Abstract
Src family tyrosine kinase is crucial in pulmonary vascular tone http://ow.ly/mGqEa
To the Editor:
We read with interest the article “Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries” by Nagaraj et al. [1]. The authors elegantly demonstrated that in physiological conditions, a low pulmonary vascular tone is maintained by Src family tyrosine kinase (SrcTK) and that inhibition of SrcTK will lead to vasoconstriction of pulmonary resistance arteries and thus to an increase in pulmonary artery pressure [1].
This finding fits well with the recent observation made in the French registry that dasatinib, a dual Src/Abl kinase inhibitor, can cause pulmonary arterial hypertension (PAH) in patients treated with this drug [2]. In some of those patients, PAH improved after withdrawal of the drug, supporting the notion that Src-mediated vasoconstriction might play a role in the development of dasatinib-induced pulmonary hypertension.
Here, we present another case of dasatinib-induced PAH. This case illustrates that dasatinib-induced PAH seems unresponsive to phosphodiesterase type 5 inhibition when dasatinib therapy is continued and is only reversed by withdrawing the drug. This case suggests that when inducing pulmonary vasoconstriction, dasatinib either acts downstream from the secondary messenger cGMP or acts via a cGMP-unrelated mechanism or independently from the classical pathobiological pathways leading to PAH [3].
A 57-year-old male was diagnosed with chronic myeloid leukaemia (CML) in 2002. Except for mild chronic obstructive pulmonary disease and hypertension, the patient had no other relevant diseases in his medical history. Imatinib treatment was initiated and because of side effects, switched to dasatinib in 2007. After 37 months of dasatinib treatment (70 mg·day−1), the patient developed progressive dyspnoea and signs of ankle oedema. Although the ankle oedema was first classified as a side effect of dasatinib, progression of dyspnoea led to further evaluation.
After performance of an echocardiogram and an exercise test, suspicion of pulmonary hypertension rose. 2 months later, the diagnosis was confirmed by a right heart catheterisation. The mean pulmonary artery pressure (mPAP) was 55 mmHg and the pulmonary vascular resistance was 721 dysnes·s·cm−5. Reversibility testing by NO was not performed. After exclusion of all possible causes, the diagnosis was made of pulmonary hypertension associated with a myeloproliferative disorder. The patient was referred to our institute for institution of treatment. At the time of admission, the patient was in New York Heart Association (NYHA) functional class 4, unable to perform exercise and showed signs of right heart failure. Although sildenafil treatment and diuretics were initiated the patient did not improve in NYHA class. After five months of unsatisfactory treatment, data emerged from the French registry that dasatinib can induce PAH. Based on this information, Dasatinib was substituted for an alternative tyrosine kinase inhibitor nilotinib 800 mg·day−1, leading to a quick and dramatic improvement in the patient's condition (NYHA 1). 3 months after discontinuation of dasatinib and sildenafil treatment, he had no symptoms and was able to resume his job. Repeated echocardiography showed that the pressure gradient over the tricuspid valve had decreased from 110 to 38 mmHg. The patient declined a second right heart catheterisation.
From this case, we can learn that PAH-specific therapy was not effective in dasatinib-associated PAH. This has not been previously reported, since the patients in the cases of Montani et al. [2] and Dumitrescu et al. [4] immediately discontinued dasatinib when PAH was diagnosed.
The quick resolution of symptoms and improvement of pulmonary hypertension in our patient indicate that vasoconstriction rather than remodelling caused the PAH. Of interest is that sildenafil had no effect in our patient, whereas it is known that sildenafil can improve exercise capacity and reduce PAH in the case of hypoxic vasoconstriction [5]. Although no firm conclusions can be made from our observation, it strongly supports the findings of Nagaraj et al. [1] that Src TK is a crucial factor for pulmonary vascular tone and mediates pulmonary vasodilation in a cGMP independent way.
Footnotes
Conflict of interest: Disclosures can be found alongside the online version of this article at www.erj.ersjournals.com
- Received February 26, 2013.
- Accepted April 28, 2013.
- ©ERS 2013