Anthracycline Cardiotoxicity May Hit Right Ventricle First

Patrice Wendling

March 19, 2020

The left ventricle (LV) has been the mainstay of cardiotoxicity monitoring during cancer therapy for decades, with little known about the incidence and prognosis of right ventricular (RV) dysfunction.

A new study that zeroed in on this overlooked ventricle, however, suggests that two parameters on 3-D transthoracic echocardiography (TTE) predict RV cardiotoxicity in patients treated with anthracyclines.

"The RV wall is thinner, so the hypothesis was that the thinner ventricle may have earlier changes, more subtle changes, such as strain or RV systolic volume change, than the EF [ejection fraction] change," senior author David H. Hsi, MD, Department of Cardiology, Stamford Hospital and Vagelos Columbia University College of Physicians and Surgeons, Connecticut, said in an interview.

Hsi and colleagues used standard 2-D and 3-D TTE with strain imaging to examine cardiac function in 74 consecutive patients with diffuse large B-cell lymphoma who received six cycles of R-CHOP chemotherapy (cyclophosphamide 750 mg/m2; vincristine 1.4 mg/m2 up to a maximum dose of 2 mg/m2; doxorubicin 50 to 70 mg/m2 on day 1; prednisone 100 mg on days 1 to 5; and rituximab 375 mg/m2 every 21 days). The average cumulative anthracycline dose was 358.20 mg/m2.

None of the patients received other cardiotoxic therapy, radiotherapy, or cardioprotective drugs during the study. Imaging was performed at baseline and after the completion of every two cycles of chemotherapy.

After six cycles of chemotherapy, 36% of patients developed cardiotoxicity, defined as a >10% relative reduction in RVEF or a relative reduction of >5% to an absolute value of <45%. RVEF declined from 54.8% at baseline to 48.3%, with the value falling below 45% in four patients.

By the end of the fourth cycle, 3D RV end-systolic volume (27.8 mL vs 31.3 mL) and RV end-diastolic volume (58.5 mL vs 64.2 mL) increased significantly, while RV longitudinal free-wall strain worsened (–27.3% vs –24.2%; P < .001 for all).

Another RV strain parameter, septal strain, did not pan out, possibly because the septal contraction of strain is influenced by the LV since they both share the septum, Hsi said.

Even though the RV is known to be more preload-dependent than the LV, the patient's body weight, blood pressure, pulmonary arterial systolic pressures, inferior vena cava diameter, and estimated right arterial pressure did not change significantly during the study, the authors note.

LV global longitudinal strain was significantly decreased only after the completion of cycle four, but no change was seen in LV volume or LVEF during follow-up.

In univariable analysis, only changes in RV end-systolic volume and RV longitudinal free-wall strain between baseline and cycle four were associated with subsequent RV cardiotoxicity (P = .002 and P = .001, respectively).

Similarly, in the ROC curve analysis, relative decreases of more than 13.2% in RV end-systolic volume (sensitivity, 71.4%; specificity, 71.7%; AUC, 0.76) and of more than 12.4% in RV longitudinal free-wall strain (sensitivity, 78.6%; specificity, 82.6%; AUC, 0.80) were able to discriminate between patients with and without RV cardiotoxicity.

Limitations of the study are the small sample size and short follow-up, which limited the ability to adjust for confounders, Hsi said. In addition, the study lacked a comparison between 3-D TEE and cardiac MRI or CT, and the definition of RV cardiotoxicity was arbitrarily defined on the basis of a relative change in RVEF.

The 45% lower limit of normal used in the study, however, is recommended by the American Society of Echocardiography, which calls for the assessment of right and left ventricular function in patients receiving cancer therapy.

"This study paves the way to go beyond the traditional parameters, from the LV to the RV, and to see which RV parameters may become commonly accepted to guide future therapy," Hsi said. "But I do see this as early-stage work."

In a related editorial, Jennifer E. Liu, MD, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, New York City, noted that until recently, the right ventricle has been "relatively neglected," mainly owing to the technical challenges of its assessment and the belief that it may not be as important in cardiovascular disease.

Although a few studies have shown a decline in RV function during cancer treatment, the present study found that RV modeling and functional impairment occur before any changes in LVEF or LV volume. "This is an important finding not previously reported, suggesting the possibility that the right ventricle might be affected earlier than the left ventricle," Liu said.

The most important limitation is the "lack of follow-up data to place the RV changes in context," she noted. Further studies are needed to establish whether the changes in RV function persist over time or predict subsequent declines in LVEF or heart failure.

Ideally, cardiac MRI, the reference standard for RV volume and function assessment, would improve the reliability of the observations, Liu said. Tissue characterization by cardiac MRI could also provide further insight into the underlying histopathologic changes.

Paaladinesh Thavendiranathan, MD, director of the cardiotoxicity prevention program at the Ted Rogers Center for Heart Research, University of Toronto, said additional information is also needed to determine whether there is a link between the observed RV changes and biomarkers of cardiac damage, such as troponin and perhaps brain natriuretic peptide.

Although MRI is the reference standard for RV and LV assessment, availability is a limitation, he noted.

"Echo still remains practical, and right ventricular ejection fraction assessment using 3-D echo has evolved tremendously; so I think if we can do this well, echo will be the go-to in routine practice," Thavendiranathan said.

An important strength of the study was the repeated RV measurements during cancer therapy; however, it's not entirely clear from the data presented why LV cardiotoxicity wasn't more prevalent, given the rather hefty doses of anthracyclines, he noted. Prior studies in this patient population suggest LV cardiotoxicity is present in 10% to 20% of patients.

In addition, their own forthcoming, unpublished data from a study of 133 women who were followed with cardiac MRI every 3 months for 15 months during cancer therapy indicate the presence of LV cardiotoxicity in about 28% of patients and of RV cardiotoxicity in about 15%.

Finally, Thavendiranathan reiterated the need to connect these findings to clinical outcomes for patients.

"One of the biggest concerns I have with all of research in cardiotoxicity is that we don't want to be fear mongering patients," he said. "What essentially is happening is we're finding more and more subtle ways to identify heart dysfunction. We're looking at the atria, for example, and saying that's affected. We're looking at the right ventricle now and saying that's affected. But does this all matter at the end of the day?"

This work is supported by grants from the National Nature Science Foundation of China and Excellent Talent Training Program of Shanghai Health System. The authors and Thavendiranathan have disclosed no relevant financial relationships. Liu serves on the advisory board for Pfizer and is a consultant for Bay Labs.

J Am Coll Cardiol CardioOnc. 2020;2:13–22, 23–25. Article, Editorial

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, join us on Twitter and Facebook.

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