Myocardial strain is associated with adverse cardiac events in patients treated with chimeric antigen receptor (CAR) T-cell therapy.

BACKGROUND: Cardiovascular events, including heart failure and arrhythmias, following chimeric antigen receptor (CAR) T-cell therapy are increasingly recognized. Although global longitudinal strain (GLS) has demonstrated prognostic utility for other cancer therapy-related cardiac dysfunction, less is known regarding the association of GLS with adverse cardiac events following CAR T-cell therapy. OBJECTIVES: To determine the association of baseline GLS with adverse cardiovascular events in adults receiving CAR-T cell therapy. METHODS: Patients who had an echocardiogram within 6 months prior to receiving CAR T-cell therapy were retrospectively identified. Clinical data and cardiac events were collected via chart review. Echocardiograms were analyzed offline for GLS, left ventricular ejection fraction, and Doppler parameters. Multivariable logistic regression was used to determine the association between adverse cardiovascular events and echocardiographic parameters. RESULTS: Among 75 CAR T-cell therapy patients (mean age 63.9, 34.7% female), nine patients (12%) experienced cardiac events (CEs) including cardiovascular death, new/worsening heart failure, and new/worsening arrhythmia within 1 year of treatment. In univariable models, higher baseline GLS (OR 0.78 [0.63, 0.96], p = .021) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.40 [1.08, 1.81], p = .012) was associated with a higher risk of CE. After adjusting for age and LDH, higher baseline GLS (OR 0.65 [0.48-0.88], p = <.01) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.56 [1.06, 2.29], p = .024) was associated with a higher risk of CE. CONCLUSION: Lower GLS and higher mitral E/e' on a baseline echocardiogram were associated with higher risk for CEs in patients receiving CAR T-cell therapy.

Circulating Biomarkers for Cardiotoxicity Risk Prediction.

OPINION STATEMENT: Improvements in cancer survival have led to the emergence of cardiovascular disease as an important determinant of adverse outcome in survivors. Cancer therapeutics-related cardiac dysfunction is the most well-known form of cardiotoxicity. However, newer cancer therapies bring a broader range of cardiotoxicities. The optimal method to identify patients at risk of these complications is unclear, but circulating biomarkers comprise one possible approach. Troponins and natriuretic peptides have garnered the broadest evidence base for cardiotoxicity risk prediction, but other markers are being investigated. In this review, we explore evidence for circulating biomarkers in cardiotoxicity prediction associated with cancer therapies.

Two-dimensional speckle-tracking strain detects subclinical cardiotoxicity in older patients treated for acute myeloid leukemia.

BACKGROUND: Patients with acute myeloid leukemia (AML) are surviving longer. There are no data on changes in myocardial mechanics from standard of care low-dose anthracycline-based induction chemotherapy in older patients with AML. The aim of this study was to demonstrate the potential utility of strain imaging in detecting early changes in left ventricular function in this patient population after induction chemotherapy. METHODS: Thirty two patients enrolled in the ECOG-ACRIN E2906 study (cytarabine and daunorubicin vs clofarabine [Genzyme/Sanofi]) from 2011 to 2014 were evaluated retrospectively. Two-dimensional transthoracic echocardiography (TTE) imaging with Doppler and two-dimensional speckle-tracking echocardiography (2DSTE) using EchoInsight software (Epsilon imaging) were performed before and after induction chemotherapy. RESULTS: Eighteen patients received cytarabine and daunorubicin (7 + 3) and 14 received clofarabine. The clofarabine group was older than the 7 + 3 cohort (67.8 ± 4.0 vs 63.7 ± 3.8, P = .007). There were no other significant differences in cardiac risk factors between groups. The 7 + 3 group had a decrease in average peak systolic global longitudinal (-19.1 ± 2.8 to -17.2 ± 3.0, P = .01) and circumferential strain (-29.4 ± 6.3 to -23.9 ± 4.3, P = .011). These changes were not demonstrated in the clofarabine group and were not associated with a decline in left ventricular ejection fraction (LVEF). CONCLUSIONS: In older AML patients, standard cytarabine and daunorubicin chemotherapy causes early changes in global longitudinal and circumferential strain not seen with clofarabine therapy. These findings demonstrate subclinical left ventricular dysfunction after exposure to low cumulative doses of anthracycline-based induction chemotherapy and may help us better identify those patients at risk for adverse long-term cardiovascular outcomes.

The value of ultrasound enhancing agents in the echocardiographic acquisition of pulmonary artery systolic pressure: An invasive to non-invasive correlation study.

PURPOSE: Right heart catheterization (RHC) is the gold standard for the assessment of pulmonary artery systolic pressures (PASP). Despite high utilization of echocardiography for the non-invasive assessment of PASP, the data comparing real-time non-invasive echocardiographic PASP with invasive PASP is limited. Furthermore, evidence regarding the utility and diagnostic accuracy of ultrasound enhancing agents (UEA) for non-invasive PASP assessment is lacking. To evaluate the accuracy of non-invasive PASP assessment with real-time invasive measures and the incremental benefit of UEA in this setting. METHODS: This was a prospective cohort study of 90 patients, undergoing clinically indicated RHC for hemodynamic assessment. All patients underwent a limited echocardiogram during RHC. Tricuspid regurgitant velocity (TRV) was measured on unenhanced echo, in the setting of centrally administrated agitated saline, then as either centrally administered or peripherally administered UEA. RESULTS: Of the 90 patients enrolled in our study, 41% had pulmonary hypertension. The overall mean PASP measured by RHC was 32.8 mmHg (+/- 11.3 mmHg). Unenhanced echocardiograms had a moderate correlation with invasive PASP (r = 0.57; p = < 0.001) which improved to a strong correlation with administration of agitated saline (r = 0.75; p = < 0.001) or centrally administered UEA (r = 0.77; p = < 0.001), with the best correlation noted with peripherally administered UEA (r = 0.83; p = < 0.001). Against invasive PASP, agitated saline enhanced PASP had the lowest bias (0.12mmHg; -15.6 to 15.8mmHg) when compared with all other non-invasive measures of PASP. CONCLUSIONS: Unenhanced echocardiographic estimation of TRV was found to have a poorer correlation with invasively measured PASP when compared to agitated saline and centrally administered UEA. Agitated saline enhanced PASP demonstrated the lowest bias with invasive PASP when compared to other non-invasive measures of PASP.

External validation of a heart failure risk score in patients with acute myeloid leukemia.

A 21-point risk score for heart failure (HF) has been developed for patients with acute myeloid leukemia (AML), stratifying patients into three groups: low, moderate, and high-risk. In this study, 193 patients with AML treated with anthracycline-based therapy were stratified using the risk score, and its prognostic utility for HF events and all-cause mortality at one year of follow-up were evaluated. HF occurred in 18% (34/193) of anthracycline-treated patients. Global longitudinal strain (GLS) was more negative among patients without HF events (-19 ± 3 vs. -17 ± 4%). One year incidence of HF was increased in the higher risk groups: 12% of low-risk, 24% of moderate-risk, and 50% of high-risk (p < 0.001). However, a higher risk score was not associated with an increased risk of all-cause mortality. This study provides external validation of a 21-point risk score for HF events but not all-cause mortality at one year in patients with AML.

High-frequency oscillations in human temporal lobe: simultaneous microwire and clinical macroelectrode recordings.

Neuronal oscillations span a wide range of spatial and temporal scales that extend beyond traditional clinical EEG. Recent research suggests that high-frequency oscillations (HFO), in the ripple (80-250 Hz) and fast ripple (250-1000 Hz) frequency range, may be signatures of epileptogenic brain and involved in the generation of seizures. However, most research investigating HFO in humans comes from microwire recordings, whose relationship to standard clinical intracranial EEG (iEEG) has not been explored. In this study iEEG recordings (DC - 9000 Hz) were obtained from human medial temporal lobe using custom depth electrodes containing both microwires and clinical macroelectrodes. Ripple and fast-ripple HFO recorded from both microwires and clinical macroelectrodes were increased in seizure generating brain regions compared to control regions. The distribution of HFO frequencies recorded from the macroelectrodes was concentrated in the ripple frequency range, compared to a broad distribution of HFO frequencies recorded from microwires. The average frequency of ripple HFO recorded from macroelectrodes was lower than that recorded from microwires (143.3 +/- 49.3 Hz versus 116.3 +/- 38.4, Wilcoxon rank sum P<0.0001). Fast-ripple HFO were most often recorded on a single microwire, supporting the hypothesis that fast-ripple HFO are primarily generated by highly localized, sub-millimeter scale neuronal assemblies that are most effectively sampled by microwire electrodes. Future research will address the clinical utility of these recordings for localizing epileptogenic networks and understanding seizure generation.