The intriguing issue of genetic predisposition and the importance of identification of pre-clinical markers of endothelial damage in radiotherapy-induced cardiotoxicity: reply

We thank Dr Gallucci for her letter about the joint EACVI/ASE expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults.1 As underlined, there is compelling evidence that chest radiotherapy can increase the risk of heart disease. Although modern radiotherapy techniques are likely to reduce the prevalence and severity of radiation-induced heart disease (RIHD), the incidence of RIHD is expected to increase in cancer survivors who have received old radiotherapy regimens. The pathophysiology of RIHD remains poorly understood. Genetic and exogenous factors certainly enhance the risk of RIHD and contribute to inter-patient disease expression differences.2 As exogenous factors have been shown to result in genomic instability, and as low-dose radiation induces long-lasting genomic instability, synergistic interaction between radiation-induced effects and pathogenic events unrelated to radiation exposure is highly probable. When normal tissues are irradiated, identifying factors modulating their sensitivity to radiation is paramount but challenging. Little is known about the genetic variants of RIHD. Recently, single-nucleotide polymorphisms in a series of genes associated with DNA repair pathways, damage response, and angiogenesis regulating pathways have been identified. As an example, TGFβ1 29C>T polymorphism, which is associated with a lower TGFβ1 serum level, has been shown to be associated with a two-fold increase in cardiovascular disease risk in breast cancer survivors who were irradiated.3 Although these data are very promising, recommendations on the systematic assessment of these genetic polymorphisms cannot yet be drawn. Also, it would be premature at this time to use these preliminary results to modify the treatment strategies. Further confirmations are needed. However, building a bio-bank of blood samples for further targeted genetic analysis makes sense. Several exogenous factors potentiate the risk of RIHD. Younger age, cardiovascular risk factors (i.e. smoking and hypertension) or pre-existing cardiovascular disease, exposure to high doses of radiation (>30 Gy), concomitant chemotherapy, anterior or left chest irradiation location, and absence of shielding are the most common risk factors associated with RIHD. In the present letter, Dr Gallucci elegantly pointed out that the ‘primum movens’ of RIHD relates to radiation-induced endothelial dysfunction. When coronary arteries are in the field of radiation, induced endothelial dysfunction may be translated into impaired coronary flow reserve (CFR). Several imaging methods, including MIBI SPECT-MPI (single-photon emission computed tomography myocardial perfusion imaging), can be used to identify reduced CFR.4 Dr Gallucci also reported her preliminary data regarding an ongoing study in which CFR was assessed before and after radiotherapy in patients with left breast cancers. After treatment, a set of abnormalities (ST-T changes, myocardial perfusion defects in the left ventricular apical region, and reduction in estimated values of CFR) was found even in patients with no other risk factors for coronary artery disease other than chest irradiation. However, as the monitoring data are still ongoing, the impact of a reduced CFR on the outcome was not reported. In the meantime, these patients have been followed up closely and treated aggressively to correct any risk factor. Even with technical improvements in radiotherapy delivery, a high incidence of left ventricular perfusion defects is found early after tangential radiotherapy for breast cancer.5,6 However, little is known about the time course and evolution of these perfusion abnormalities. In addition, whether these radiation-induced heart SPECT defects might persist or be the premises of later effects is still unknown. Microvascular disease, endothelial dysfunction, vascular spasm, or coronary artery disease might all contribute at various degrees to these perfusion abnormalities. Similar mechanisms contribute to stress-induced perfusion defects and reduced CFR during the provocative test. Therefore, they do not necessarily correspond to a typical coronary territory. So far, the clinical significance of these perfusion abnormalities remains unclear. So, although of potential interest, it is premature to consider the systematic evaluation of CFR as a preclinical marker of endothelial damage after thoracic radiotherapy. ECG represents the traditional support and completion to the clinical examination, but ECG ST-T abnormalities are often non-specific in cancer survivors. Moreover, in the short term, these ECG changes are often reversible and seem to be functionally insignificant.7 The adequate strategy for screening of RIHD remains a source of debate in the medical community. The lack of strong evidence has led the EACVI/ASE Writing Committee to suggest consensus statements rather than strict guidelines. Large prospective studies are thus required to confirm the clinical utility of non-invasive imaging for comprehensive screening and surveillance of asymptomatic cancer survivors. Other unsolved issues would deserve specific actions: collection of standardized incidence data, trials to evaluate preventive measures, genomic testing to explain variability of incidence and onset, investigation of the impact on new agents that might share common signalling pathways with those involved in cardiac damage, and management of interventional strategies to reduce the burden of cardiovascular complications by acting simultaneously on multiple risk factors. Conflict of interest: None declared.