Increased vascular alpha1-adrenergic sensitivity in patients with renal failure: receiving recombinant erythropoeitin

End stage renal disease (ESRD) is associated with altered hemodynamic regulation as a result of the pathophysiology or treatment of renal failure. Hypertension, common among dialysis patients, is a recognized complication of recombinant human erythropoietin (rHuEPO) therapy. We determined vascular adrenergic and nitric-oxide-mediated responsiveness in 7 patients with established ESRD on rHuEPO treatment and in 13 healthy volunteers using the dorsal hand vein technique. Sensitivity to the alpha1-adrenergic selective agonist phenylephrine was significantly increased in patients with ESRD on rHuEPO. The mean dose of phenylephrine producing 50% venoconstriction (ED50) was 38 +/- 1.6 ng/min in patients with ESRD and 135 +/- 1.3 ng/min in healthy volunteers-almost a 4-fold increase in dose, P = 0.01. In contrast, maximal venodilation mediated by bradykinin, an endothelium-dependent vasodilator, was not different in the 2 groups. To determine whether rHuEPO has a direct vasoconstrictor effect, we studied venous responsiveness to local infusions of rHuEPO in healthy volunteers. Increasing concentrations of rHuEPO produced no vasoconstriction in hand veins of healthy volunteers. These results suggest that vascular responsiveness to alpha-adrenergic stimulation in patients with ESRD on rHuEPO is increased whereas bradykinin-mediated venodilation remains intact. This increase in vascular alpha-adrenergic responsiveness may contribute to the increased peripheral vascular resistance and hypertension seen in patients with ESRD on rHuEPO.     

Classification of anti-estrogens according to intramolecular FRET effects on phospho-mutants of estrogen receptor alpha

Anti-estrogen resistance is a major clinical problem in the treatment of breast cancer. In this study, fluorescence resonance energy transfer (FRET) analysis, a rapid and direct way to monitor conformational changes of estrogen receptor alpha (ERalpha) upon anti-estrogen binding, was used to characterize resistance to anti-estrogens. Nine different anti-estrogens all induced a rapid FRET response within minutes after the compounds have liganded to ERalpha in live cells, corresponding to an inactive conformation of the ERalpha. Phosphorylation of Ser(305) and/or Ser(236) of ERalpha by protein kinase A (PKA) and of Ser(118) by mitogen-activated protein kinase (MAPK) influenced the FRET response differently for the various anti-estrogens. PKA and MAPK are both associated with resistance to anti-estrogens in breast cancer patients. Their respective actions can result in seven different combinations of phospho-modifications in ERalpha where the FRET effects of particular anti-estrogen(s) are nullified. The FRET response provided information on the activity of ERalpha under the various anti-estrogen conditions as measured in a traditional reporter assay. Tamoxifen and EM-652 were the most sensitive to kinase activities, whereas ICI-182,780 (Fulvestrant) and ICI-164,384 were the most stringent. The different responses of anti-estrogens to the various combinations of phospho-modifications in ERalpha elucidate why certain anti-estrogens are more prone than others to develop resistance. These data provide new insights into the mechanism of action of anti-hormones and are critical for selection of the correct individual patient-based endocrine therapy in breast cancer.     

Effect of phentolamine on the hyperemic response to adenosine in patients with microvascular disease

For accurate measurement of the fractional flow reserve (FFR) of the myocardium, the presence of maximum hyperemia is of paramount importance. It has been suggested that the hyperemic effect of the conventionally used hyperemic stimulus, adenosine, could be submaximal in patients who have microvascular dysfunction and that adding alpha-blocking agents could augment the hyperemic response in these patients. We studied the effect of the nonselective alpha-blocking agent phentolamine, which was administered in addition to adenosine after achieving hyperemia, in patients who had microvascular disease and those who did not. Thirty patients who were referred for percutaneous coronary intervention were selected. Of these 30 patients, 15 had strong indications for microvascular disease and 15 did not. FFR was measured using intracoronary adenosine, intravenous adenosine, and intracoronary papaverine before and after intracoronary administration of the nonselective alpha blocker phentolamine. In patients who did not have microvascular disease, no differences in hyperemic response to adenosine were noted, whether or not alpha blockade was given before adenosine administration; FFR levels before and after phentolamine were 0.76 and 0.75, respectively, using intracoronary adenosine (p = 0.10) and 0.75 and 0.74, respectively, using intravenous adenosine (p = 0.20). In contrast, in patients who had microvascular disease, some increase in hyperemic response was observed after administration of phentolamine; FFR levels decreased from 0.74 to 0.70 using intracoronary adenosine (p = 0.003) and from 0.75 to 0.72 using intravenous adenosine (p = 0.04). Although statistically significant, the observed further decrease in microvascular resistance after addition of phentolamine was small and did not affect clinical decision making in any patient. In conclusion, when measuring FFR, routinely adding an alpha-blocking agent to adenosine does not affect clinical decision making.     

Thrombolytic therapy is indicated for patients over 75 years of age with st-elevation acute myocardial infarction: antagonist viewpoint

From the available data, one cannot conclude whether thrombolytic therapy is beneficial or detrimental in patients older than age 75 years with acute myocardial infarction. Data favor the use of primary percutaneous transluminal coronary angioplasty rather than thrombolysis in eligible patients older than age 75 years with acute myocardial infarction to reduce mortality, recurrent myocardial infarction, stroke, and intracranial hemorrhage. High-risk elderly patients with acute myocardial infarction, such as those with a large anterior myocardial infarction complicated by heart failure and hypotension, those with persistent ischemic pain or marked ST-segment changes, those with hemodynamic instability, and those at high risk for stroke or bleeding complications, should, especially, be treated with percutaneous transluminal coronary angioplasty.     

Prevalence of left ventricular diastolic dysfunction in obese persons with and without diabetes mellitus

Forty obese diabetic patients (mean age 48 +/- 9 years) and 93 obese nondiabetic patients (mean age 43 +/- 9 years) underwent Doppler and tissue Doppler echocardiographic evaluation of left ventricular diastolic function before gastric bypass surgery. Moderate or severe left ventricular diastolic dysfunction was present in 24 of 40 obese diabetics (60%) and in 21 of 93 obese nondiabetics (23%) (p <0.001).     

CRT plus ICD in congestive heart failure. Use of cardiac resynchronization therapy and an implantable cardioverter-defibrillator in heart failure patients with abnormal left ventricular dysfunction

Cardiac resynchronization therapy (CRT) significantly improves functional status, exercise duration, left ventricular (LV) ejection fraction, death from progressive congestive heart failure (CHF), and hospitalization for CHF in patients with moderate-to-severe CHF, an abnormal LV ejection fraction, and a QRS duration on the electrocardiogram of 120 msec or more. In these patients, CRT reduces all-cause mortality, though not significantly. However, CRT plus. an implantable cardioverter-defibrillator (ICD) significantly reduces all-cause mortality. Compared with placebo, ICD therapy significantly reduced all-cause mortality by 33% in patients with class II or III CHF, an abnormal LV ejection fraction, and a QRS duration on the electrocardiogram of 120 msec or more.     

First heart sound: A phono-echocardiographic correlation with mitral,tricuspid, and aortic valvular events

We evaluated the relationship of S₁ recorded by phonocardiography at the mitral area with motion of the mitral, tricuspid, and aortic valves, recorded by simultaneous echocardiography in 20 cardiac patients with a normal PR interval. The first major component of S₁ coincided with mitral valve closure in 20 of 20 patients (100%) and also with tricuspid valve closure in 14 of 20 patients (70%). The second major component of S₁ coincided with aortic valve opening in 20 of 20 patients and also with tricuspid valve closure in six of 20 patients (30%). We conclude that the first major component of S₁ coincides with mitral valve closure in all patients but may also coincide with tricuspid valve closure in many patients, and the second major component of S₁ coincides with aortic valve opening in all patients but may also coincide with tricuspid valve closure in some patients.     

Treatment of the Elderly Post-Myocardial Infarction Patient

Coronary risk factors should be modified in older persons after myocardial infarction (MI). Aspirin 160–325 mg daily and β blockers should be administered indefinitely. Anticoagulants should be administered post-MI to patients unable to tolerate daily aspirin, to those with persistent atrial fibrillation, and to those with left ventricular thrombus. Nitrates, along with βblockers, should be used to treat angina pectoris. Angiotensin-converting enzyme inhibitors should be administered after MI to patients who have congestive heart failure, an anterior MI, or a left ventricular ejection fraction of =40%. There are no class I indications for the use of calcium channel blockers after MI. Complex ventricular arrhythmias should be treated with βblockers. Persons with life-threatening ventricular tachycardia or ventricular fibrillation or who are at very high risk for sudden cardiac death after MI should receive an automatic implantable cardioverter-defibrillator. There are no class I indications for the use of hormonal therapy in postmenopausal women after MI. Indications for coronary revascularization after MI in older individuals are prolongation of life and relief of unacceptable symptoms despite optimal medical management.     

Racial variations in cardiology care among hospitalized older heart failure patients

In this retrospective follow-up study, the authors examined the association between race and the receipt of cardiology care in 1062 Medicare beneficiaries 65 years of age and older who were hospitalized with heart failure. The primary outcome measure was receipt of care from a cardiologist (via admission or consultation). Using logistic regression analyses, crude and adjusted odds ratios (OR) and 95% confidence intervals (95%CI) of receipt of cardiology care were estimated for nonwhite versus white patients. Two hundred (19%) patients were nonwhites and 483 (46%) patients received care from cardiologists. Proportion of patients receiving cardiology care was lower among nonwhite patients (35% versus 48% among whites; P = 0.001), and nonwhite race was associated with a lower odds of receiving cardiology care (crude OR = 0.57; 95%CI = 0.42-0.79). After adjustment for various patient characteristics and process-of-care variables, the magnitude and precision of the association between nonwhite race and a lower odds of receiving care from a cardiologist remained unchanged (adjusted OR = 0.43; 95% CI = 0.30-0.62). These findings suggest that nonwhite elderly hospitalized heart failure patients are less likely to be cared for by cardiologists.