Joseph M. Delehanty

Skeletal muscle gene expression profiles in 20-29 year old and 65-71 year old women.

Gene expression profiling may provide leads for investigations of the molecular basis of functional declines associated with aging. In this study, high-density oligonucleotide arrays were used to probe the patterns of gene expression in skeletal muscle of seven young women (20-29 years old) and eight healthy older women (65-71 years old). The older subjects had reduced muscle mass, strength, and peak oxygen consumption relative to young women. There were approximately 1000 probe sets that suggested differential gene expression in younger and older muscle according to statistical criteria. The most highly overexpressed genes (>3-fold) in older muscle were p21 (cyclin-dependent kinase inhibitor 1A), which might reflect increased DNA damage, perinatal myosin heavy chain, which might reflect increased muscle fiber regeneration, and tomoregulin, which does not have a defined function in muscle. More than 40 genes encoding proteins that bind to pre-mRNAs or mRNAs were expressed at higher levels in older muscle. More than 100 genes involved in energy metabolism were expressed at lower levels in older muscle. In general, these results support previous observations on the differences in gene expression profiles between younger and older men.

Cardiac noradrenergic nerve terminal abnormalities in dogs with experimental congestive heart failure.

BACKGROUND We have shown previously that norepinephrine (NE) uptake activity is reduced in the failing right ventricle of animals with right heart failure (RHF) produced by tricuspid avulsion and progressive pulmonary constriction. However, it is unknown whether this defect in neuronal NE uptake is related to reduction of noradrenergic nerve terminals or whether these changes also occur in animals with left heart failure (LHF). It is also unknown whether increased NE release in heart failure contributes to the noradrenergic nerve abnormalities. METHODS AND RESULTS We measured myocardial NE content. NE uptake function, and noradrenergic nerve profiles in dogs with either RHF or LHF induced by rapid ventricular pacing. NE uptake activity was measured using [3H]NE, and noradrenergic nerve profiles were visualized by glyoxylic acid (SPG)-induced histofluorescence and tyrosine hydroxylase immunocytochemical staining. To study the effects of excess NE, we exposed normal dogs to 8 weeks of chronic NE infusion using subcutaneous osmotic minipumps. RHF and LHF animals exhibited reduced myocardial contractile function and congestive heart failure, as evidence by reduced cardiac output and elevated right atrial pressure. However, unlike that in LHF, left atrial pressure was not increased in RHF. The animals also showed an increase in plasma NE and a decrease in cardiac NE. In addition, SPG-induced histofluorescence correlated significantly with NE uptake activity (r = .712, P < .001) and tyrosine hydroxylase immunoreactive profiles (r = .569, P < .001) in the right ventricles of RHF dogs and in both ventricles of LHF dogs. The numbers of catecholaminergic profiles and tyrosine hydroxylase profiles significantly correlated with cardiac filling pressures. Chronic infusion of NE decreased heart rate in normal dogs but had no effect on either mean aortic pressure or left atrial pressure; like heart failure, it resulted in significant decreases in myocardial NE uptake activity and numbers of SPG-induced catecholaminergic histofluorescence and immunoreactive tyrosine hydroxylase profiles. CONCLUSIONS Myocardial NE uptake activity was reduced only in the failing ventricles with elevated filling pressure in RHF and LHF. These changes probably were caused by loss of noradrenergic nerve terminals in the failing ventricles, as evidenced by the reductions of catecholaminergic histofluorescence and tyrosine hydroxylase immunostained profiles. Furthermore, since similar reductions of myocardial NE uptake and noradrenergic nerve profiles could be produced by chronic NE infusion in normal dogs, elevated NE levels may play a role in the development of cardiac noradrenergic nerve abnormalities in congestive heart failure.

The Outcomes of Emergency Pharmacist Participation During Acute Myocardial Infarction

BACKGROUND Current guidelines recommend door-to-balloon times of 90 min or less for patients presenting to the emergency department (ED) with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES To determine if a clinical pharmacist for the ED (EPh) is associated with decreased door/diagnosis-to-cardiac catheterization laboratory (CCL) time and decreased door-to-balloon time. METHODS A retrospective observational cohort study of ED patients with STEMI requiring urgent cardiac catheterization was conducted. Blinded data collection included timing of ED and CCL arrival, diagnostic electrocardiogram (ECG), and balloon angioplasty. For cases diagnosed after ED arrival, diagnosis time was substituted for door time. Diagnosis was the time ST elevations were evident on serial ECG. EPh present and not-present groups were compared. During the study period there were two EPhs and presence was determined by their scheduled time in the ED. Univariate and multivariate analyses was used to detect differences. RESULTS Multivariate analysis of 120 patients, controlled for CCL staff presence and arrival by pre-hospital services, determined that EPh presence is associated with a mean 13.1-min (95% confidence interval [CI] 6.5-21.9) and 11.5-min (95% CI 3.9-21.5) decrease in door/diagnosis-to-CCL and door-to-balloon times, respectively. Patients were more likely to achieve a door/diagnosis-to-CCL time≤ 30 min (odds ratio [OR] 3.1, 95% CI 1.3-7.8) and≤ 45 min (OR 2.9, 95% CI-1.0, 8.5) and a door-to-balloon time≤ 90 min (OR 1.9, 95% CI 0.7-5.5) more likely when the EPh was present. CONCLUSIONS EPh presence during STEMI presentation to the ED is independently associated with a decrease in door/diagnosis-to-CCL and door-to-balloon times.

Short-term effects of naloxone hemodynamics and baroreflex function in conscious dogs with pacing-induced congestive heart failure

OBJECTIVES The purpose of this study was to determine the effects of naloxone on systemic hemodynamics and reflex function in dogs with congestive heart failure induced by rapid pacing. BACKGROUND We have shown previously that naloxone, an opiate receptor antagonist, improves cardiac output, aortic blood pressure, systolic performance and the baroreflex function in conscious dogs with chronic right-sided congestive heart failure. However, whether endogenous opioids also play a role n mediating the reduction of myocardial and baroreflex function in animals with left heart failure remains controversial. METHODS We administered naloxone (1 mg/kg body weight) and normal saline solution to 15 dogs with pacing-induced congestive heart failure (225 beats/min for 8 weeks) and 11 control dogs. In addition to systemic hemodynamic measurements, the slope of pressure-area relation obtained from echocardiography with intravenous bolus injection of phenylephrine was taken as a load-independent index of myocardial contractility. Baroreflex function was estimated by the slope of the regression line relating systolic aortic pressure and RR interval. RESULTS Plasma beta-endorphin levels were elevated in dogs with congestive heart failure. Naloxone administration increased heart rate, mean aortic pressure, first derivative of left ventricular pressure, cardiac output and myocardial contractility in pacing-induced congestive heart failure. These changes correlated significantly with basal plasma beta-endorphin levels and were accompanied by increases in plasma beta-endorphin and catecholamines after naloxone administration. However, unlike the hemodynamic and cardiac effects of naloxone, baroreflex function did not change after naloxone in dogs with congestive heart failure. CONCLUSIONS The increase in basal plasma beta-endorphin suggests that the endogenous opiate system is activated in left-sided congestive heart failure. Because naloxone improves the systemic hemodynamics and myocardial contractile function under this condition, the endogenous opioids appear to play an important role in mediating the myocardial depression that occurs in heart failure. However, the endogenous opiate system has no apparent effect on the regulation of baroreflex control in heart failure induced by rapid pacing.

Clinical predictors of survival in patients treated with therapeutic hypothermia following cardiac arrest

INTRODUCTION Therapeutic hypothermia has been shown to provide neuroprotection and improved survival in patients suffering a cardiac arrest. We report outcomes of consecutive patients receiving therapeutic hypothermia for cardiac arrest and describe predictors of short and long-term survival. METHODS Eighty patients receiving therapeutic hypothermia between January 2005 and December 2008 were identified and categorized as those who survived and died. Outcomes and predictors of survival were determined. RESULTS Forty-five patients (56%) survived to hospital discharge and were alive at 30 days and among survivors 41 (91%) were alive 1 year after discharge. Survivors were younger, were more likely to present with VF, required less epinephrine during resuscitation, were more likely to have preserved renal function, and were less likely to be taking beta-blockers and ACE inhibitors. Predictors of survival included VF on presentation (OR 14.9, CI 2.7-83.2, p=0.002), pre-cardiac arrest aspirin use (OR 9.7, CI 1.6-61.1, p=0.02), return of spontaneous circulation <20 min (OR 9.4, CI 2.2-41.1, p=0.003), absence of coronary artery disease (OR 5.3, CI 1.1-24.7, p=0.002) and preserved renal function. CONCLUSION Therapeutic hypothermia is useful in the treatment of patients suffering a cardiac arrest. Several clinical factors may aid in predicting patients who are likely to survive after a cardiac arrest.

Elevated myocardial interstitial norepinephrine concentration contributes to the regulation of Na+,K+-ATPase in heart failure

Myocardial Na+,K(+)-ATPase is reduced in congestive heart failure. To study the regulation of Na+,K(+)-ATPase in congestive heart failure, we performed Western and Northern blot analyses of ventricular myocardium of dogs with pacing-induced congestive heart failure and chronic norepinephrine infusion, using isoform-specific antibodies and cDNA probes. Congestive heart failure and norepinephrine infusion caused similar increases in myocardial interstitial norepinephrine concentration and reductions of myocardial Na+,K(+)-ATPase alpha 3-subunit protein, but differed in their effects on myocardial Na+,K(+)-ATPase alpha 3-subunit gene expression. Chronic norepinephrine infusion produced no changes in the steady-state mRNA level for the alpha 3-subunit of Na+,K(+)-ATPase, suggesting that the changes in Na+,K(+)-ATPase protein were induced via a post-transcriptional mechanism. In contrast, down-regulation of the Na+,K(+)-ATPase alpha 3-subunit in the failing heart was accompanied by a decreased alpha 3-subunit mRNA level, indicating the presence of a transcriptional event. The alpha 1-subunit protein content and mRNA level were not affected by either norepinephrine infusion or rapid ventricular pacing. We conclude that, while elevated myocardial interstitial norepinephrine levels may contribute substantially to the down-regulation of the Na+,K(+)-ATPase alpha 3-subunit in the failing myocardium, additional regulatory factors are responsible for the decreased myocardial alpha 3-subunit mRNA expression in congestive heart failure.

Effects of dobutamine on ischemic vasodilation of the forearm in patients with severe congestive heart failure

BACKGROUND The significant changes that occur in the peripheral circulatory system in heart failure are well known. Although the central hemodynamic effects of dobutamine have been well described, data on its effect on peripheral vascular function in patients with severe left ventricular dysfunction are limited. METHODS AND RESULTS Resting and hyperemic forearm blood flow and resistance were measured using forearm venous occlusion plethysmography in patients with advanced congestive heart failure (CHF) before and during the infusion of increasing doses of dobutamine. Total hyperemia was also calculated. We studied eight patients with New York Heart Association classes III to IV CHF who had a mean age of 62 +/- 5 years and a mean ejection fraction of 17.4% +/- 2.9%. Resting forearm blood flow increased from 2.3 +/- 0.2 to 3.4 +/- 0.4 mL/min/100 mL during peak dobutamine infusion (P < .05). Resting forearm vascular resistance decreased from 39 +/- 3 to 29 +/- 4 units (P < .02). Peak hyperemic forearm blood flow increased from 25 +/- 3 to 34 +/- 6 mL/min/100 mL of tissue (P < .02) and peak hyperemic vascular resistance decreased from 3.7 +/- 0.4 to 2.9 +/- 0.3 units (P < .01). Total hyperemia increased from 14.3 +/- 1.9 to 19.4 +/- 2.4 mL/100 mL (P < .01). CONCLUSIONS The data show that in patients with advanced CHF, intravenous dobutamine not only increases resting forearm blood flow and decreases resting forearm vascular resistance, but augments the reactive hyperemic flow and improves the vasodilatory response of the forearm vessels to transient ischemic occlusion. The underlying mechanism for this response and its clinical significance remain to be identified.

Trifurcation triple balloon angioplasty in a dual left anterior descending coronary artery: The “Ménage à trois” revisited

We describe a case of simultaneous triple balloon angioplasty of a trifurcation stenosis in a dual left anterior descending coronary artery variant using over-the-wire and monorail balloon catheters and a single guide catheter.

Metabolic control of the circulation: Implications for congestive heart failure

The role of metabolic processes in the control of the normal circulation will be discussed with particular emphasis on how metabolic events, particularly those that occur with the performance of exercise, result in production of vasoactive substances and sympathetic activation. Heart failure patients will have altered metabolism, particularly in skeletal muscle, that may result in a lesser degree of peripheral vasodilation and will also have an abnormal response to sympathetic stimuli, with less cardiac stimulation but preserved peripheral vasoconstriction. The consequences of these abnormalities on the hemodynamics and metabolic processes that occur with exercise in the heart failure patient will be discussed in detail. The effect of therapeutic interventions such as drug therapy and exercise training will be reviewed.

Reasons for Use of Hormone Replacement Therapy in Women Undergoing Coronary Angiography

The recommendation has been made that all women be counseled about the risks and benefits of hormone replacement therapy (HRT). Use of HRT among women undergoing coronary angiography was explored to assess whether patterns of use were similar to data drawn from community samples. Using a descriptive design, a convenience sample of 414 postmenopausal women was interviewed. Fifty-eight percent had never used HRT, 18.3% were past users, and 23.7% were currently using HRT. The primary reason given for ever using HRT was for symptoms of menopause. Less than 14% of women cited coronary heart disease (CHD) or osteoporosis as their primary reason for using HRT. The most common reasons for stopping HRT were side effects and fear of cancer. The most common reasons given for never having used HRT were that their healthcare provider had never talked about it and that they had never thought about it. Use of HRT among women undergoing coronary angiography is similar to that found in community samples. The challenge is to promote patient-provider interactions that include information about HRT based on the scientific model as well as attention to womens individual concerns.