Neovascular age-related macular degeneration (ARMD), diabetic macular edema (DME) and macular edema due to central retinal vein occlusion (RVO) are among the leading causes of blindness worldwide.1 Most retinal conditions associated with systemic diseases such as diabetes, hypertension and thrombosis are characterized by neovascularization resulting from vascular occlusion, hypoxia and ischemia.2 Hypoxia stimulates the transcription of the vascular endothelial growth factor (VEGF)-A gene by the endothelium, pericytes and retinal pigment epithelium via hypoxia inducible factor-1α (HIF-1α).3,4 VEGF plays a key role in the process of angiogenesis, both in physiological conditions such as the menstrual cycle and in proliferative diabetic retinopathy (DR), retinopathy of prematurity, retinal neovascularization and tumor growth.5 Anti-VEGF agents were first used in oncology to inhibit tumor-induced angiogenesis that feeds neoplastic tissues. Later, bevacizumab and other specific agents were developed for intravitreal administration in the treatment of AMD, high-risk DR and other conditions characterized by retinal edema and/or neovascularization.6,7

Intravitreal injections (IVI) have revolutionized the treatment of AMD, DME, proliferative DR, RVO, pathologic myopia, uveitis and many more. They are also currently considered the most viable treatment option for a variety of retinal and choroidal disorders, based on their ability to enhance the ocular therapeutic effects of many agents and reduce the incidence of serious systemic adverse events.8 Systemic administration of anti-VEGF agents in oncology has been associated with multiple events, including increased risk of arterial hypertension and embolism, whereas agents for ophthalmic indications are administered locally to the eyeball in much smaller amounts. However, clinical observations suggest that anti-VEGF agents may increase cardiovascular risk in elderly and/or diabetic patients.2

Speckle tracking echocardiography (STE) is an echocardiographic method that automatically tracks the movement of ultrasound signals, enables the measurement of myocardial tension, reduces measurement errors compared to tissue Doppler imaging, and evaluates all segments of the myocardium.9 Global longitudinal strain (GLS) has emerged as a new marker of subclinical ventricular dysfunction and has demonstrated a stronger association with prognosis than left ventricular ejection fraction (LVEF) in non-oncology heart disease populations.10,11 Previous studies have shown anti-VEGF left ventricular (LV) dysfunction has been demonstrated through GLS in metastatic colorectal and renal cell cancer patients treated with agents and it has been stated that it can be used to detect early LV dysfunction.12,13

In our study, we aimed to investigate the effects of anti-VEGF agents on left heart functions after IVI via STE.

For our study, 68 patients were scanned between 01 May 2021 and 01 February 2022. Of these, four patients were excluded from the study because of poor echocardiographic image quality, five patients had been previously treated with anti-VEGF agents, and five patients did not give consent. Echocardiography was performed on 54 patients at month 0, just before anti-VEGF treatment was started. Up until the 3rd month of follow-up, one patient with a new diagnosis of CAD and two patients with hypertension were excluded from the study. Additionally, seven patients who did not come for the third month follow-up were excluded from the study. A total of 44 patients were included in the study and control echocardiography was performed at the 3rd month. The flow diagram of patient selection is shown in Figure 2.

Figure 2.

Flow diagram. CAD: coronary artery disease. VEGF: vascular endothelial growth factor.

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The study involved participants aged 45–88; 52.3% of the patients were male. 36.4% had diabetes, 40.9% had hypertension, and 13.6% had CAD. The indication for intravitreal bevacizumab application was determined as ARMD in 45.5% of the patients, DRP in 29.5%, and RVO in 25%. The demographic and clinical characteristics of the 44 patients included in the study are shown in Table 1.

There was no significant difference in the systolic blood diastolic blood pressure values recorded before the echocardiographic evaluation in month 0 and the third month in the study group (p=0.29 and p=0.96, respectively). Heart rate was also similar (p=0.19). In addition, no patient required a change in medical treatment at 0 and 3 months. Clinical assessment and the NT-pro-BNP values were used specifically to monitor participants’ loading condition on a case-by-case basis, and there was no change over the study period.

The two-dimensional (2D) echocardiography revealed a statistically significant difference only in LA diameter at 0 and 3 months (3.71±0.47, 3.74±0.44, p=0.02). When E and A waves, E/A, lateral e′ and a′, septal e′ and a′ and E/e′ measurements obtained by Doppler echocardiography were compared, no significant change was found at 0 and 3 months. Doppler and 2D echocardiography findings of the patients are shown in Table 2.

The third month measurements revealed there was a statistically significant decrease in the mean values of GLS (GLS4CH) obtained from the apical 4 space image, GLS (GLSAPLAX) obtained from apical long axis image and GLS (GLS2CH) obtained from apical 2 space image at month 0 and month 3 (−19.08±2.39, −18.93±2.26, p=0.004; −18.81±2.29, −18.60±2.12, p=0.001; −18.44±2.31, −18.27±2.12, p=0.013, respectively). Accordingly, global longitudinal strain (GLSAVER) values, which are the average of GLS4CH, GLSAPLAX and GLS2CH values, were also lower and this was statistically significant (−18.77±2.17, −18.60±2.01, p=0.001). The change in GLS values is shown in Table 3. The change in average GLS values is shown in Figure 3.

Figure 3.

Global longitudinal strain change at month 0 and month 3.

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In our study designed to evaluate early evidence of cardiotoxicity and left heart function in patients treated with intravitreal bevacizumab, we found a significant decrease in mean GLS and GLS in apical long axis, two space and four space images using the STE method. According to our results, intravitreal anti-VEGF applications are not cardiac innocent and may cause increased cardiovascular outcomes in the future.

Anti-VEGF therapy is effective in inhibiting tumor angiogenesis, an integral mechanism that promotes the continued growth and metastasis of tumors.17 One of the most widely used anti-VEGF agents is bevacizumab, a monoclonal antibody used in the treatment of patients with metastatic colorectal cancer.18 Despite their benefits in reducing morbidity and mortality in patients with metastatic colorectal and renal cell carcinoma, these drugs have been associated with a number of cardiotoxic side effects including hypertension, left ventricular systolic dysfunction and heart failure.19 Hypertension is the most commonly reported adverse event under anti-VEGF therapy. It occurs within hours or days, is dose-dependent and usually reverses with drug withdrawal.20,21 During the course of our study, the newly diagnosed hypertension in two patients was thought to be drug-related and these patients were not included in the final analysis.

Cancer treatment-related cardiac dysfunction (CTRCD) was defined as a 10% decline in LVEF to a final value of less than 53% or a >15% relative decline in GLS compared with baseline, confirmed on subsequent imaging performed 2–3 weeks after the initial measurement.22 CTRCD has traditionally been assessed using clinical symptoms and reductions in LVEF. This assessment is disadvantaged by the high interobserver variability of traditional echocardiographic analyzes and the fact that LVEF decline is relatively insensitive for diagnosing cardiotoxicity at an early stage. A detectable LVEF decline occurs only after the loss of a large amount of myocardial tissue; therefore, a reduced LVEF after chemotherapy is usually a sign of already extensive myocardial damage and overt HF.23–25 Recently, 2D-STE analysis has been investigated with cancer patients. STE may offer a more sensitive approach than LVEF to measure cardiotoxicity because of its advantage in detecting subtle wall motion abnormalities of regional function that do not reduce overall LVEF. It has also been recognized as a potential measure to identify early subclinical myocardial damage.22,26,10

Twenty-five patients were included in the study designed by Sonaglioni et al. to investigate whether 2D-STE could noninvasively detect early evidence of cardiotoxicity in metastatic colorectal cancer patients treated with bevacizumab. Echocardiographic control was performed on the patients at baseline, 3rd and 6th months. The primary endpoint was defined as a decrease in GLS of >15%, and the secondary endpoint was newly diagnosed hypertension. The number of patients with more than 15% decrease in GLS was 9.13 In a study by Nhola et al. involving 40 patients with metastatic colon cancer and metastatic renal cell carcinoma, echocardiographic control was performed at the 1st, 3rd and 6th months of anti-VEGF therapy. Eight percent of patients developed clinically asymptomatic cancer therapeutic-induced cardiac dysfunction; 30% of patients developed clinically significant decreases in GLS, which is a marker for early subclinical cardiac dysfunction.27 In our study, although there was a statistically significant decrease in mean GLS values at the 3rd month controls, no patient had a GLS decrease of more than 15%. There were no significant changes in LV size or LVEF, consistent with our study, and no cases of clinically symptomatic heart failure were observed in these bevacizumab-treated patients. The use of E/e′ to estimate left ventricular filling pressures is valuable and recommended.15 There was no difference in the E/e′ value in our findings, but in our study the lack of change may be related to the fact that there was no decrease in GLS by >15%.

Although anti-VEGF agents were first used in oncology, they also have great importance in ophthalmology practice today. Ranibizumab is the only monoclonal antibody approved in Europe and the United States for the treatment of AMD, RVO, and DME. Bevacizumab is approved for the treatment of metastatic solid cancers but is widely used as an off-label treatment for AMD, DME, and RVO. Because of its lower cost and comparable efficacy compared with other treatments, its off-label use is valuable.28 However, the systemic side effect profile of these intravitreal agents is unknown. Bevacizumab concentration remains close to plasma IC50 (concentration required to inhibit 50% of VEGF biological activity) for 30 days after intravitreal administration; this makes cardiovascular side effects potentially possible, as they are associated with detectable levels in systemic circulation.29,30 Although intravitreal bevacizumab is administered at a dose of 1.0–2.5 mg (150 times less than the systemic dose used in cancer), it has been suggested that VEGF inhibition may cause systemic adverse effects that may be serious for patients with diabetes or elderly patients at high risk for cardiovascular adverse events.31,32 In Hanhart et al.’s retrospective study of 5385 patients with AMD who received bevacizumab as monotherapy, 1063 (19.7%) died during follow-up after bevacizumab compared with 1298 (12.1%) in the control group (p<0.001). After adjusted Cox survival regression, mortality differed significantly between groups (OR=1.69, 95% CI 1.54–1.84; p<0.001).33 In the study of Maloney et al., which included 23348 patients treated with a diagnosis of DME, 13365 patients were treated with laser, 9219 patients were treated with intravitreal anti-VEGF, and 764 patients were treated with intravitreal corticosteroid. There was an increased risk of all-cause hospitalization in the group treated with anti-VEGF compared with macular laser (HR, 1.17; 95% CI, 1.05–1.30; p=0.01).34

Our study was conducted due to the lack of information on detailed evaluation of the cardiac effects of intravitreal anti-VEGF applications. Intravitreal administration of bevacizumab reduced GLS. However, the 15% absolute GLS decrease determined in previous studies was not observed. It is important to note that lower GLS has been associated with higher cardiovascular risk.35,36 Although a 15% decrease was not observed in the study group, further GLS decreases may be observed in larger scale studies or in longer follow-up periods after repeated applications. Intravitreal anti-VEGF applications may not be innocent. Large-scale studies evaluating cardiovascular outcomes with longer follow-up periods are needed.

We examined the change in GLS in patients administered intravitreal anti-VEGF using the STE method and detected a statistically significant decrease, although low in percentage, in the GLS values obtained from the mean GLS and apical long axis, 2-chamber and 4-chamber images separately.

Although it is known that a serious decrease in GLS is associated with an increase in the risk of cardiovascular events, the slight decrease in GLS in our study suggests that the use of intravitreal anti-VEGF agents may have cardiac effects. However, more comprehensive randomized controlled studies are needed to obtain more information on this subject and to guide treatment.

The authors have no conflicts of interest to declare.