Sildenafil: a novel therapy in the management of cardiac syndrome X

Cardiac syndrome X (CSX) is characterised by anginal pain in the presence of positive myocardial stress-testing but normal vessels on coronary angiography. Driven by dysfunction of the coronary microvasculature (small vessel angina), prognosis is usually excellent, but symptoms can be limiting. Management is aimed at symptom control and is based on standard anti-anginal drugs.1,2Case reportA 42-year-old man was limited by daily, exertional, anginal chest pains for 6 months. Symptoms could also occur during rest. He was a non-smoker and generally well, with mild hypercholesterolaemia (total cholesterol 6.4 mmol/L). Exercise ECG testing replicated his chest pain at 7 minutes on a standardised Bruce protocol with ECG changes diagnostic for ischaemia.Subsequent coronary angiography revealed normal epicardial coronary vessels. He was further investigated with adenosine stress-perfusion cardiac magnetic resonance imaging (CMR) which showed diffuse subendocardial hypoperfusion, suggesting a diagnosis of cardiac syndrome X (Figure 1).The image was obtained during the last minute of a 4-minute adenosine infusion (140 03bcg/kg/min) with a saturation prepared single shot fast spoiled gradient echo pulse sequence. This image is a short-axis view of the left ventricle (arrow at 9 oclock positioned over septum, clockwise from this point are the six segment separated by white markers: anterior septum, anterior wall, lateral wall, posterior wall, inferior wall and inferior septum). The dark rim around the left ventricle demonstrates subendocardial ischaemia.Sequential attempts to control symptoms using conventional anti-anginal drugs (long-acting nitrates, calcium-channel inhibitors, beta-blockers, and nicorandil) failed due to his intolerance to these medications, primarily citing headaches. A novel approach of 25 mg sildenafil daily was tried. This vastly improved his chest pain symptoms without side effects.At 3 years follow-up, he remains stable with an extremely low symptom burden (less than three episodes per year). On occasions he has tried to discontinue therapy which has led to recurrence of symptoms. This raises the possibility of using sildenafil for the treatment of cardiac syndrome X (CSX). Figure 1. Diffuse subendocardial hypoperfusion (arrow) persisting more than 5 cycles post appearance of gadolinium contrast within the LV myocardium in the short axis using a 1.5T whole body MRI scanner* *Magnetom Sonata, Siemens, Erlangen, Germany. The image was obtained during the last minute of a 4 minute adenosine infusion (140 03bcg/kg/min) with a saturation prepared single shot fast spoiled gradient echo pulse sequence. This image is a short-axis view of the left ventricle (arrow at 9 oclock positioned over septum, clockwise from this point are the six segment separated by white markers: anterior septum, anterior wall, lateral wall, posterior wall, inferior wall and inferior septum). The dark rim around the left ventricle demonstrates subendocardial ischaemia. Discussion The diagnosis of CSX can be aided using stress-perfusion CMR, which as shown by Panting and colleagues demonstrates diffuse subendocardial hypoperfusionduring intravenous administration of adenosine (Figure 1). This supports the notion that CSX is ischaemic in origin1. It has been suggested that myocardial ischaemia in CSX results from dysfunctional small coronary arteries not visible at angiography, described as microvascular angina. Mosseri and colleagues demonstrated that endomyocardial biopsies show luminal narrowing and fibromuscular thickening in vessels under 1mm in diameter in CSX.2 Functional abnormalities of the coronary microvasculature have also been demonstrated. Piatti and colleagues reported that patients with CSX have a blunted nitric oxide (NO 2022) response and endothelin-1 inhibition to insulin, suggesting defective endothelium-dependentdilatation.3 Therefore both anatomical and functional abnormalities exist in CSX. Phosphodiesterase-5 enzymes are found in most vascular beds and by causing their inhibition, NO 2022 driven cyclic guanosine-monophosphate breakdown is reduced, resulting in potent vasodilatation.4Sildenafil, a PDE-5 inhibitor is a vasoactive drug developed for the treatment of erectile-dysfunction also used in the management of pulmonary hypertension and Raynauds phenomenon. Adverse cardiac effects have been reported in patients with ischaemic heart disease using sildenafil for erectile-dysfunction. These include myocardialinfarction, arrhythmias, and hypotension. These concerns have been questioned, suggesting that these adverse events may instead stem from thecardiac demands of sexual activity, the health of thepopulation for whom sildenafil is prescribed, and adverse interactionwith nitrates. Indeed, Arruda-Olson and colleagues demonstrated that in patients with stable coronary artery disease who were not taking nitrates,sildenafil did not potentiate myocardial ischemia.5 Our case is the first to demonstrate the effectiveness of sildenafil in treating CSX. It could potentially counter the functional defects noted within the coronary microvasculature. It may have a future role in managing CSX.