Circulation, 08/20/2013 Exclusive Author Commentary Clinical Article
Ghebremariam YT et al. – Proton pump inhibitors (PPIs) are gastric acid–suppressing agents widely prescribed for the treatment of gastroesophageal reflux disease. Recently, several studies in patients with acute coronary syndrome have raised the concern that use of PPIs in these patients may increase their risk of major adverse cardiovascular events. The mechanism of this possible adverse effect is not known. Whether the general population might also be at risk has not been addressed. The authors present a plausible biological mechanism to explain the association of PPIs with increased major adverse cardiovascular events in patients with unstable coronary syndromes. Of concern, this adverse mechanism is also likely to extend to the general population using PPIs. This finding compels additional clinical investigations and pharmacovigilance directed toward understanding the cardiovascular risk associated with the use of the PPIs in the general population.
- Plasma asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase.
- Elevated plasma ADMA is associated with increased risk for cardiovascular disease, likely because of its attenuation of the vasoprotective effects of endothelial nitric oxide synthase.
- The authors find that PPIs elevate plasma ADMA levels and reduce nitric oxide levels and endothelium-dependent vasodilation in a murine model and ex vivo human tissues.
- PPIs increase ADMA because they bind to and inhibit dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA.
John P. Cooke (08/20/2013) comments:
In the Circulation paper, we describe our discovery that the proton pump inhibitors PPIs), as a class, impair vascular relaxation. The PPIs have this effect by suppressing the activity of a key enzyme required for cardiovascular health. The enzyme is known as DDAH (for dimethylarginine dimethylaminohydrolase). This enzyme is critical in clearing ADMA (asymmetric dimethylarginine) from tissues and the circulation. Because ADMA is an endogenous inhibitor of nitric oxide synthase, accumulation of ADMA impairs vascular relaxation and vascular homeostasis. Previously, we and others have found that, by inhibiting endothelium-derived nitric oxide, ADMA accelerates vascular disease in preclinical models. In humans, ADMA is linked to the severity of vascular disease, and is an independent risk factor for major adverse cardiovascular events (MACE). Thus, the effect of PPIs to inhibit DDAH would be anticipated to impair cardiovascular health, and to increase the risk of MACE. The finding that PPIs impair the generation of endothelium derived nitric oxide in human endothelial cells and human blood vessels was surprising, and disturbing. PPIs are widely used for gastroesophageal disease (GERD). Whereas their short term use appears to be safe, these drugs were never approved for long-term use. Now that many of these agents are over-the-counter, they are being used by millions of people, and often for years. These individuals may be a greater risk for cardiovascular disease. Patients should discuss with their doctors the risks of long-term PPI use, which include low magnesium levels, tendency for irregular heartbeats, and an increased risk of bone fractures. Our new data adds another potential risk of long-term use. Patients that require long-term suppression of gastric acidity might be switched to H2-receptor antagonists like ranitidine, which does not have the adverse effect on the vasculature described in our report. More work needs to be done. Pharmacovigilance studies, using electronic medical records from large databases, may be useful in confirming the risk of long-term use of PPIs. Analysis of data from these pharmacovigilance studies are currently under review. In addition, smaller mechanistic studies to provide further documentation that PPIs can impair vascular function in patients should be performed. Subsequently, further regulatory review may be required.
Circulation. 2013 Aug 20;128(8):845-53. doi: 10.1161/CIRCULATIONAHA.113.003602. Epub 2013 Jul 3.
Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine.
Ghebremariam YT1, LePendu P, Lee JC, Erlanson DA, Slaviero A, Shah NH, Leiper J, Cooke JP.
Abstract
BACKGROUND:
Proton pump inhibitors (PPIs) are gastric acid-suppressing agents widely prescribed for the treatment of gastroesophageal reflux disease. Recently, several studies in patients with acute coronary syndrome have raised the concern that use of PPIs in these patients may increase their risk of major adverse cardiovascular events. The mechanism of this possible adverse effect is not known. Whether the general population might also be at risk has not been addressed.
METHODS AND RESULTS:
Plasma asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. Elevated plasma ADMA is associated with increased risk for cardiovascular disease, likely because of its attenuation of the vasoprotective effects of endothelial nitric oxide synthase. We find that PPIs elevate plasma ADMA levels and reduce nitric oxide levels and endothelium-dependent vasodilation in a murine model and ex vivo human tissues. PPIs increase ADMA because they bind to and inhibit dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA.
CONCLUSIONS:
We present a plausible biological mechanism to explain the association of PPIs with increased major adverse cardiovascular events in patients with unstable coronary syndromes. Of concern, this adverse mechanism is also likely to extend to the general population using PPIs. This finding compels additional clinical investigations and pharmacovigilance directed toward understanding the cardiovascular risk associated with the use of the PPIs in the general population.