Early Diastolic Dysfunction after Cancer Chemotherapy: Primary Endpoint Results of a Multicenter Cardio-Oncology Study

Abstract

Asymptomatic diastolic dysfunction (DD) with preserved left ventricular ejection fraction (LVEF) is suspected to precede late cardiac events in cancer survivors treated by chemotherapy. We conducted the first multicenter study of early DD induced by chemotherapy. Patients who were candidates for standard dose chemotherapy were screened for the absence of cardiovascular risk factors, LVEF ≥50%, normal-for-age diastolic function at echocardiography (E/A ratio, E wave deceleration time; DT), normal levels of potential DD biomarkers like Nt-proBNP (≤125 pg/mL), and cardiac troponin I (cTnI, ≤0.05 ng/mL). Mitral Doppler (E/E’) was left at the investigator’s discretion. Chemotherapy-induced DD with preserved LVEF was diagnosed for patients showing LVEF ≥50% and any of the following: Nt-proBNP > 125 pg/mL, cTnI > 0.05 ng/mL, and out-of-range E/A and DT. Eighty patients (68 males, 12 females, median age 49 years) were evaluated at 1 week after chemotherapy (T1). Thirty-three protocol-defined diastolic events were observed (15 Nt-proBNP > 125 pg/mL, 14 grade I DD by E/A and DT, 4 cTnI > 0.05 ng/mL). The events occurred in 29 asymptomatic patients with LVEF ≥50% (36% incidence of DD with preserved LVEF). Interactions occurred between biomarkers and grade I DD. E/E’ abnormalities were not observed. Both anthracycline-based and nonanthracycline regimens induced DD. These findings show that biomarkers and echocardiography intercept early DD in otherwise asymptomatic low-risk cancer patients treated by standard dose chemotherapy. These findings therefore call for the adequate cardiac management of cancer patients.

Role of cardiovascular imaging in cancer patients receiving cardiotoxic therapies: a position statement on behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio‐Oncology Council of the European Society of Cardiology (ESC)

“…Several small studies have analysed the serial measurement of LV diastolic function using tissue and transmitral Doppler (E/e ′ ) in various cancer populations. 25,26 Most have not found improved sensitivity compared with measurements of LV systolic function for detection of cardiotoxicity. A sequential relation between diastolic and systolic impairment has not been proven, either in experimental, or in clinical settings.…”

Pharmacology of Ranolazine versus Common Cardiovascular Drugs in Patients with Early Diastolic Dysfunction Induced by Anthracyclines or Nonanthracycline Chemotherapeutics: A Phase 2b Minitrial

“…We observed that asymptomatic diastolic dysfunction occurred in 36% of such low-risk patients and could be detected at 1 week after the last chemotherapy cycle. Of note, all patients showed a normal systolic function, as evidenced by a preserved left ventricular ejection fraction (LVEF) (Calabrese et al, 2018). These findings highlight diastolic dysfunction as a very early manifestation of cardiotoxicity, regardless of the influence of competing risk factors.…”

“…Diastolic dysfunction was detected as impaired relaxation at echocardiography, but it also occurred in the form of high circulating levels of B-type natriuretic peptide (BNP) (Calabrese et al, 2018). We in fact demonstrated that high BNP levels caused cardiac relaxant effects (positive lusitropic effects) that compensated for impaired relaxation before this could be detected by echocardiography.…”

Ivabradine in Cancer Treatment-Related Left Ventricular Dysfunction

“…Heart rate therefore has been seen as a potential modifiable risk factor [14] that, based on these findings, can be treated pharmacologically. Unlike BB, ivabradine reduces the heart rate without causing ­hypotension and improves diastolic function, which seems to precede CTrLVD [15]. Moreover, anticancer treatments cause substantial endothelial dysfunction [16, 17] that may be reduced through heart rate reduction with ivabradine [18].…”