Cardiac uses of phosphodiesterase-5 inhibitors

Phosphodiesterase-5 inhibitors (PDE5Is) improve erectile function by enhancing nitric oxide availability in the penis and its supplying vasculature, resulting in vasodilation and increased blood flow. PDE5Is might benefit cardiovascular diseases because phosphodiesterase-5 is also located elsewhere in the body, including the pulmonary and systemic vasculature and in hypertrophied myocardium. PDE5Is are approved for pulmonary arterial hypertension, given that they improved several hemodynamic and clinical parameters in large randomized trials. Initial evidence suggests that PDE5Is benefit patients with congestive heart failure and secondary pulmonary hypertension. PDE5Is seem to improve hemodynamic and clinical parameters in patients with high-altitude pulmonary edema (HAPE) and high-altitude pulmonary hypertension. In climbers with prior episodes of HAPE, PDE5Is prevented HAPE in 2 small randomized trials. In small randomized trials of PDE5Is, patients with Raynaud's phenomenon demonstrated improved blood flow, fewer symptoms and frequency of attacks, and resolution of digital ulcers. In addition to enhancing vasodilation, PDE5Is seem to protect the myocardium through complex pathways that involve nitric oxide, cyclic guanosine monophosphate, protein kinase G, extracellular-signal-regulated kinase, B-cell lymphoma protein-2, and Rho kinase inhibition. In animal models of acute myocardial infarction, PDE5Is consistently reduced infarct size indicating cardioprotection and PDE5Is also promote reverse remodeling and reduce myocardial apoptosis, fibrosis, and hypertrophy. PDE5Is might also benefit patients with treatment-resistant hypertension, preeclampsia, or peripheral arterial disease. This review presents the pathophysiology and trial data with regard to the use of PDE5Is for cardiac diseases.     

A Systematic Review of the Association Between Erectile Dysfunction and Cardiovascular Disease

Context

Erectile dysfunction (ED) is considered a vascular impairment that shares many risk factors with cardiovascular disease (CVD). A correlation between ED and CVD has been hypothesized, and ED has been proposed as an early marker of symptomatic CVD.

Objective

To analyze the relationship between ED and CVD, evaluating the pathophysiologic links between these conditions, and to identify which patients would benefit from cardiologic assessment when presenting with ED.

Evidence acquisition

A systematic literature review searching Medline, Embase, and Web of Science databases was performed. The search strategy included the terms erectile dysfunction, cardiovascular disease, coronary artery disease, risk factors, pathophysiology, atherosclerosis, low androgen levels, inflammation, screening, and phosphodiesterase type 5 inhibitors alone or in combination. We limited our search to studies published between January 2005 and May 2013.

Evidence synthesis

Several studies reported an association between ED and CVD. The link between these conditions might reside in the interaction between androgens, chronic inflammation, and cardiovascular risk factors that determines endothelial dysfunction and atherosclerosis, resulting in disorders of penile and coronary circulation. Because penile artery size is smaller compared with coronary arteries, the same level of endothelial dysfunction causes a more significant reduction of blood flow in erectile tissues compared with that in coronary circulation. Thus ED could be an indicator of systemic endothelial dysfunction. From a clinical standpoint, because ED may precede CVD, it can be used as an early marker to identify men at higher risk of CVD events. ED patients at high risk of CVD should undergo detailed cardiologic assessment and receive intensive treatment of risk factors.

Conclusions

ED and CVD should be regarded as two different manifestations of the same systemic disorder. ED usually precedes CVD onset, and it might be considered an early marker of symptomatic CVD.     

Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial.

AIMS: The purpose of this analysis was to determine whether the efficacy of adenosine vs. placebo was dependent on the timing of reperfusion therapy in the second Acute Myocardial Infarction Study of Adenosine (AMISTAD-II). METHODS AND RESULTS: Patients presenting with ST-segment elevation anterior AMI were randomized to receive placebo vs. adenosine (50 or 70 microg/kg/min) for 3 h starting within 15 min of reperfusion therapy. In the present post hoc hypothesis generating study, the results were stratified according to the timing of reperfusion, i.e. > or = or < the median 3.17 h, and by reperfusion modality. In patients receiving reperfusion < 3.17 h, adenosine compared with placebo significantly reduced 1-month mortality (5.2 vs. 9.2%, respectively, P = 0.014), 6-month mortality (7.3 vs. 11.2%, P = 0.033), and the occurrence of the primary 6-month composite clinical endpoint of death, in-hospital CHF, or rehospitalization for CHF at 6 months (12.0 vs. 17.2%, P = 0.022). Patients reperfused beyond 3 h did not benefit from adenosine. CONCLUSION: In this post hoc analysis, 3 h adenosine infusion administered as an adjunct to reperfusion therapy within the first 3.17 h onset of evolving anterior ST-segment elevation AMI enhanced early and late survival, and reduced the composite clinical endpoint of death or CHF at 6 months.     

Genetic contributors toward increased risk for ischemic heart disease

Cardiovascular disease is a leading cause of mortality in the United States, and is a significant cause of death worldwide. In 2002, it accounted for 38.0% of all deaths in the US, and approximately one-third of all global deaths. It has a significant economic impact, with an estimated cost in the US of 393.5 billion US dollars for 2005. The most common form of heart disease is coronary heart disease (CHD)(1)/coronary artery disease (CAD) resulting from atherosclerosis. Thirteen million Americans are affected by CHD annually, with 7.1 million of these experiencing a myocardial infarction (MI). Five to ten percent of new MI's occur in individuals younger than age 50, and the lifetime risk of developing CAD after age 40 ranges from 32% in women to 49% in men. Because of its major impact on morbidity and mortality, as well as its contribution to annual health care costs, it is of the utmost importance that improved strategies for preventing and treating CAD be developed. A promising, but inherently difficult, area of study is the identification of genes that predispose to or directly cause CAD. The identification of these genes may lead to screening tests that will allow persons at risk for developing CAD to be identified early enough that prevention/intervention strategies can be implemented to prevent or ameliorate the disease process, and may also lead to the development of gene therapy mechanisms useful in the treatment of ischemic heart disease (IHD). Because an exhaustive review of all the genes being studied in relation to CAD and MI is difficult within the confines of a review article, this review will focus on describing representative studies investigating the genes considered most likely to potentially contribute toward an increased risk for CAD and MI. Genes resulting in inherited disorders with which an increased risk of CAD and MI is associated will be discussed, as well as a number of candidate genes that may play a role in the multifactorial inheritance of CHD risk.     

A flow- and time-dependent index of ischemic injury after experimental coronary occlusion and reperfusion.

The purpose of the present study was to determine whether an ischemic index--expressed as the product of flow deprivation (FD) and the duration of occlusion (T), FD X T--correlated with biochemical and early morphologic alterations of the subendocardial myocardium and could predict ultimate development of irreversible injury after coronary reperfusion. Myocardial biopsy specimens for measurement of ATP and other purines and for ultrastructure studies were obtained in vivo during coronary occlusion in a canine model and were considered relative to development of necrosis after coronary reperfusion. FD X T correlated negatively with ATP content [ATP, nmol/mg of cardiac protein = 23.6 - 0.24(FD X T) + 0.0007(FD X T)2; r = -0.81] and with a semiquantitative early histologic index of damage (r = 0.70). Values of (FD X T) less than 18 were associated with reversible injury--i.e., complete salvage after coronary reperfusion. (FD X T) greater than 18 was associated with varying degrees of necrosis; necrosis was severe (78 +/- 12% of subendocardial biopsy specimens) when ATP less than 10 nmol/mg of protein and total purine pool was decreased by 50%. FD X T correlated with the eventual percentage of subendocardial necrosis (r = 0.85). Accordingly, as an index of ischemic injury, FD X T may be useful in assessing whether ischemic myocardial tissue will benefit from early restoration of blood flow to the ischemic area.