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Biomedical subjects

Paul M Heerdt

Publications and source records attributed to Paul M Heerdt.

17 recordsLinked to original sources
PubMed2007

Pulmonary resection in the elderly.

PURPOSE OF REVIEW: With increasing longevity, altered demographics of the lung cancer population, and preoperative interventions to enhance the efficacy of surgical therapy, increasing numbers of elderly people will present for anesthesia and pulmonary resection. RECENT FINDINGS: The geriatric population often exhibits wide disparity between chronologic and physiologic senescence which is underscored by data indicating that outcome following lung resection for cancer is influenced more by tumor stage, preoperative functional status and comorbidities than age alone. Nonetheless, the normal process of cardiopulmonary aging can limit the physiological reserve necessary to compensate for perioperative stress even in otherwise healthy elderly patients. Data indicate a relatively favorable risk-benefit relationship for lung resection in the elderly given the poor prognosis for patients undergoing palliative care or chemotherapy or radiation alone. Emerging experience now suggests that minimally invasive surgical techniques for the treatment of lung cancer may parallel conventional thoracotomy in terms of oncologic efficacy while decreasing perioperative morbidity in the elderly. SUMMARY: The combination of an aging population, recent advances in neoadjuvant therapies, data supporting the oncologic efficacy of resection, and minimally invasive surgical techniques strongly suggests that more elderly patients will be candidates for surgical management of their lung cancer, thus presenting anesthesiologists with unique challenges.

Aged↗
PubMed2006

Cardiomyopathic etiology and SERCA2a reverse remodeling during mechanical support of the failing human heart.

Many hearts in end-stage, chronic failure (CHF) retain the capacity to reverse abnormal expression of genes regulating myocyte calcium cycling when supported with a left ventricular assist device (LVAD). In the present study, we determined whether LVAD-induced upregulation of the gene encoding for the key calcium cycling protein sarcoplasmic endoreticular calcium adenosine triphosphatase subtype 2a (SERCA2a) is influenced by the nature of underlying disease broadly characterized as ischemic (ICM) or idiopathic dilated (DCM) cardiomyopathy. Data from Northern blot analysis of SERCA2a messenger (m)RNA within 84 heart samples (50 CHF [23 DCM and 27 ICM] and 34 CHF+LVAD [18 DCM and 16 ICM]) were used for characterizing gene expression. In addition, measurements of the force-frequency relationship (FFR), a reflection of in vivo SERCA2a function, were obtained in myocardial trabeculae isolated from 75 hearts (51 CHF [29 DCM and 22 ICM] and 24 CHF+LVAD [10 DCM and 14 ICM]). SERCA2a mRNA demonstrated upregulation after LVAD that was not influenced by ICM or DCM. However, only in DCM hearts was the proportion of trabeculae exhibiting a normal FFR increased after LVAD. Thus, although upregulated SERCA2a gene expression after LVAD support is independent of myopathic origin, normalization of myocardial FFR, an index of SERCA2a function, is not. These data provide new insight into the process of cardiac "reverse molecular remodeling," and underscore potential differences in the impact of disease processes on posttranscriptional events.

Adult↗
PubMed2005

Hemodynamic effects of di-sec-butyl phenol, an anesthetic substituted phenol.

Dose- and age-related hemodynamic effects were determined for an anesthetic substituted phenol, 2,6-di-sec-butyl phenol (DSB). DSB, 7.5 mg/kg, induced hypnosis in young rabbits and increased mean blood pressure to 170 +/- 14% and heart rate to 150 +/- 21% of control values. In elderly rabbits, 7.5 mg/kg DSB induced hypnosis, had no effect on blood pressure, but increased the heart rate to 130 +/- 2% of control. After ganglionic blockade with hexamethonium, 7.5 mg/kg DSB caused a decline in mean blood pressure (71 +/- 5% of control) without change in heart rate. DSB increased norepinephrine release from SH-SY5Y cells, a human neuroblastoma cell line (5.4 +/- 1.7% vs. 3.5 +/- 0.3%). DSB produced age-dependent elevation of mean blood pressure in rabbits, probably by causing release of catecholamines from the sympathetic nervous system.

Age Factors↗
PubMed2005

Ectonucleoside triphosphate diphosphohydrolase 1/CD39, localized in neurons of human and porcine heart, modulates ATP-induced norepinephrine exocytosis.

Using a guinea pig heart synaptosomal preparation, we previously observed that norepinephrine (NE) exocytosis was attenuated by a blockade of P2X purinoceptors, potentiated by inhibition of ectonucleoside triphosphate diphosphohydrolase-1 (E-NTPDase1)/CD39, and reduced by soluble CD39, a recombinant form of human E-NTPDase1/CD39. This suggests that norepinephrine and ATP are coreleased upon depolarization of cardiac sympathetic nerve endings and that ATP enhances norepinephrine exocytosis by an action modulated by E-NTPDase1/CD39 activity. Whether E-NTPDase1/CD39 is localized to cardiac neurons and modulates norepinephrine exocytosis in intact heart tissue remained untested. We report that E-NTPDase1/CD39 is selectively localized in human and porcine cardiac neurons and that depolarization of porcine heart tissue elicits omega-conotoxin-inhibitable release of both norepinephrine and ATP. Inhibition of E-NTPDase1/CD39 with ARL67156 markedly potentiated ATP release, demonstrating that E-NTPDase1/CD39 is a major determinant of ATP availability at sympathetic nerve terminals. Notably, inhibition of E-NTPDase1/CD39 enhanced both ATP and NE exocytosis, whereas administration of soluble CD39 reduced both ATP and NE exocytosis. The strong correlation between ATP and norepinephrine release was abolished in the presence of the purinergic P2X receptor (P2XR) antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). We conclude that released ATP governs norepinephrine exocytosis by activating presynaptic P2XR and that this action is controlled by neuronal E-NTPDase1/CD39. Clinically, excessive norepinephrine release is a major cause of arrhythmic and coronary vascular dysfunction during myocardial ischemia. By curtailing NE release, in addition to its effects as an antithrombotic agent, soluble CD39 may constitute a novel therapeutic approach to ischemic complications in the myocardium.

Adenosine Triphosphatases↗
PubMed2005

Anesthetic-induced alteration in expression of myocardial calcium cycling proteins.

OBJECTIVE: The purpose of this study was to test the hypothesis that anesthesia alone or in combination with high F(I)(O)2 alters expression of the myocardial calcium cycling proteins, sarcoplasmic endoreticular calcium adenosine triphosphatase subtype 2a (SERCA2a), and the sarcolemmal sodium-calcium exchanger (NCX). DESIGN: Multigroup comparison of protein expression using analysis of variance. SETTING: University research laboratory. SUBJECTS: Twenty-seven New Zealand white rabbits. INTERVENTIONS: After sedation and the induction of anesthesia, animals underwent either tracheal intubation and ventilation for 5 hours with 1.0% end-tidal halothane in oxygen (HAL-O(2) , n = 5) or air (HAL-air, n = 5) or time-control recovery while spontaneously breathing oxygen (TC-O(2) , n = 5) or air (TC-air, n = 5) for 5 hours. Halothane dose was based on pilot data from 2 rabbits. Animals were then sacrificed, and the hearts were removed for Western blot analysis. Data were normalized to those from a group of rabbits immediately sacrificed (n = 5) without any prior treatment. MEASUREMENTS AND MAIN RESULTS: In comparison to their respective time controls, SERCA2a was decreased 23 % in both HAL-air and HAL-O(2) groups, whereas NCX was increased 34% and 122%, respectively. Expression was distinctly different between HAL-air and HAL-O(2) for both SERCA2a (p = 0.009) and NCX (p < 0.001), indicating an influence of high F(I)O(2). Similarly, SERCA2a in the TC-O(2) group was reduced 25% relative to the TC-air group. CONCLUSION: Halothane alters the expression of myocardial calcium cycling proteins, and this effect is potentiated by high F(I)O(2) . These data offer the broad conclusion that perioperative interventions may influence the study of myocardial molecular remodeling and suggest the possibility of anesthetic-induced myocardial molecular remodeling.

Analysis of Variance↗
PubMed2005

Autonomic mechanisms in the age-related hypotensive effect of propofol.

We hypothesized that age-related differences in cardiovascular regulatory processes play a role in the augmented vasodepressor response to anesthetic induction with propofol in older subjects. To test this hypothesis, differences in baroreceptor responsiveness (BR) were first demonstrated in young adult (6-12 mo, n=12) and aged (>42 mo, n=12) New Zealand rabbits, and then the vasodepressor effect of propofol was compared in both the absence and presence of ganglionic blockade. For each age group, half of the animals were pretreated with 20 mg/kg IV hexamethonium (HEX) with the remaining half designated as controls. BR was first assessed by plotting cardiac cycle length as a function of the decline in mean arterial blood pressure (MAP) produced by multiple IV boluses of tri-nitroglycerine. Propofol was then given as an IV bolus of 4.5, 6.4, or 8.4 mg/kg over 3 s. Each animal was studied three times, receiving a single dose in variable order with at least 7 days between injections. In control animals, marked age-related differences in BR were evident and propofol produced larger peak decreases in MAP in older rabbits at all doses. HEX pretreatment abolished BR for both young and aged rabbits. However, after HEX administration the vasodepressor response to propofol in young animals was enhanced by 150% at 4.5, 125% at 6.4, and 61% at 8.4 mg/kg, respectively, whereas the impact in aged animals was only 25%, 30%, and -10%, respectively. These data support the hypothesis that age-related enhancement of propofol-induced hypotension is largely a reflection of diminished BR.

Aging↗
PubMed2005

Statin use is associated with a reduction in atrial fibrillation after noncardiac thoracic surgery independent of C-reactive protein.

STUDY OBJECTIVES: The level of C-reactive protein (CRP) has been shown to be elevated in patients with atrial fibrillation/flutter (AF) unrelated to surgery, and statins are known to lower the CRP level. To determine whether an elevated CRP level predisposes the patient to postoperative AF and whether statin use is associated with a reduced AF incidence, we studied a consecutive group of patients who were at risk for AF after undergoing thoracic surgery (age, > or = 60 years). DESIGN AND SETTING: A prospective study in a tertiary care cancer center of 131 patients (mean [+/- SD] age, 73 +/- 6 years) who had undergone major lung or esophageal resection. High-sensitivity CRP and interleukin (IL)-6 levels were measured before surgery, on arrival at the postanesthesia care unit, and on the first morning after surgery. Continuous telemetry was used for 72 to 96 h to detect AF. RESULTS: AF occurred in 38 of 131 patients (29%) at a median time after surgery of 3 days. Although CRP and IL-6 levels increased significantly (p < 0.001) in response to surgery, patients with or without AF did not differ in perioperative values. In a stepwise logistic regression, statin use was associated with a threefold decrease in the odds of developing AF (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.08 to 0.82; p = 0.022) and a greater PR interval (OR, 1.11 per 5-ms increments; 95% CI, 1.01 to 1.22; p = 0.027) predicted an increase in the risk of AF. CONCLUSIONS: The preoperative use of statins was associated with a protective effect against postoperative AF independent of CRP levels. In contrast to AF in the general population, early markers of inflammation did not predict the postoperative occurrence of AF.

Aged↗
PubMed2004

Tobacco smoke induces CYP1B1 in the aerodigestive tract.

Several members of the P450 family, including cytochrome P450 1B1 (CYP1B1), can convert tobacco smoke (TS) procarcinogens, including benzo[a]pyrene (B[a]P), to carcinogenic intermediates. In this study we investigated the effects of TS condensate and B[a]P on the expression of CYP1B1 in vitro and in vivo. CYP1B1 mRNA and protein were induced by both TS condensate and B[a]P in cell lines derived from the human aerodigestive tract. Treatment with TS condensate stimulated binding of the aryl hydrocarbon receptor (AhR) to an oligonucleotide containing a canonical xenobiotic response element (XRE) site and induced XRE-luciferase activity. These findings are consistent with prior evidence that polycyclic aromatic hydrocarbons, known ligands of the AhR, stimulate CYP1B1 transcription by an XRE-dependent mechanism. To determine whether these in vitro findings applied in vivo, both murine and human studies were carried out. Short-term exposure to TS induced CYP1B1 in the tongue, esophagus, lung and colon of experimental mice. In contrast, CYP1B1 was not induced by TS in the aorta of these mice. Levels of CYP1B1 mRNA were also elevated in the bronchial mucosa of human tobacco smokers versus never smokers (P < 0.05). Taken together, these results support a role for CYP1B1 in TS-induced carcinogenesis in the aerodigestive tract.

Aryl Hydrocarbon Hydroxylases↗
PubMed2004

Cardiopulmonary effects of the novel neuromuscular blocking drug GW280430A (AV430A) in dogs.

BACKGROUND: This investigation determined the cardiopulmonary side effects of a novel nondepolarizing neuromuscular blocking drug with an ultrashort duration of action in anesthetized male beagles. METHODS: The ED95 for GW280430A was first determined in four animals. These data were then used to guide bolus dosing in multiples of ED95 in six dogs instrumented for hemodynamic measurements as well as inspiratory pressure and pulmonary compliance. Cardiopulmonary data were compared before and after the conclusion of a 60- to 90-min GW280430A infusion and in response to subsequent incremental bolus dosing starting with 3.125 x ED95. An adverse response was regarded as an alteration of 10% or greater in any variable. Arterial blood was obtained for histamine analysis before and 1 min after each dose. RESULTS: The ED95 of GW280430A was 0.064 +/- 0.01 mg/kg, and stable neuromuscular blockade was maintained with infusion of 0.012 +/- 0.002 mg.kg(-1).min(-1). With the exception of a late 14% increase in heart rate, there were no cardiopulmonary changes during infusion. Bolus dosing produced no cardiopulmonary change until a decrease in mean arterial pressure was elicited in four of six dogs at 25 x ED95. This response was modest, transient, and associated with a concomitant increase in plasma histamine concentration. There were no accompanying changes indicative of direct myocardial depression, pulmonary vasoconstriction, or bronchospasm. CONCLUSIONS: These data indicate that GW280430 does not produce demonstrable cardiovascular effects in the anesthetized dog until doses far in excess of the ED95 are administered as a bolus.

Animals↗
PubMed2003

Phospholipid abnormalities in children with Barth syndrome.

OBJECTIVES: We sought to identify characteristic lipid abnormalities in patients with Barth syndrome (BTHS) and to correlate the lipid profile to phenotype and genotype. BACKGROUND: Barth syndrome typically includes cardiomyopathy, skeletal myopathy, neutropenia, growth retardation, and 3-methylglutaconic aciduria, and it is commonly associated with mutations in the tafazzin (TAZ) gene, whose products are homologous to phospholipid acyltransferases. However, clinical features of BTHS have also been found in patients with normal TAZ gene. METHODS: We analyzed molecular species of phospholipids in left and right ventricle, skeletal muscle, platelets, lymphoblasts, and fibroblasts from 19 children with BTHS (positive TAZ mutation), 6 children with BTHS-like syndromes (wild-type TAZ), 4 children with isolated cardiomyopathy (wild-type TAZ), and various controls. RESULTS: Cardiolipin, the specific lipid found only in mitochondria, was decreased in all tissues from BTHS patients, whereas concentrations of other phospholipids were normal. The molecular composition of cardiolipin was altered in all tissues from BTHS patients. The molecular compositions of phosphatidylcholine and phosphatidylethanolamine were altered in the heart. Cardiolipin abnormalities were only found in children with true BTHS, not in children with BTHS-like disease or with isolated cardiomyopathy. The degree of cardiolipin deficiency was tissue-specific but did not correlate with severity or specific phenotypic expression of BTHS. CONCLUSIONS: Abnormal cardiolipin is a specific diagnostic marker of cardiomyopathies caused by TAZ mutations. These mutations lead to alterations in the fatty acid composition of several phospholipids, supporting the idea that TAZ encodes a human acyltransferase.

Acyltransferases↗
PubMed2003

Increased severity of reperfusion arrhythmias in mouse hearts lacking histamine H3-receptors.

We had previously reported that activation of histamine H(3)-receptors (H(3)R) on cardiac adrenergic nerve terminals decreases norepinephrine (NE) overflow from ischemic hearts and alleviates reperfusion arrhythmias. Thus, we used transgenic mice lacking H(3)R (H(3)R(-/-)) to investigate whether ischemic arrhythmias might be more severe in H(3)R(-/-) hearts than in hearts with intact H(3)R (H(3)R(+/+)). We report a greater incidence and longer duration of ventricular fibrillation (VF) in H(3)R(-/-) hearts subjected to ischemia. VF duration was linearly correlated with NE overflow, suggesting a possible cause-effect relationship between magnitude of NE release and severity of reperfusion arrhythmias. Thus, our findings strengthen a protective antiarrhythmic role of H(3)R in myocardial ischemia. Since malignant tachyarrhythmias cause sudden death in ischemic heart disease, attenuation of NE release by selective H(3)R agonists may represent a new approach in the prevention and treatment of ischemic arrhythmias.

Adrenergic alpha-Agonists↗
PubMed2002

Deficiency of tetralinoleoyl-cardiolipin in Barth syndrome.

Barth syndrome is an X-linked cardiac and skeletal mitochondrial myopathy. Barth syndrome may be due to lipid alterations because the product of the mutated gene is homologous to phospholipid acyltransferases. Here we document that a single mitochondrial phospholipid species, tetralinoleoyl-cardiolipin, was lacking in the skeletal muscle (n = 2), right ventricle (n = 2), left ventricle (n = 2), and platelets (n = 6) of 8 children with Barth syndrome. Tetralinoleoyl-cardiolipin is specifically enriched in normal skeletal muscle and the normal heart. These findings support the notion that Barth syndrome is caused by alterations of mitochondrial lipids.

Adolescent↗
PubMed2002

Disease-specific remodeling of cardiac mitochondria after a left ventricular assist device.

BACKGROUND: Failing hearts can exhibit elements of structural and molecular "reverse remodeling" after support with a left ventricular assist device (LVAD). The present study examined LVAD-induced remodeling of cardiac mitochondria. METHODS: Left ventricular tissue from 20 failing and 21 LVAD-supported hearts, catagorized as ischemic (ICM) or dilated (DCM) cardiomyopathy and four nonfailing hearts were studied. Myocyte mitochondrial ultrastructure was assessed by high-performance liquid chromatography determination of cardiolipin, a specific lipid component of the inner membrane, and its three major molecular species: L4, L3O, and L2O2. RESULTS: Both failing and LVAD-supported hearts exhibited a reduction in cardiolipin content that was independent of the type of cardiomyopathy. However, in failing/ICM hearts, there was a 25% increase in the L4/L3O ratio and a 70% increase in the L4/L2O2 ratio, indicating a change in cardiolipin composition. These alterations were normalized by LVAD support. In sharp contrast, molecular species ratios in DCM hearts were the same as those in nonfailing hearts regardless of whether LVAD support had been used or not. CONCLUSIONS: These data demonstrate LVAD-induced reverse remodeling of myocyte cardiolipin composition in ICM but not DCM hearts.

Adult↗
PubMed2002

The effects of advanced age on the incidence of supraventricular arrhythmias after pneumonectomy in dogs.

UNLABELLED: Because advanced age is the strongest independent risk factor for the development of supraventricular arrhythmias after lung resection, we compared the incidence and premorbid events of supraventricular arrhythmias after pneumonectomy in young and elderly dogs with the aim of better understanding potential age-related arrhythmogenic mechanisms. Right pneumonectomy was performed in 15 male mongrel dogs ("old" > or =8 yr [n = 8], "young" <4 yr [n = 7]) and the electrocardiogram continuously recorded by an implantable telemetry system for 1 wk before euthanizing. After surgery, 7 of 8 older animals (88%) developed a total of 23 episodes of sustained (>30 s) paroxysmal supraventricular tachycardia (SVT), compared with 0 of 7 (0%) young dogs, P = 0.0014. Analysis of heart rate over the 60 min preceding the onset of SVT revealed a progressive increase in sinus rhythm beginning 15 min before the arrhythmia. Comparison of the heart rate and rhythm obtained in younger animals from the corresponding postoperative hour demonstrated that although older animals developed more atrial (P = 0.03) and ventricular premature contractions (P = 0.056) and episodes of nonsustained ventricular tachycardia (P = 0.01), heart rate was similar for both groups until the increase in elderly dogs preceding the onset of SVT. Histologic examination of the atria showed interstitial fibrosis in old but not young animals. In addition, 4 of 8 (50%) elderly animals exhibited an inflammatory response within the atria consistent with acute myo- and epicarditis. We conclude that elderly dogs have an increased supraventricular arrhythmogenic potential within the first week after pneumonectomy than younger animals, perhaps because of increased atrial fibrosis and inflammation. Heart rate analysis before SVT onset suggests that adrenergic predominance was a probable responsible trigger. IMPLICATIONS: In this canine pneumonectomy model, advanced age was associated with an increased incidence of supraventricular arrhythmias, perhaps because of increased atrial fibrosis and inflammation.

Age Factors↗