Faculty Bibliography

We advocate an evidence-based discussion for a patient first philosophy when considering "the right test for the right patient." Numerous test options exist for the evaluation of symptoms of possible stable ischemic heart disease. Major guidelines have traditionally focused on functional testing with or without imaging to clarify symptoms, diagnose ischemia, stratify prognosis, and guide management. Recently, industry advocates have emphasized modality-specific approaches such as computed tomography (CT First) as an initial test strategy for possible stable CAD. We review the key evidence to demonstrate that current best practice would focus on a patient first approach rather than a modality-specific approach.

There is a wealth of evidence about the role of a variety of diagnostic testing modalities to define coronary artery disease (CAD) risk in women presenting for evaluation of suspected myocardial ischemia. The exercise electrocardiogram (ECG) is the core index procedure, which can define risk in women capable of performing maximal exercise. Stress imaging, using echocardiography or myocardial perfusion single-photon emission computed tomography/positron emission tomography, is useful for symptomatic women with an abnormal resting ECG or for those who are functionally disabled. For women with low-risk stress imaging findings, there is a very low risk of CAD events, usually < 1%. There is a gradient relationship between the extent and severity of inducible abnormalities and CAD event risk. Women at high risk are those defined as having moderate to severely abnormal wall motion or abnormal perfusion imaging findings. In addition to stress imaging, the evidence of the relationship between CAD extent and severity and prognosis has been clearly defined with coronary computed tomographic angiography. In women, prognosis for those with mild but nonobstructive CAD is higher when compared with those without any CAD. The current evidence base clearly supports that women presenting with chest pain can benefit from one of the commonly applied diagnostic testing modalities.

Gender differences in cardiovascular outcomes were compared in asymptomatic men and women with type 2 diabetes (T2DM) in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study. Of 1123 participants, 290 men and 271 women were randomised to screening with stress myocardial perfusion imaging (MPI); 311 men and 251 women were randomised to no screening. Follow-up was 4.8+/-0.9 years for the occurrence of cardiac events (CE; cardiac death or non-fatal myocardial infarction). The frequency of abnormal screening was similar in men (24%) and women (19%), (p=0.2), although women trended to have smaller MPI abnormalities. CE rates were lower in women than men (1.7% vs. 3.8%, p=0.04). No CEs occurred in 17 high-risk (UKPDS risk engine) women, whereas 14 (11.2%) occurred in 125 high-risk men. Asymptomatic women with T2DM have significantly better cardiac outcomes than their male counterparts and represent a subgroup for which screening for coronary artery disease does not appear warranted

Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31), an adhesion molecule expressed on hematopoietic and endothelial cells, mediates apoptosis, cell proliferation, and migration and maintains endothelial integrity in addition to its roles as a modulator of lymphocyte and platelet signaling and facilitator of neutrophil transmigration. Recent data suggest that CD31 functions as a scaffolding protein to regulate phosphorylation of the signal transducers and activators of transcription (STAT) family of signaling molecules, particularly STAT3 and STAT5. STAT3 regulates the acute phase response to innate immune stimuli such as lipopolysaccharide (LPS) and promotes recovery from LPS-induced septic shock. Here we demonstrate that CD31-deficient mice have reduced survival during endotoxic LPS-induced shock. As compared to wild-type controls, CD31-deficient mice showed enhanced vascular permeability; increased apoptotic cell death in liver, kidney, and spleen; and elevated levels of serum tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFNgamma), MCP-1, MCP-5, sTNRF, and IL-6. In response to LPS in vivo and in vitro, splenocytes and endothelial cells from knockout mice had reduced levels of phosphorylated STAT3. These results suggest that CD31 is necessary for maintenance of endothelial integrity and prevention of apoptosis during septic shock and for STAT3-mediated acute phase responses that promote survival during septic shock.

The pathogenesis, clinical course, and treatment of chronic heart failure (HF) are different in elderly women from those of patients recruited in the landmark trials of chronic HF. Patients included in these landmark trials were predominantly men whose age was 10-15 years younger than the average age of patients with chronic HF in the United States. Diastolic dysfunction resulting in impaired left ventricular (LV) filling is the preponderant LV functional alteration that leads to chronic HF in elderly women. Gender differences in the LV remodeling process that accompanies chronic cardiac pressure are likely to be responsible for the preponderance of LV diastolic dysfunction over systolic dysfunction in elderly women. In response to chronic pressure overload, the LV wall becomes thicker in women than in men. Consequently, in response to chronic pressure overload, women are able to normalize LV wall stress and preserve LV systolic function to a greater extent than men. However, impaired LV filling is an undesirable consequence of the greater increase in LV wall thickness in women. Thus, clinical observations and therapeutic guidelines derived from data collected in the landmark trials of chronic HF may not apply to elderly women with chronic HF. In view of the lack of evidence-based information needed to guide the management of elderly women with chronic HF, special attention should be given to include a substantial number of elderly women in future therapeutic trials recruiting patients with chronic HF.

Losartan, an angiotensin II type 1 receptor (AT1) antagonist, was developed as a more specific alternative to angiotensin-converting enzyme (ACE) inhibitors. At a daily dose of 50 mg, losartan is currently evaluated in large outcome trials involving patients with hypertension and postmyocardial infarction. The current study evaluated the level and duration of blockade of a pressor response to angiotensin II by 50 and 150 mg of losartan, compared with 32 mg of candesartan. Eight normotensive volunteers were randomly assigned to a single dose of losartan 50 or 150 mg, candesartan 32 mg, or placebo. Subjects were re-randomized after a 2-week washout period to complete all four study arms. Radial artery systolic pressure response to exogenous angiotensin II was measured at 2, 6, 12, and 24 h after administration of drug. Losartan 50 mg reduced the pressure response to exogenous angiotensin II significantly only at 6 h. In contrast, candesartan and losartan 150 mg produced a greater reduction in the pressure response to angiotensin II throughout the 24-h period. This suppression was not paralleled by a reduction in resting systemic arterial pressure. Higher doses than 50 mg of losartan might be evaluated to elicit optimal clinical effects.