Right Ventricular Dysfunction: An Early Sign of Anthracycline Induced Cardiotoxicity - Case Series

doi:10.21203/rs.3.rs-4901602/v1

Background: Anthracycline-induced cardiotoxicity is clinically distinguished by a reduction in left ventricular ejection fraction (LVEF) exceeding 10% and an LVEF below 50%. Due to these guidelines, alterations in right ventricular (RV) structure and function are often neglected as indicators of cardiotoxicity. In this report, we present two cases of anthracycline-induced cardiotoxicity that initially manifested as RV dilation and dysfunction.

Case presentations: Patient One, A 41-year-old woman with a history of sub-massive pulmonary embolism and obesity, was diagnosed with right pulmonary artery sarcoma and treated with surgical resection, radiation therapy, and adjuvant doxorubicin. Months after starting chemotherapy, she experienced progressive dyspnea on exertion and lower extremity swelling; a follow-up TTE demonstrated normal LV size and function, RV dilation, and RV pressure and volume overload. Since LVEF did not fall under the definition of cardiotoxicity, she continued doxorubicin treatment. Her clinical condition worsened, leading to severe RV dilation, reduced function, and new ECG abnormalities. Eventually, a cardiac MRI revealed reduced biventricular function and RV volume overload, with a final diagnosis of biventricular failure due to chemotherapy.

Patient Two, a 21-year-old male diagnosed with osteosarcoma at age 12, underwent surgical resection, endoprosthesis reconstruction, and adjuvant chemotherapy with cisplatin and doxorubicin. A 7-year post-chemotherapy follow-up echocardiogram noted increased RV pressure suggestive of pulmonary hypertension. Follow-up TTE showed normal LVEF with borderline normal GLS, visually normal RV size and systolic function, and borderline elevated RVSP of 35 mmHg. Subsequent cardiac MRI revealed reduced right and left ventricular function and non-ischemic cardiomyopathy.

Conclusions: These cases illuminate a critical gap in the current diagnostic criteria and definition of cardiotoxicity, emphasizing the necessity for more comprehensive echocardiographic approaches to assess cardiotoxicity. Specifically, they underscore the importance of including changes in right ventricular (RV) structure and function, which are often overlooked but can serve as early indicators of cardiotoxicity.

Anthracycline-induced cardiotoxicity

RV dysfunction

case report

echo

chemotherapy

Anthracyclines are cornerstone chemotherapeutic agents used in the treatment of various malignancies, including breast cancer, lymphoma, leukemia, sarcomas, and multiple metastatic cancers. However, their use is often limited because of the associated dose-dependent cardiotoxicity, which can ultimately lead to heart failure.¹ Initially considered irreversible, there is now growing evidence suggesting the potential for myocardial recovery following anthracycline-induced damage if it is detected within an early timeframe.² According to the American Society of Echocardiography and the most recent European Society of Cardiology guidelines for cardio-oncology, cancer therapeutic-related cardiotoxicity (CTRCD) is characterized by decreased left ventricular ejection fraction (LVEF) exceeding 10–15% and a reduction of LVEF to below 50%.^3,4 Given the current clinical guidelines and definitions, right ventricular (RV) function changes are often overlooked when assessing patients for anthracycline-induced cardiotoxicity. Consequently, alterations to RV structure and function frequently remain undetected. Herein, we present two cases in which anthracycline-induced cardiotoxicity initially manifested through RV dysfunction, as identified via transthoracic echocardiogram (TTE). Traditionally, cardio-oncology-related studies have focused on left ventricular (LV) systolic function, utilizing left ventricular ejection fraction (LVEF) or echocardiographic global longitudinal strain (GLS) to evaluate cardiotoxicity and guide therapeutic interventions. These cases highlight a significant gap in the current diagnostic criteria and underscore the need for more comprehensive echocardiographic approaches to assess cardiotoxicity. Furthermore, these findings advocate for additional studies focusing on the RV, which may serve as an early marker of cardiotoxicity before GLS or LVEF starts to decline.

Patient 1

A 41-year-old woman with a history of sub-massive pulmonary embolism and obesity was diagnosed with right pulmonary artery sarcoma, which was treated with surgical resection and reconstruction. She subsequently received radiation therapy and adjuvant chemotherapy with doxorubicin. A few months after starting chemotherapy, she reported progressive dyspnea on exertion. A pre-chemotherapy TTE was reported as normal in LV size and function, LVEF 56%, and qualitatively normal in RV size and systolic function. However, a follow-up TTE indicated signs of RV pressure and volume overload. Despite the progression of her dyspnea, she continued to receive doxorubicin, with dexrazoxane eventually added to her regimen. The RV changes on TTE were initially attributed to her earlier PE and sarcoma. However, it was important to note that initial TTE after PE showed no changes to RV function or pressure. Later, a repeat TTE revealed severe RV dilation, reduced RV systolic function, and normal LV size and function. Repeat ECGs demonstrated a new first-degree AV block, incomplete right bundle branch block, and right axis deviation.

An initial right heart catheterization (RHC) showed elevated right-sided filling pressures, normal left-sided filling pressures, mildly elevated mean pulmonary artery (PA) pressure, mildly elevated pulmonary vascular resistance (PVR), and mildly reduced cardiac output (CO) and cardiac index (CI). This led to a working diagnosis of RV failure, likely due to the treatment and surgery for her pulmonary sarcoma. Her dyspnea and lower extremity swelling continued to worsen, prompting a repeat RHC three months later. The repeat RHC showed severely elevated right-sided filling pressures, normal PA pressure, low CO, and normal left-sided filling pressures. She was then referred to the cardio-oncology clinic.

Given a significant anthracycline dose, a cardiac MRI was performed with suspicion of anthracycline-induced cardiotoxicity, which revealed reduced biventricular function (LVEF 18% and RVEF 27%), diffuse global hypokinesis, and end-diastolic flattening of the interventricular septum to the left suggestive of RV volume overload; without late gadolinium enhancement, and elevated extracellular volume (ECV) value. With a cumulative anthracycline dose of 495 mg/m², she was diagnosed with anthracycline-induced cardiotoxicity and started on guideline-directed medical therapy (GDMT), leading to partial recovery of left ventricular (LV) function, LVEF 47%. Had the earlier changes to her RV been attributed to chemotherapy, it might have been possible to have prevented both LV and RV failure.

Patient 2

A 21-year-old male with a history of osteosarcoma of the left femur at age 12 was treated with surgical resection and endoprosthesis reconstruction. He subsequently received adjuvant chemotherapy with cisplatin and doxorubicin. A pre-chemotherapy TTE was reported as normal in LV size and function, LVEF was 61%, and RV size and systolic function were qualitatively normal. He was initially monitored with yearly post-chemotherapy TTEs, which were reported as unremarkable, and then transitioned to TTE every two years. At the 7-year post-chemotherapy follow-up, TTE indicated signs of increased RV systolic pressure of 35 mmHg suggestive of pulmonary hypertension, LVEF 56% with borderline normal GLS of 16.8%. ECG pre- and post-chemotherapy both showed normal sinus rhythm and no reported abnormalities.

The patient self-referred to our cardio-oncology clinic due to abnormal echocardiogram findings performed at the outside hospital. At the time of consultation, he was a physically active college student without any symptoms, including shortness of breath, orthopnea, or lower extremity edema. A cardiac MRI was performed given a high dose of anthracycline and suspicion for anthracycline-induced cardiotoxicity. The CMR revealed reduced left ventricular systolic function with diffuse global hypokinesis: LVEF 48%, RVEF 51%, normal native myocardial T1 value 984ms, ECV 24%, and myocardial T2 49 ms. With a cumulative anthracycline dose of 450 mg/m² and findings on imaging, he was diagnosed with anthracycline-induced cardiomyopathy. The patient was initiated on GDMT, which he tolerated well. He remained asymptomatic from a cardiac standpoint and remained physically active. Repeat TTE following initial GDMT demonstrated improved LVEF of 55% compared to CMR LVEF of 48%. Similar to patient one, this patient would have benefitted and possibly avoided LV dysfunction if he had been referred earlier at the time of RV chamber changes noted on TTE.

However, upon retrospective review of his TTE during chemotherapy, he had RV dilation with a lack of inferior vena cava (IVC) respiratory variation during chemotherapy treatment. Unfortunately, the RV size was not documented on his TTE report. This is a crucial measurement in this patient population. When changes to RV are seen, patients should be referred for cardio-oncology evaluation for potentially early diagnosis of anthracycline-induced cardiotoxicity in the right patient.

Table 1. Patient Demographic and Clinical Data

Clinical background	Patient 1	Patient 2
Sex	Female	Male
Age	44 yrs.	21 yrs.
Baseline LVEF	56%	61%
Baseline RV parameters	Qualitatively Normal	Qualitatively Normal
Echo Before Chemo
LVEDV	113 ml	Qualitatively Normal
GLS	===	===
LVIDd	4.6 cm	4.6 cm
RV FAC	Qualitatively Normal	Qualitatively Normal
RVEDA	Qualitatively Normal	Qualitatively Normal
IVC	Small compressed	Normal
Echo post chemo
LVEF	Qualitatively > 55%	56%
LVEDV	Qualitatively Normal	119
GLS	===	16.8
LVIDd	4.6 cm	5.1 cm
RV FAC	Qualitatively Moderate to Severely Decreased	Qualitatively Normal
RVEDA	Qualitatively Severely Dilated with septal flattening	Qualitatively Normal
IVC	Dilated, no respiratory variation, systolic flow reversal	Lack of respiratory variability
IVC Compressibility Index	5.4%	28.6%
ECG before chemo
Rhythm	Sinus	Sinus
QT/QTc (ms)	374/409	384/435
Other findings	Normal	Normal
ECG post chemo
Rhythm	Sinus	Sinus
QT/QTc (ms)	524/549	349/437
Other findings	Right axis deviation, first-degree AV block, and incomplete right bundle branch block	Normal

The RV has often been overlooked in evaluating CTRCD, with current guidelines predominantly directing clinicians to assess LV systolic function using GLS or LVEF. In this report, we present two cases of anthracycline-induced cardiotoxicity that initially manifested as RV dysfunction. The first case involved an initial misdiagnosis of RV dysfunction, which was attributed to a prior sub-massive pulmonary embolism and resection of a pulmonary artery sarcoma. In the second case, an asymptomatic patient was found to have elevated RV pressure on routine TTE. In this instance, RV measurements were not obtained during chemotherapy cycles, leading to the oversight of early chamber dilation. These cases underscore the critical need for comprehensive and quantitative assessment of the RV in the context of CTRCD. The RV has been a predictor of prognosis in heart failure patients. Data suggests that early RV dysfunction parallels LV dysfunction in breast cancer patients.⁵ Additionally, a prospective study using 2D speckle-tracking echocardiography demonstrated that anthracyclines can cause RV dysfunction but not LV dysfunction in adult patients with lymphoma.⁶ In both cases we presented, RV dilation and RV dysfunction eventually lead to LV dysfunction; we recommend careful attention to the RV along with LV for early detection of CTRCD. Furthermore, standardizing RV structural and functional evaluation like RV size, RV volume with 3D, RV GLS, and RV systolic function using fractional area change (FAC) or 3D RVEF will allow for longitudinal follow-up and comparison.

Clinicians should be aware that anthracycline-induced cardiotoxicity can impair RV structure, function, and mechanics. The RV has less mass than the LV. Since anthracycline-induced cardiotoxicity can cause changes at the cellular level,⁷ the RV is bound to be affected similarly to the LV and potentially even sooner. We want to reiterate that it is crucial to recognize RV structure, function, and IVC compressibility index in the cardiac assessment of patients undergoing chemotherapy, especially those receiving anthracyclines. These cases demonstrate the importance of early recognition of anthracycline cardiotoxicity based on RV structure, function, and IVC compressibility before the LV systolic function starts to decline. We need more prospective studies with larger data sets to see if 3D RV assessment and RV GLS would allow for even earlier detection of RV changes in this patient population. In both cases, changes in RV were noted on TTE before decreased LVEF. There may also be changes in a patient’s ECG, including prolonged QT/QTc and bundle branch blocks, which can help identify possible anthracycline cardiotoxicity. Further research and more extensive studies are needed to evaluate the use of RV structural and functional changes for the initiation of treatment for chemotherapy-induced cardiac dysfunction before LV function declines.

Consent for publication

Written consent was obtained for each patient presented in this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests
The authors declare that they have no competing interests.

Funding

No funding sources were used to support this case series.

Author Contribution

C.B. Wrote the main text of manuscript and prepared figuresB.L. Wrote main text of manuscript and prepared figuresT.B. Wrote the main text of the manuscript and prepared the tableN.D. Collected the data and wrote the main text of manuscriptA.A.-Wrote the main text of the manuscript and prepared figures

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No competing interests reported.

Right Ventricular Dysfunction: An Early Sign of Anthracycline Induced Cardiotoxicity - Case Series

Status:

Version 1

Abstract

Figures

Introduction

Case Report

Patient 1

Patient 2

Discussion

Declarations

Consent for publication

Competing interests
The authors declare that they have no competing interests.

Funding

Author Contribution

References

Additional Declarations

Status:

Version 1

Right Ventricular Dysfunction: An Early Sign of Anthracycline Induced Cardiotoxicity - Case Series

Status:

Version 1

Abstract

Figures

Introduction

Case Report

Patient 1

Patient 2

Discussion

Declarations

Consent for publication

Competing interests The authors declare that they have no competing interests.

Funding

Author Contribution

References

Additional Declarations

Status:

Version 1

Competing interests
The authors declare that they have no competing interests.