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Biomedical subjects

Robert L Hamlin

Publications and source records attributed to Robert L Hamlin.

At least 19 recordsLinked to original sources
PubMed2006

Animal models of ventricular arrhythmias.

Limitations in understanding of arrhythmias stem from lack of animal models which serve as surrogates for man. The purpose of this review is to discuss iatrogenic and naturally occurring animal models that are useful in our understanding of the mechanisms of ventricular arrhythmia and of antiarrhythmic and proarrhythmic agents. It is not surprising however that some information obtained from studies on infrahuman mammals may not be extrapolated to man. Need for anesthesia affects profoundly the electrophysiology of the heart, including autonomic affects. Most of the animal are modification of the Harris' 2-stage model. A model proposed by Schwartz, Billman and Stone has evolved as one that produces arguably the most information on the pathophysiology of arrhythmia production, including the role of the autonomic nervous system and the interaction with pharmacological agents. Intoxication with digitalis and escalating doses of epinephrine are commonly used models for production of ventricular arrhythmias. No matter what model of ventricular arrhythmias is used, programmed electrical stimulation can be useful to uncover increased tendency for arrhythmia, even if no arrhythmia occurs spontaneously. Models of spontaneous ventricular arrhythmia occur in German shepherd puppies, Boxer dogs, Doberman pinchers with dilated cardiomyopathy, and in large dogs with gastric dilatation or splenic torsion. Models are necessary because they allow for controlled studies and methods of exploration impossible, for legal and ethical reasons, in humans. Nonetheless, ethical considerations in using animal models are still important, and there is a continual search for non-animal models to explore ventricular arrhythmias.

Anesthesia↗
PubMed2006

Use of a failing rabbit heart as a model to predict torsadogenicity.

Humans with underlying cardiovascular disease are at greater risk than humans with normal hearts for developing torsade de pointes (TdP) following exposure to some drugs that prolong ventricular repolarization. This study was designed to test the hypothesis that rabbits with ischemic myocardial failure are at similarly increased risk of developing QTc prolongation and TdP following exposure to escalating doses of drugs, which is known to have a capacity to induce TdP in humans. Coronary artery ligation was performed in 28 rabbits, causing significant (p < 0.05) reduction in left ventricular shortening fraction and systolic myocardial dysfunction 4 weeks after ligation in all operated animals compared to 38 normal, nonoperated controls. All studies were performed on rabbits anesthetized with ketamine (35 mg/kg) and xylazine (5 mg/kg). Rabbits were exposed to escalating doses of amiodarone (3, 10, 30 mg/kg/10 min), cisapride (0.10, 0.25, 0.50 mg/kg/10 min), clofilium (0.1, 0.2, 0.4 mg/kg/10 min), dofetilide (0.005, 0.01, 0.02, 0.04 mg/kg/10 min), quinidine (3, 10, 30 mg/kg/10 min), and verapamil (0.25, 0.5, 1.0 mg/kg/10 min). A greater percentage of rabbits with failing hearts developed TdP following intravenous infusion of escalating doses of dofetilide (85%), clofilium (100%), or cisapride (50%) than did normal rabbits exposed to the same drug protocol (20, 33, and 0%, respectively). None of the rabbits in either group developed TdP when exposed to escalating doses of amiodarone, verapamil, or quinidine. Two out of four test articles lengthened QTc more in rabbits with myocardial failure than in normals, and TdP occurred in 13 out of 28 rabbits with myocardial failure as opposed to only four out of 38 rabbits with normal myocardial function.

Amiodarone↗
PubMed2006

A search to predict potential for drug-induced cardiovascular toxicity.

This is a brief review of properties of cardiovascular function that should be considered for interrogation in studies of toxicology and/or safety pharmacology for non-cardiologists and non-physiologists. Since concern over the rarely occurring, unusual, and drug-induced tachycardia, Torsade de pointes, is a leading cause for cessation of development of potential drugs and for removal of drugs from the market, therefore, the toxic manifestation of drugs will be emphasized. The putative origin of torsade de pointes, and the origin of the electrocardiogram and electrocardiographic features of ventricular arrhythmias will be discussed.

Animals↗
PubMed2006

Variations in hemodynamic parameters and ECG in healthy, conscious, freely moving telemetrized beagle dogs.

Interpretation of the dynamic cardiovascular parameters on safety pharmacology studies is a challenging process; sometimes, it is difficult to separate normal physiological variations from the effects of the test drug. Data from healthy control Beagle dogs (41 males and 25 females) implanted with telemetry transmitters (DSI, St. Paul, MN) from 34 studies performed from 2003 to 2005 were analyzed. Telemetry data were collected for a 30-s period every 10 min for 24 h after sham dosing. One-hour averages were analyzed. Prior to dosing, heart rate (HR) was 95.6 +/- 26.6 bpm; mean, systolic, and diastolic blood pressure (BP) were 105.3 +/- 12.7, 142.5 +/- 5.3, and 84.7 +/- 11.1 mmHg, respectively. PR, QRS, QT, and corrected (Van de Water) QT intervals were 121 +/- 13, 33 +/- 3, 217 +/- 23, and 245 +/- 18 ms, respectively. Seasonal and slight diurnal patterns were noticed only in HR; BP and body temperature were more stable. PR and QT intervals were inversely related to HR; in addition, the duration of PR was influenced by the light cycle. A comparison of three QT correction formulas demonstrated that Van de Water's formula provided the optimal results in Beagle dogs over a wide range of HR.

Animals↗
PubMed2005

Abnormal intrastore calcium signaling in chronic heart failure.

Diminished Ca release from the sarcoplasmic reticulum (SR) is an important contributor to the impaired contractility of the failing heart. Despite extensive effort, the underlying causes of abnormal SR Ca release in heart failure (HF) remain unknown. We used a combination of simultaneous imaging of cytosolic and SR intraluminal [Ca] in isolated cardiomyocytes and recordings from single-ryanodine receptor (RyR) channels reconstituted into lipid bilayers to investigate alterations in intracellular Ca handling in an experimental model of chronic HF. We found that diastolic free [Ca] inside the SR was dramatically reduced because of a Ca leak across the SR membrane, mediated by spontaneous local release events (Ca sparks), in HF myocytes. Additionally, the magnitudes of intrastore Ca depletion signals during global and focal Ca release events were blunted, and [Ca]SR recovery was slowed after global but not focal Ca release in HF myocytes. At the single-RyR level, the sensitivity of RyRs to activation by luminal Ca was greatly enhanced, providing a molecular mechanism for the maintained potentiation of Ca sparks (and increased Ca leak) at reduced intra-SR [Ca] in HF. This work shows that the diminished SR Ca release characteristic of failing myocardium could be explained by increased sensitivity of RyRs to luminal Ca, leading to enhanced spark-mediated SR Ca leak and reduced intra-SR [Ca].

Animals↗
PubMed2005

Canine nonischemic left ventricular dysfunction: a model of chronic human cardiomyopathy.

BACKGROUND: The mechanisms of cardiac remodeling during chronic heart failure remain poorly defined. We sought to advance a chronic canine model of nonischemic cardiomyopathy. METHODS AND RESULTS: Male dogs (n = 6) received decremental right ventricular apical tachypacing (12 months) to achieve and maintain stable left ventricular (LV) dysfunction. After 10 months of tachypacing, 120 beats/min was sufficient to maintain stable LV dysfunction. Electrocardiography, echocardiography, and tissue Doppler imaging were done to evaluate electrophysiology, LV dimensions and function, and dyssynchrony during normal sinus rhythm. The 6-minute walk test was used to evaluate functional capacity. We observed increases in both QRS duration (P < .0001) and QRS amplitude (P < .0001). LV fractional shortening was reduced from a baseline of 38.0 +/- 1.4% to 11.2 +/- 1.4% (P < .0001). LV end-diastolic dimension increased from 3.8 +/- 0.1 cm at baseline to 5.3 +/- 0.3 cm (P < .0001); LV end-systolic dimension increased from 2.3 +/- 0.1 cm to 4.7 +/- 0.2 cm (P < .0001). LV mass increased from 85.9 +/- 3.5 g at baseline to 179 +/- 13.7 g (P < .0001). There was evidence of LV dyssynchrony (P < .04) during both normal sinus rhythm and right ventricular tachypacing, compared with control dogs. The distance a dog walked in 6 minutes was significantly less at 12 months compared with normal controls (540 +/- 32 m versus 277 +/- 64 m, P < .008). CONCLUSION: This nonischemic model of canine cardiomyopathy reproduces many aspects of chronic human heart failure including reduced fractional shortening, dilated ventricular dimensions, increased LV mass, decreased functional capacity, and dyssynchrony.

Animals↗
PubMed2005

Geriatric heart diseases in dogs.

A discussion of the diagnosis and therapy of heart disease in an aged pet does not differ significantly from that in a pet of any age. Mitral regurgitation constitutes by far the most important geriatric heart disease, and the selection of drugs to treat heart disease of aging pets is based on identification of specific pathologic features (eg, atrial fibrillation, left atrial enlargement) for which each aspect of treatment (eg, diuretics, angiotensin-converting enzyme inhibitors, spironolactone) is specific.

Adrenergic beta-Antagonists↗
PubMed2005

Acute effects of tacrolimus (FK506) on left ventricular mechanics.

Tacrolimus (FK506) is a macrolide antibiotic used to minimize transplant rejections. Several macrolides affect ventricular function, but the effects of tacrolimus are unknown. This study evaluated acute effects of escalating doses of tacrolimus on heart rate (HR), left ventricular inotropy, lusitropy, preload (end-diastolic short axis radius on a 2D directed M-mode echocardiogram), and afterload (product of end-diastolic radius and diastolic arterial pressure divided by end-diastolic wall thickness) in anesthetized dogs. Tacrolimus at 0.025 mg kg(-1) increased HR and inotropy with continued escalation up to a dose of 0.1 mg kg(-1) (p<0.01). Conversely, tacrolimus at 0.025 mg kg(-1) decreased lusitropy and preload, which never achieved steady states (p<0.05). Afterload tended to increase between doses of 0.0125 and 0.025 mg kg(-1), and tended to decrease at higher doses, achieving baseline at a dose of 0.1 mg kg(-1). Tacrolimus significantly prolonged the QT interval (QTc) between doses of 0.0125 (p<0.05) and 0.1mg kg(-1) (p<0.001). These effects are consistent with altered calcium kinetics leading to increased cytosolic calcium. Tacrolimus at a clinically relevant dose of 0.1 mg kg(-1) possesses profound, acute effects on left ventricular mechanics, suggesting that cardiovascular monitoring may be necessary in tacrolimus-treated patients. Potential adverse effects include myocardial stiffness, transient increase in systemic arterial pressure, and tendency for ventricular arrhythmia.

Animals↗
PubMed2005

Effects of ambasilide in isolated perfused guinea pig heart: use dependence.

There has been increased interest in class III antiarrhythmic drugs for con-version of atrial fibrillation to sinus rhythm. Ambasilide, a class III antiarrhythmic, has been shown to block multiple cardiac channels in a variety of animals including humans. Although the electrophysiological effects of ambasilide are characterized on the cellular level, its effects on an organ level have yet to be investigated. We investigated escalating doses of ambasilide in isolated, per-fused guinea pig hearts. Ambasilide prolonged the RR, PQ, QRS, QT, and QTc (F) in a concentration-dependent manner in either normal sinus rhythm or with reduced heart rate (atriectomy). dP/dtmin was increased (became less negative) in the presence of increasing concentrations of ambasilide, whereas the vehicle produced less negative lusitropy. Ambasilide demonstrated use dependence by prolonging QTc (F) less at slower heart rates. Ambasilide also inhibited isoproterenol-induced tachycardia, suggesting it exerts beta-adrenergic blocking properties. In conclusion, this study suggests that ambasilide has multichannel blocking properties including beta-adrenergic antagonism.

Aminobenzoates↗
PubMed2004

Effects of thalidomide on QTc, inotropy, and lusitropy in the isolated guinea pig heart.

There has been a resurgence in the use of thalidomide over the past several years; however, little is known about its potential cardiac toxicity. Isolated, perfused guinea pig hearts were exposed to escalating concentrations of thalidomide or vehicle, and changes in RR interval, QT duration and QTc duration, and left ventricular inotropy and lusitropy comparing escalating concentrations of thalidomide with vehicle were sought. RR interval lengthened and QTc prolonged significantly at 10 microM concentrations. QT did not change. dP/dtmax increased and dP/dtmin decreased in response to thalidomide. Based on results using this preparation, thalidomide has a potential liability for lengthening QTc, but only at concentrations of 10 microM or greater. It possesses both positive inotropic and positive lusitropic properties.

Animals↗
PubMed2004

Evaluation of the six-minute walk test in dogs.

OBJECTIVE: To determine the feasibility for use of a 6-minute walk test (6-MWT) in dogs with congestive heart failure (CHF) and document that the distance walked in 6 minutes decreases when a dog has CHF. ANIMALS: 16 young mature male hound-crossbred dogs weighing between 25 and 37 kg. PROCEDURE: An unobstructed path (22.73 m) was measured in a hallway. Each dog was walked on a leash for 6 minutes; each dog was allowed to set its own pace. At the end of 6 minutes (as measured by use of a stopwatch), the total distance walked was measured. Heart rate (HR) obtained by auscultation and mean systemic arterial pressure (MAP) obtained by oscillometry were recorded before and after the 6-MWT. Heart failure was induced by use of rapid ventricular pacing. Mean of the distance walked, HR, and MAP before and after the 6-MWT were compared between the control period and after dogs developed induced CHF. RESULTS: Dogs with CHF had a significant increase in resting HR, significant decrease in MAP, and a significant decrease in the distance walked in 6 minutes. The MAP increased slightly after exercise during the control period but decreased slightly after exercise during the CHF period. Fractional shortening decreased significantly when dogs had CHF. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of these results indicated that the distance walked in 6 minutes decreased significantly when a dog had CHF. The 6-MWT requires little time, space, or equipment and may replace the treadmill exercise test.

Analysis of Variance↗
PubMed2003

QT and RR intervals in conscious and anesthetized guinea pigs with highly varying RR intervals and given QTc-lengthening test articles.

A facile system for obtaining electrocardiograms from conscious animals was used to conduct studies on 12 animals studied both conscious and anesthetized, on 4 conscious animals given vehicle (0.5% methylcellulose) and QT-lengthening test articles, and on 6 animals given test articles thought to not lengthen QTc. In 12 animals whose ECGs were monitored via a bipolar transthoracic ECG, heart rates were slowed with 1.0 mg/kg zatebradine, while they were conscious in their slings, and after being anesthetized with ketamine/xylazine. The following regression equations were obtained relating QT to RR: QT = 44.7 ln RR - 132.9, r2 = 0.7, for conscious animals; QT = 79.4 ln RR - 287.4, r2 = 0.8 for anesthetized animals, with RR intervals varying between 150 and 550 ms. The anesthetic increases QT at all RR intervals (p < 0.001), but does not change the slope of the relationship between QT and RR when compared with the conscious guinea pig. The Fridericia method was best for correcting QT for RR interval in conscious guinea pigs, but the Bazett method was best for correcting in anesthetized animals. QTc lengthened significantly in all conscious guinea pigs given, orally, cisapride, ketoconazole, and sotalol (positive test articles) and did not change with methylcellulose (the vehicle) or with propranolol, verapamil, or enalapril (negative controls). These techniques and relationships demonstrate that this methodology may be useful in exploring torsadogenic effects of novel pharmacological entities.

Anesthesia↗
PubMed2003

Age and anesthetic effects on murine electrocardiography.

Murine models offer potential insights regarding human cardiac disease, but efficient and reliable methods for phenotype evaluation are necessary. We employed non-invasive electrocardiography (ECG) in mice, investigating statistical reliability of these parameters with respect to anesthetic and animal age. Mice (C57BL/6, 8 or 48 weeks) were anesthetized by ketamine/xylazine (K/X, 80/10 mg/kg ip) or by inhalation anesthetic (halothane, HAL; sevoflurane, SEV) and 6 lead ECGs were recorded. P wave duration and QT interval was significantly prolonged with K/X compared to HAL and SEV, indicating slowed atrial and ventricular conduction. P-R interval (atrio-ventricular conduction) was significantly increased in aged mice under all anesthetics. Heart rate was inversely correlated to QT interval and P wave duration. We also detected significant age effects with respect to optimal approaches for QT interval corrections. Power analysis showed 4-fold higher number of mice/group, were required for K/X, to achieve identical statistical sensitivity. These data demonstrate the importance of anesthetic selection for relevant and reliable ECG analysis in mice and illustrate the selective influences of anesthetics and age on cardiac conductance in this species.

Aging↗
PubMed2003

Effects of changing heart rate on electrophysiological and hemodynamic function in the dog.

Cardiovascular parameters were measured in dogs after RR interval was changed from 0.25 s to 1.2 s with atropine and graded doses of zatebradine, an I(f)-channel blocker. Left ventricular (LV) pre-ejection period (PEP), systemic vascular resistance, tau (an estimate of myocardial stiffness), PQ, QTc, dLVP/dt(max) and dLVP/dt(min), aortic pressure, and right atrial pressure did not change when each parameter was plotted against RR interval (r(2)'s < or = 0.5). LV end-diastolic pressure, stroke volume index, LV ejection time (ET), and QT all increased either linearly or curvilinearly as RR interval prolonged. Cardiac output index and PEP/ET decreased curvilinearly. When heart rate (HR) was fixed by pacing, and graded doses of zatebradine were given, changes in cardiovascular function were minimal. Thus zatebradine affects cardiovascular function principally by changing HR and not by affecting function directly. This study provides data on the effects of changing HR, alone, on cardiovascular parameters measured frequently during pharmacological and toxicological studies. It should prove useful when physiological variables, including HR, change, and there is need to know what change in HR, alone, contributes.

Animals↗
PubMed2002

Comparison of the effects of four antiarrhythmic treatments for familial ventricular arrhythmias in Boxers.

OBJECTIVE: To evaluate the effect of 4 antiarrhythmic treatment protocols on number of ventricular premature complexes (VPC), severity of arrhythmia, heart rate (HR), and number of syncopal episodes in Boxers with ventricular tachyarrhythmias. DESIGN: Randomized controlled clinical trial. ANIMALS: 49 Boxers. PROCEDURE: Dogs with > 500 VPC/24 h via 24-hour ambulatory ECG (AECG) were treated with atenolol (n = 11), procainamide (11), sotalol (16), or mexiletine and atenolol (11) for 21 to 28 days. Results of pre- and posttreatment AECG were compared with regard to number of VPC/24 h; maximum, mean, and minimum HR; severity of arrhythmia; and occurrence of syncope. RESULTS: Significant differences between pre- and posttreatment number of VPC, severity of arrhythmia, HR variables, or occurrence of syncope were not observed in dogs treated with atenolol or procainamide. Significant reductions in number of VPC, severity of arrythmia, and maximum and mean HR were observed in dogs treated with mexiletine-atenolol or sotalol; occurrence of syncope was not significantly different between these 2 treatment groups. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with sotalol or mexiletine-atenolol was well tolerated and efficacious. Treatment with procainamide or atenolol was not effective.

Animals↗
PubMed2002

Electrocardiographic and hemodynamic effects of cisapride alone and combined with erythromycin in anesthetized dogs.

The cardiovascular effects of cisapride administered intravenously at escalating doses with and without pretreatment with erythromycin were evaluated in morphine/chloralose anesthetized dogs. Dogs were instrumented to permit simultaneous recording of ECGs, left ventricular (LVP) and aortic (AoP) pressures, as well as programmed electrical stimulation (PES). Escalating intravenous doses of cisapride from 2 to 8 mg/kg (four times the recommended therapeutic dose) increased the heart rate (HR) and prolonged the corrected QT interval (QTc) (p < 0.05) compared to controls. Pretreatment with erythromycin failed to enhance the effect of cisapride on either HR or QTc. Cisapride with or without erythromycin pretreatment had no effect on AoP, but depressed indices of left ventricular contractility (dP/dt(max) decreased while PEP/ET increased) compared to controls. No dogs developed spontaneous arrhythmias, and arrhythmias were not inducible by PES. Cisapride with or without erythromycin pretreatment altered the orientation of the T-wave vector (p < 0.05) compared to controls, indicating a primary effect of cisapride on ventricular repolarization. The QTc and T wave changes observed were consistent with the known action of cisapride on canine I(Kr) channels.

Anesthesia, Intravenous↗