.

Effect on cardiac function among patients with type 2 diabetes following high-dose mineralocorticoid receptor antagonist using echocardiography; data from the MIRAD randomized clinical trial.

BACKGROUND: Early heart failure prevention is central in patients with type 2 diabetes, and mineralocorticoid receptor antagonists (MRAs) have shown to improve prognosis. We investigated the effect of high-dose MRA, eplerenone, on cardiac function and structure in patients with type 2 diabetes and established or increased risk of cardiovascular disease but without heart failure. METHODS: In the current randomized, placebo-controlled clinical trial, 140 patients with high-risk type 2 diabetes were randomized to high-dose eplerenone (100-200 mg daily) or placebo as add-on to standard care for 26 weeks. Left ventricular systolic and diastolic function, indexed left ventricular mass (LVMi), and global longitudinal strain (GLS) were assessed using echocardiography at baseline and after 26 weeks of treatment. RESULTS: Of the included patients, 138 (99%) had an echocardiography performed at least once. Baseline early diastolic in-flow velocity (E-wave) indexed by mitral annulus velocity (e') was mean (SD) 11.1 (0.5), with 31% of patients reaching above 12. No effect of treatment on diastolic function was observed measured by E/e' (0.0, 95%CI [-1.2 to 1.2], P = 0.992) or E/A (-0.1, 95%CI [-0.2 to 0.0], P = 0.191). Mean left ventricular ejection fraction (LVEF) at baseline was 59.0% (8.0). No improvement in systolic function was observed when comparing groups after 26 weeks (LVEF: 0.9, 95%CI [-1.1 to 2.8], P = 0.382; GLS: -0.4%, 95%CI [-1.5 to 0.6], P = 0.422), nor in LVMi (-3.8 g/m2 95%CI [-10.2 to 2.7], P = 0.246). CONCLUSION: In the present echo sub-study, no change in left ventricular function was observed following high-dose MRA therapy in patients with type 2 diabetes when evaluated by conventional echocardiography. TRIAL REGISTRATION: Date of registration 25/08/2015 (EudraCT number: 2015-002,519-14).

Prognostic value of left ventricular global longitudinal strain on speckle echocardiography for predicting chemotherapy-induced cardiotoxicity in breast cancer patients: A systematic review and meta-analysis.

BACKGROUND: Literature suggests that left ventricular global longitudinal strain (LV-GLS) on speckle echocardiography has the potential to predict cardiotoxicity amongst breast cancer patients receiving chemotherapy such as anthracycline, taxane, cyclophosphamide, and trastuzumab. Our study aimed to collect evidence for the prognostic value of LV-GLS for predicting chemotherapy-induced cardiotoxicity in breast cancer patients. METHODS: A detailed search of the PubMed, Google Scholar, Cochrane Library, and Scopus databases was conducted for published articles up to August 31, 2022. In our meta-analysis, we looked at 13 studies with a total of 1007 breast cancer patients getting chemotherapy that looked at the predictive value of GLS. RESULTS: Absolute GLS change during treatment showed a pooled sensitivity of 84% (95% CI 74% to 91%) and a pooled specificity of 77% (95% CI 68% to 84%).  For a relative change in GLS, we observed a pooled sensitivity of 76% (95% CI 56% to 89%) and a pooled specificity of 83% (95% CI 73% to 90%).  For an absolute change in GLS, we observed a positive likelihood ratio (LR), and the negative LR was 4 and .21. Summary receiver operating characteristics curve with prediction and confidence intervals represents a promising summary area under the curve (sAUC) of .88, 95% CI ranges from .85 to .91 for absolute change in GLS, as well as for relative change (sAUC, .87, 95% CI .84 to .90). CONCLUSION: Our results demonstrated an estimation of LV-GLS after the beginning of required chemotherapy, including anthracyclines and trastuzumab, had a promising prognostic value for predicting the likelihood of cancer therapeutics-related cardiac dysfunction. To confirm our findings, well-designed prospective adequately powered diagnostic randomised trials are necessary.

A systematic review and meta-analysis of beta-blockers and renin-angiotensin system inhibitors for preventing left ventricular dysfunction due to anthracyclines or trastuzumab in patients with breast cancer.

AIMS: Trastuzumab and anthracyclines, often used in the treatment of breast cancer, may impair myocardial function, and reduce left ventricular ejection fraction (LVEF), potentially causing heart failure. Randomized controlled trials (RCTs) have evaluated the effects of beta-blockers (BBs), angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme inhibitors (ACEI) on trastuzumab- and anthracycline-associated cardiotoxicity. We report a meta-analysis of these RCTs in patients with breast cancer. METHODS AND RESULTS: The primary analysis was on the effect of BBs and ACEI/ARBs on LVEF in patients treated with either trastuzumab or anthracyclines. A secondary analysis was done investigating the effect of BBs or ACEI/ARBs on LVEF in trastuzumab and anthracycline treatments. Only RCTs were included using the search term 'ARBs, ACEIs, BBs, anthracyclines, trastuzumab, and breast cancer' in PubMed, Embase, and CENTRAL up to 31 March 2021. A meta-analysis was conducted to estimate the mean difference (MD) in LVEF between intervention and placebo groups at follow-up. A total of nine RCTs (n = 1362) were included in the analysis. All patients were women. BBs and ACEI/ARBs were shown to attenuate the decline in LVEF during trastuzumab and anthracycline treatments [MD: 2.4; 95% confidence interval (CI): 0.3-4.2 and MD: 1.5; 95% CI: -0.6 to 3.7]. Compared with placebo, LVEF was significantly higher in patients assigned to BB or ACEI/ARB on trastuzumab (MD: 2.3; 95% CI: 0.0-4.6) but not on anthracyclines (MD: 1.9; 95% CI: -0.5 to 4.2). CONCLUSION: Both BB and ACEI/ARB therapies were associated with the preservation of LVEF during trastuzumab and anthracycline-containing regimens as compared with placebo, suggesting both to be beneficial.

The effect of empagliflozin on contractile reserve in heart failure: Prespecified sub-study of a randomized, double-blind, and placebo-controlled trial.

BACKGROUND: Sodium-glucose co-transporter-2 inhibitors improve cardiac structure but most studies suggest no change in left ventricular (LV) systolic function at rest. Whether sodium-glucose co-transporter-2 inhibitors improve LV contractile reserve is unknown. We investigated the effect of empagliflozin on LV contractile reserve in patients with heart failure (HF) and reduced ejection fraction. METHODS: Prespecified sub-study of the Empire HF trial, a double-blind, placebo-controlled, and randomized trial. Patients with LV ejection fraction (LVEF) ≤ 40% on guideline-directed HF therapy were randomized (1:1) to empagliflozin 10 mg or placebo for 12 weeks. The treatment effect on contractile reserve was assessed by low dose dobutamine stress echocardiography. RESULTS: In total, 120 patients were included. The mean age was 68 (SD 10) years, 83% were male, and the mean LVEF was 38 (SD 10) %. Respectively 60 (100%) and 59 (98%) patients in the empagliflozin and placebo groups completed stress echocardiography. No statistically significant effect of empagliflozin was observed for the contractile reserve assessed by LV-GLS (adjusted mean absolute change, empagliflozin vs placebo, 0.7% [95% confidence interval {CI} -0.5 to 2.0, P = .25]) or LVEF (adjusted mean absolute change, empagliflozin vs placebo, 2.2% [95% CI -1.4 to 5.8, P = .22]) from baseline to 12 weeks. LV-GLS contractile reserve was associated with accelerometer-measured daily activity level (coefficient -24 accelerometer counts [95% CI -46 to -1.8, P = .03]). CONCLUSIONS: Empagliflozin for 12 weeks added to guideline-directed HF therapy did not improve LV contractile reserve in patients with HF and reduced ejection fraction.

Empagliflozin in patients post myocardial infarction rationale and design of the EMPACT-MI trial.

BACKGROUND: Patients with acute myocardial infarction (MI) are at risk for developing heart failure (HF) and subsequently are at an increased risk of mortality. Sodium-glucose cotransporter-2 inhibitors have been proven to improve outcomes in patients with HF with reduced ejection fraction, and, in the case of empagliflozin, in HF with preserved ejection fraction even without diabetes, but their efficacy and safety in the post-MI population has not yet been evaluated. METHODS: The EMPACT-MI trial will evaluate the safety and efficacy of empagliflozin compared with placebo in patients hospitalized for MI with or at high risk of new onset HF, in addition to standard care. EMPACT-MI is a streamlined, multinational, randomized, double-blind, placebo-controlled trial randomizing 5,000 participants at approximately 480 centers in 22 countries. Eligible patients presenting with spontaneous MI must have new signs or symptoms of pulmonary congestion requiring treatment or new left ventricular dysfunction (LVEF<45%), and at least 1 additional risk factor for development of future HF. Eligible and consenting patients are randomized to empagliflozin 10mg or placebo daily in addition to standard of care within 14 days of hospital admission for MI. The primary composite end point is time to first hospitalization for HF or all-cause mortality. CONCLUSIONS: EMPACT-MI will inform clinical practice regarding the role of empagliflozin in patients after an MI with high-risk for the development of future HF and mortality.

Myocardial injury detected by T1 and T2 mapping on CMR predicts subsequent cancer therapy-related cardiac dysfunction in patients with breast cancer treated by epirubicin-based chemotherapy or left-sided RT.

OBJECTIVES: Cancer therapy-related cardiac dysfunction (CTRCD) is a relevant clinical problem and needs early prediction. This study aimed to analyze myocardial injury using serial laboratory and cardiac magnetic resonance imaging (CMR) parameters after epirubicin-based chemotherapy compared with left-sided radiotherapy and to study their value for early prediction of CTRCD. METHODS: Sixty-six consecutive women (53 ± 13 years) including n = 39 with epirubicin-based chemotherapy and n = 27 with left-sided radiotherapy were prospectively studied by 3 T CMR including left ventricular (LV) mass and volumes for ejection fraction (LVEF), as well as feature-tracking with global longitudinal strain (GLS) and T1/T2 mapping. CMR was performed at baseline, at therapy completion (follow-up 1, FU1), and after 13 ± 2 months (FU2). CTRCD was defined as LVEF decline of at least 10% to < 55% or a > 15% GLS change at FU2. RESULTS: T1 and T2 increased at FU1 after epirubicin-based chemotherapy, but not after left-sided radiotherapy. CTRCD occurred in 20% of patients after epirubicin-based chemotherapy and in 4% after left-sided radiotherapy. T1 at FU1 was the best single parameter to predict CTRCD with an area under the curve (AUC) of 0.712 (CI 0.587-0.816, p = 0.005) with excellent sensitivity (100%, 66-100%), but low specificity (44%, 31-58%). Combined use of increased T1 and LVEF ≤ 60% at FU1 improved AUC to 0.810 (0.695-0.896) resulting in good sensitivity (78%, 44-95%) and specificity (84%, 72-92%). CONCLUSION: Only epirubicin-based chemotherapy, but not left-sided radiotherapy, resulted in increased T1/T2 myocardial relaxation times as a marker of myocardial injury. Combined use of CMR parameters may allow an early prediction of subsequent CTCRD. KEY POINTS: • Myocardial T1 and T2 relaxation times increased at FU1 after epirubicin-based chemotherapy, but not after left-sided radiotherapy. • Cancer therapy-related cardiac dysfunction (CTRCD) occurred in 20% of patients after epirubicin-based chemotherapy and in 4% after left-sided radiotherapy. • Combined use of increased T1 and reduced LVEF had an AUC of 0.810 (0.695-0.896) to predict CTRCD with good sensitivity (78%, 44-95%) and specificity (84%, 72-92%).

Evaluation of left atrial remodeling using cardiovascular magnetic resonance imaging in breast cancer patients treated with adjuvant trastuzumab.

OBJECTIVES: We evaluated left atrial (LA) remodeling using cardiac MRI (CMR) in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer during and after trastuzumab therapy. METHODS: In this prospective 2-center longitudinal study, 41 women with HER2-positive breast cancer received adjuvant trastuzumab for 12 months, in addition to standard chemotherapy. Serial CMRs were performed at baseline, 6, 12, and 18 months after initiation of trastuzumab. LA volumes were measured by a blinded reader. Linear mixed model was used to evaluate longitudinal changes. RESULTS: Of 41 women (mean age 52 ± 11 [SD] years; 56% received anthracycline), one patient experienced trastuzumab-induced cardiotoxicity (TIC) for which trastuzumab was interrupted for one cycle. Mean baseline left ventricular ejection fraction (LVEF) was 68.0 ± 5.9% and LA ejection fraction (LAEF) was 66.0 ± 6.6%. Compared to baseline, LAEF decreased significantly at 6 months (62.7 ± 5.7%, p = 0.027) and 12 months (62.2 ± 6.1%, p = 0.003), while indexed LA minimum volume (LAmin) significantly increased at 12 months (11.6 ± 4.9 ml/m2 vs 13.8 ± 4.5 ml/m2, p = 0.002). At 18 months, all changes from baseline were no longer significant. From baseline to 6 months, change in LAEF correlated with change in LVEF (Spearman's r = 0.41, p = 0.014). No significant interactions (all p > 0.10) were detected between time and anthracycline use for LA parameters. CONCLUSIONS: Among trastuzumab-treated patients with low incidence of TIC, we observed a small but significant decline in LAEF and increase in LAmin that persisted for the duration of therapy and recovered 6 months after therapy cessation. These findings suggest that trastuzumab has concurrent detrimental effects on atrial and ventricular remodeling. KEY POINTS: • In trastuzumab-treated breast cancer patients evaluated by cardiac MRI, left atrial ejection fraction declined and minimum volume increased during treatment and recovered to baseline after trastuzumab cessation. • Changes in left atrial ejection fraction correlated with changes in left ventricular ejection fraction in the first 6 months of trastuzumab treatment. • Trastuzumab therapy is associated with concurrent detrimental effects on left atrial and ventricular remodeling.