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Background Desoxycorticosterone pivalate (DOCP) is a commonly used mineralocorticoid replacement for dogs with primary hypoadrenocorticism (HA), but manufacturer-recommended dosing protocols can be cost-prohibitive. Recent reports also have raised concerns that label dose protocols could be excessive. Objective To investigate the relative efficacy and adverse effects of 2 DOCP dosages in dogs with primary glucocorticoid and mineralocorticoid deficient HA. Animals Thirty-seven dogs, including 19 test population dogs and 18 controls. Methods Randomized controlled double-blinded clinical trial. Dogs with newly diagnosed primary HA were assigned to standard (2.2 mg/kg q30d, control population) or low-dose (1.1 mg/kg q30d, test population) DOCP treatment. Clinical and laboratory variables were assessed 10 to 14 days and approximately 30 days after each DOCP treatment for 90 days. Results Mean serum sodium to potassium ratios at reevaluations were ≥32 in both populations throughout the study. No dog developed electrolyte abnormalities warranting medical treatment, although hypokalemia occurred on at least 1 occasion in 9 controls and 6 test population dogs. Urine specific gravities (median, interquartile range) were lower in control dogs (1.022, 1.016-1.029) as compared to test population dogs (1.033, 1.023-1.039; P = .006). Plasma renin activity was overly suppressed on 84 of 104 (80.8%) assessments in control dogs whereas increased renin activity occurred on 23 of 112 (20.5%) assessments in test population dogs. Conclusions and clinical importance Low-dose DOCP protocols appear to be safe and effective for treatment of HA in most dogs. Standard-dose protocols are more likely to result in biochemical evidence of overtreatment.

Background Cushing’s syndrome in humans shares many similarities with its counterpart in dogs in terms of etiology (pituitary versus adrenal causes), clinical signs, and pathophysiologic sequelae. In both species, treatment of pituitary- and adrenal-dependent disease is met with limitations. ATR-101, a selective inhibitor of ACAT1 (acyl coenzyme A:cholesterol acyltransferase 1), is a novel small molecule therapeutic currently in clinical development for the treatment of adrenocortical carcinoma, congenital adrenal hyperplasia, and Cushing’s syndrome in humans. Previous studies in healthy dogs have shown that ATR-101 treatment led to rapid, dose-dependent decreases in adrenocorticotropic hormone (ACTH) stimulated cortisol levels. The purpose of this clinical study was to investigate the effects of ATR-101 in dogs with Cushing’s syndrome. Methods ATR-101 pharmacokinetics and activity were assessed in 10 dogs with naturally-occurring Cushing’s syndrome, including 7 dogs with pituitary-dependent disease and 3 dogs with adrenal-dependent disease. ATR-101 was administered at 3 mg/kg PO once daily for one week, followed by 30 mg/kg PO once daily for one (n = 4) or three (n = 6) weeks. Clinical, biochemical, adrenal hormonal, and pharmacokinetic data were obtained weekly for study duration. Results ATR-101 exposure increased with increasing dose. ACTH-stimulated cortisol concentrations, the primary endpoint for the study, were significantly decreased with responders (9 of 10 dogs) experiencing a mean ± standard deviation reduction in cortisol levels of 50 ± 17% at study completion. Decreases in pre-ACTH-stimulated cortisol concentrations were observed in some dogs although overall changes in pre-ACTH cortisol concentrations were not significant. The compound was well-tolerated and no serious drug-related adverse effects were reported. Conclusions This study highlights the potential utility of naturally occurring canine Cushing’s syndrome as a model for human disease and provides proof of concept for ATR-101 as a novel agent for the treatment of endocrine disorders like Cushing’s syndrome in humans.

Pulse wave velocity (PWV) is the most important index of arterial stiffness. It is conventionally estimated by noninvasively measuring central and peripheral blood pressure (BP) and/or velocity (BV) waveforms and then detecting the foot-to-foot time delay between the waveforms wherein wave reflection is presumed absent. We developed techniques for improved estimation of PWV from the same waveforms. The techniques effectively estimate PWV from the entire waveforms, rather than just their feet, by mathematically eliminating the reflected wave via an arterial tube-load model. In this way, the techniques may be more robust to artifact while revealing the true PWV in absence of wave reflection. We applied the techniques to estimate aortic PWV from simultaneously and sequentially measured central and peripheral BP waveforms and simultaneously measured central BV and peripheral BP waveforms from 17 anesthetized animals during diverse interventions that perturbed BP widely. Since BP is the major acute determinant of aortic PWV, especially under anesthesia wherein vasomotor tone changes are minimal, we evaluated the techniques in terms of the ability of their PWV estimates to track the acute BP changes in each subject. Overall, the PWV estimates of the techniques tracked the BP changes better than those of the conventional technique (e.g., diastolic BP root-mean-squared errors of 3.4 versus 5.2 mmHg for the simultaneous BP waveforms and 7.0 versus 12.2 mmHg for the BV and BP waveforms (p

Pulse transit time (PTT) measured as the time delay between invasive proximal and distal blood pressure (BP) or flow waveforms (invasive PTT [I‐PTT]) tightly correlates with BP. PTT estimated as the time delay between noninvasive proximal and distal arterial waveforms could therefore permit cuff‐less BP monitoring. A popular noninvasive PTT estimate for this application is the time delay between ECG and photoplethysmography (PPG) waveforms (pulse arrival time [PAT]). Another estimate is the time delay between proximal and distal PPG waveforms (PPG‐PTT). PAT and PPG‐PTT were assessed as markers of BP over a wide physiologic range using I‐PTT as a reference. Waveforms for determining I‐PTT, PAT, and PPG‐PTT through central arteries were measured from swine during baseline conditions and infusions of various hemodynamic drugs. Diastolic, mean, and systolic BP varied widely in each subject (group average (mean ± SE) standard deviation between 25 ± 2 and 36 ± 2 mmHg). I‐PTT correlated well with all BP levels (group average R 2 values between 0.86 ± 0.03 and 0.91 ± 0.03). PPG‐PTT also correlated well with all BP levels (group average R 2 values between 0.81 ± 0.03 and 0.85 ± 0.02), and its R 2 values were not significantly different from those of I‐PTT. PAT correlated best with systolic BP (group average R 2 value of 0.70 ± 0.04), but its R 2 values for all BP levels were significantly lower than those of I‐PTT (P

We developed a technique to calculate forward and backward arterial waves from proximal and distal pressure waveforms. First, the relationship between the waveforms is represented with an arterial tube model. Then, the model parameters are estimated via least-squares fitting. Finally, the forward and backward waves are calculated using the parameter estimates. Thus, unlike most techniques, the arterial waves are determined without a more difficult flow measurement or an experimental perturbation. We applied the technique to central aortic and femoral artery pressure waveforms from anesthetized dogs during drug infusions, volume changes, and cardiac pacing. The calculated waves predicted an abdominal aortic pressure waveform measurement more accurately (2.4 mmHg error) than the analyzed waveforms (5.3 mmHg average error); reliably predicted relative changes in a femoral artery flow measurement (14.7% error); and changed as expected with selective vasoactive drugs. The ratio of the backward- to forward-wave magnitudes was 0.37 ± 0.05 during baseline. This index increased by ∼50% with phenylephrine and norepinephrine, decreased by ∼60% with dobutamine and nitroglycerin, and changed little otherwise. The time delay between the waves in the central aorta was 175 ± 14 ms during baseline. This delay varied by ±∼25% and was inversely related to mean pressure.

Objective—To determine the effect of semen in urine specimens on urine protein concentration measured by means of dipstick analysis. Sample Population—14 urine samples from 3 adult castrated male dogs and 14 semen samples from 7 adult sexually intact male dogs. Procedures—Serial dilutions of the whole ejaculate or spermatozoa-free seminal fluid in urine were created, and unaltered and diluted urine samples were analyzed by means of a commercially available dipstick; pH and specific gravity of the samples were also measured. Spermatozoa and WBC counts of the semen samples and protein concentration of the seminal fluid were determined. Results—Protein concentrations determined by means of dipstick analysis of urine samples to which whole ejaculate (dilutions of 1:1, 1:2, 1:16, 1:64, and 1:256) or seminal fluid (dilutions of 1:1, 1:2, 1:16, and 1:64) had been added were significantly higher than concentrations in unaltered urine samples. All 13 samples to which whole ejaculate was added at a dilution of 1:2 and 10 of 12 samples to which seminal fluid was added at a dilution of 1:2 were positive for blood on dipstick analysis. There was no significant linear correlation between spermatozoa or WBC count of the semen sample and protein concentration of the spermatozoa-free seminal fluid. Conclusions and Clinical Relevance—Results suggested that regardless of whether spermatozoa were present, semen contamination could result in false-positive results for protein and blood during dipstick analysis of urine samples from sexually intact male dogs.

Objective: To report a case of myocardial perforation by a stick foreign body in a dog. Case Summary: A 3-year-old castrated male Labrador Retriever was examined because of a puncture wound seen after an unsupervised run in the woods. The wound was suspected to penetrate into the thoracic cavity on the basis of physical exam and radiographs. Uniform ventricular premature complexes (VPCs) and junctional beats were noted on electrocardiogram (ECG). Thoracotomy was performed and a 6-cm wooden stick was seen protruding from the right ventricle through the pericardium toward the sternum. The stick was removed while purse string sutures were tied around the resultant myocardial defect. Follow-up echocardiography revealed intact intracardiac structures. VPCs were treated with lidocaine and resolved completely within 24 hours of presentation. New or Unique Information Provided: Thoracic trauma can result in myocardial injury; penetration into the myocardium represents a life-threatening situation for the emergency clinician. Cardiac injury should be included in the differential diagnoses of penetrating thoracic foreign bodies.

OBJECTIVE To evaluate pharmacokinetics of ammonium tetrathiomolybdate (TTM) after IV and oral administration to dogs and effects of TTM administration on trace mineral concentrations. ANIMALS 8 adult Beagles and Beagle crossbreds (4 sexually intact males and 4 sexually intact females). PROCEDURES Dogs received TTM (1 mg/kg) IV and orally in a randomized crossover study. Serum molybdenum and copper concentrations were measured via inductively coupled plasma mass spectrometry in samples obtained 0 to 72 hours after administration. Pharmacokinetics was determined via noncompartmental analysis. RESULTS For IV administration, mean ± SD terminal elimination rate constant, maximum concentration, area under the curve, and half-life were 0.03 ± 0.01 hours−1, 4.9 ± 0.6 μg/mL, 30.7 ± 5.4 μg/mL•h, and 27.7 ± 6.8 hours, respectively. For oral administration, mean ± SD terminal elimination rate constant, time to maximum concentration, maximum concentration, area under the curve, and half-life were 0.03 ± 0.01 hours−1, 3.0 ± 3.5 hours, 0.2 ± 0.4 μg/mL, 6.5 ± 8.0 μg/mL•h, and 26.8 ± 8.0 hours, respectively. Oral bioavailability was 21 ± 22%. Serum copper concentrations increased significantly after IV and oral administration. Emesis occurred after IV (2 dogs) and oral administration (3 dogs). CONCLUSIONS AND CLINICAL RELEVANCE Pharmacokinetics for TTM after a single IV and oral administration was determined for clinically normal dogs. Absorption of TTM after oral administration was variable. Increased serum copper concentrations suggested that TTM mobilized tissue copper. Further studies will be needed to evaluate the potential therapeutic use of TTM in copper-associated chronic hepatitis of dogs.

Objective—To determine whether autologous jugular veins provide functional grafts with high 30-day patency rates in an experimental model of systemic-to-pulmonary shunting performed with a modified Blalock-Taussig procedure. Animals—15 healthy Beagles. Procedure—A segment of the left jugular vein was implanted between the left subclavian and pulmonary arteries. Echocardiograms were obtained prior to surgery, at day 4 to 7, and at day 30 after surgery. Selective angiograms were performed immediately after surgery and on day 30. Oximetric shunt calculations were made via terminal angiography prior to euthanasia. Gross and histologic evaluations of the grafts were conducted. Results—Grafts were patent in 12 of 15 dogs 30 days after surgery as assessed via auscultation, color Doppler ultrasonography, angiography, and histologic examination. Echocardiographic analysis revealed compensatory eccentric left ventricular hypertrophy. Mean pulmonary-to-systemic flow ratio was 1.5:1. Histologic evidence of endothelialization of the anastomotic sites and vein graft arterialization was detectable at 30 days. Conclusions and Clinical Relevance—Autologous jugular vein grafts were effectively used to create a systemic-to-pulmonary shunt by use of a modified Blalock-Taussig procedure. High patency, ready accessibility, low cost, and theoretical adaptative remodeling during patient growth make autologous jugular vein grafts a valuable alternative to synthetic materials.

Atrial fibrillation is a common arrhythmia in dogs with structural cardiac disease and can result in significant clinical signs. Several methods of electrical cardioversion of atrial fibrillation have been described. Biphasic transthoracic cardioversion of atrial fibrillation in dogs with naturally occurring heart disease has been described in veterinary medicine and has been shown to be highly successful. In humans and research animals intracardiac and transesophageal cardioversion of atrial fibrillation has been described as an alternative to transthoracic cardioversion. While transesophageal cardioversion is very successful in humans and research animals, this technique has not been previously described in a clinical patient with naturally occurring heart disease in veterinary medicine. This report describes the use of transesophageal cardioversion in a dog with atrial fibrillation and structural cardiac disease. Cardioversion was unsuccessful using two electrodes positioned within the esophagus. Cardioversion of atrial fibrillation to normal sinus rhythm was successfully achieved and maintained using one electrode positioned within the esophagus and one electrode positioned within the right atrium using a synchronized monophasic shock of 50 J.

Determining the cause of episodes of collapse can be difficult. Even in patients with frequent collapsing episodes due to cardiac causes, diagnostic surface electrocardiogram and 24 hr ambulatory electrocardiographic (Holter) monitoring are sometimes inconclusive. Event monitors with multiple leads can be challenging to use in veterinary medicine over long periods of time due to lead dislodgment. Implantable leadless loop recorders (ILRs) are useful, but owners are sometimes unwilling to have an ILR implanted due to the associated risks and/or costs. In this case report, the authors describe the use of cutaneously placed ILRs in two dogs with unexplained episodes of collapse/exercise intolerance. Data recorded provided clinically useful information. Cutaneously placed ILRs can be used effectively in veterinary medicine to evaluate patients with unexplained episodes of collapse.

A 9-year-old dog with spontaneous ascites was found to have hepatic vein distension and a tortuous vena cava on abdominal ultrasound. In right lateral recumbency, the caudal vena cava crossed the diaphragm and became kinked before entering into the right atrium. Following this observation, we performed an experimental study in a normal dog to determine whether kinking of the caudal vena cava could be the result and not the cause of ascites. Ascites was induced using warm saline injected through a needle inserted into the abdominal cavity. Venograms were collected from different body positions, under four conditions: before and after a total of one, two and 3 liters of saline had been injected. Caudal vena cava kinking was observed in the experimental dog after 2 liters of fluid had been injected. Vena cava obstruction may cause ascites, but we found that sometimes caudal vena cava kinking can be the result and not the cause of the peritoneal effusion.

We compared pulse arrival time (PAT) and pulse transit time (PTT) in terms of their ability to track diastolic pressure (DP). We performed the comparison using high fidelity, invasive arterial waveforms recorded from six dogs during multiple interventions. On average, DP ranged from 40 to 106 mmHg and therefore varied widely. PAT and PTT were able to predict DP with average root-mean-squared-errors of 9.8 ± 5.8 mmHg and 5.7 ± 2.0 mmHg (p = 0.02). Thus, even though PAT is simpler to measure, we can only recommend using PTT for tracking DP.

A 9-year-old dog with spontaneous ascites was found to have hepatic vein distension and a tortuous vena cava on abdominal ultrasound. In right lateral recumbency, the caudal vena cava crossed the diaphragm and became kinked before entering into the right atrium. Following this observation, we performed an experimental study in a normal dog to determine whether kinking of the caudal vena cava could be the result and not the cause of ascites. Ascites was induced using warm saline injected through a needle inserted into the abdominal cavity. Venograms were collected from different body positions, under four conditions: before and after a total of one, two and 3 liters of saline had been injected. Caudal vena cava kinking was observed in the experimental dog after 2 liters of fluid had been injected. Vena cava obstruction may cause ascites, but we found that sometimes caudal vena cava kinking can be the result and not the cause of the peritoneal effusion.

Pulse wave velocity (PWV) determined through the foot-to-foot time delay between carotid and femoral artery waveforms is an index of aortic stiffness with proven clinical value. However, handheld transducers, which are often used to non-invasively measure the waveforms, are prone to motion artifact that may limit the full potential of this index. Here, we conceived an artifact robust technique to estimate PWV based on an arterial tube model. We applied the technique to high fidelity canine arterial pressure waveforms before and after contamination with known amounts of noise. Our results showed that, as the signal-to-noise ratio decreased, the PWV estimates of the technique predicted diastolic and mean arterial pressure with increasingly greater accuracy than the PWV estimates of the conventional foot-to-foot detection technique.

We developed a new technique to mathematically transform a peripheral artery pressure (PAP) waveform distorted by wave reflections into the physiologically more relevant aortic pressure (AP) waveform. First, a transfer function relating PAP to AP is defined in terms of the unknown parameters of a parallel tube model of pressure and flow in the arterial tree. The parameters are then estimated from the measured PAP waveform along with a one-time measurement of the wave propagation delay time between the aorta and peripheral artery measurement site (which may be accomplished noninvasively) by exploiting preknowledge of aortic flow. Finally, the transfer function with its estimated parameters is applied to the measured waveform so as to derive the AP waveform. Thus, in contrast to the conventional generalized transfer function, the transfer function is able to adapt to the intersubject and temporal variability of the arterial tree. To demonstrate the feasibility of this adaptive transfer function technique, we performed experiments in 6 healthy dogs in which PAP and reference AP waveforms were simultaneously recorded during 12 different hemodynamic interventions. The AP waveforms derived by the technique showed agreement with the measured AP waveforms (overall total waveform, systolic pressure, and pulse pressure root mean square errors of 3.7, 4.3, and 3.4 mmHg, respectively) statistically superior to the unprocessed PAP waveforms (corresponding errors of 8.6, 17.1, and 20.3 mmHg) and the AP waveforms derived by two previously proposed transfer functions developed with a subset of the same canine data (corresponding errors of, on average, 5.0, 6.3, and 6.7 mmHg).

Chronic iron overload associated with hereditary hemochromatosis or repeated red cell transfusions is known to cause cardiac failure. Cardiac arrhythmias have been incidentally noted in patients with iron overload, but they are often dismissed as being related to comorbid conditions. Studies with anesthetized iron-loaded gerbils using short recordings suggest a role for iron in the development of arrhythmias. Our goal was to characterize iron-induced arrhythmias in the chronically instrumented, untethered, telemetered gerbil. Electrocardiograms were recorded for 10 s every 30 min for approximately 6 months in iron-loaded (n=23) and control (n=8) gerbils. All gerbils in both groups showed evidence of frequent sinus arrhythmia. There was no difference in heart rate, electrocardiographic parameters, or number of arrhythmias per minute between groups. Gerbils rarely showed significant arrhythmias. Body weight and heart weight were not significantly different between groups, whereas liver weight increased with increasing iron dose in the treated group. Cardiac and hepatic iron concentrations were significantly increased in iron-loaded gerbils. Eight of 14 gerbils loaded to 6.2 g/kg body weight developed ascites. We conclude that an iron load sufficient to cause clinical liver disease does not cause cardiac arrhythmias in the gerbil model of iron overload.

We developed a technique to continuously (i.e., automatically) monitor cardiac output (CO) and left atrial pressure (LAP) by mathematical analysis of the pulmonary artery pressure (PAP) waveform. The technique is unique to the few previous related techniques in that it jointly estimates the two hemodynamic variables and analyzes the PAP waveform over time scales greater than a cardiac cycle wherein wave reflections and inertial effects cease to be major factors. First, a 6-min PAP waveform segment is analyzed so as to determine the pure exponential decay and equilibrium pressure that would eventually result if cardiac activity suddenly ceased (i.e., after the confounding wave reflections and inertial effects vanish). Then, the time constant of this exponential decay is computed and assumed to be proportional to the average pulmonary arterial resistance according to a Windkessel model, while the equilibrium pressure is regarded as average LAP. Finally, average proportional CO is determined similar to invoking Ohm's law and readily calibrated with one thermodilution measurement. To evaluate the technique, we performed experiments in five dogs in which the PAP waveform and accurate, but highly invasive, aortic flow probe CO and LAP catheter measurements were simultaneously recorded during common hemodynamic interventions. Our results showed overall calibrated CO and absolute LAP root-mean-squared errors of 15.2% and 1.7 mmHg, respectively. For comparison, the root-mean-squared error of classic end-diastolic PAP estimates of LAP was 4.7 mmHg. On future successful human testing, the technique may potentially be employed for continuous hemodynamic monitoring in critically ill patients with pulmonary artery catheters.

We developed a technique to quantify forward and backward arterial waves by model-based analysis of aortic and femoral artery pressure waveforms. Thus, in contrast to conventional techniques, our technique does not require a more difficult arterial flow measurement. We validated the forward and backward waves through a set of canine experiments by showing that the waves accurately predicted a third arterial pressure waveform measurement and changed in the expected manner to interventions of known effect. We also calculated the waves during nine different hemodynamic conditions. Our results showed that the relative magnitude of the backward wave was smallest during nitroglycerin and dobutamine and largest during phenylephrine and hemorrhage, while the time delay between the two waves was smallest during atrial pacing and about the same during the remaining eight conditions.

We developed a technique to monitor left ventricular ejection fraction (EF) by model-based analysis of the aortic pressure waveform. First, the aortic pressure waveform is represented with a lumped parameter circulatory model. Then, the model is fitted to each beat of the waveform to estimate its lumped parameters to within a constant scale factor equal to the arterial compliance (C (a)). Finally, the proportional parameter estimates are utilized to compute beat-to-beat absolute EF by cancelation of the C (a) scale factor. In this way, in contrast to conventional imaging, EF may be continuously monitored without any ventricular geometry assumptions. Moreover, with the proportional parameter estimates, relative changes in beat-to-beat left ventricular end-diastolic volume (EDV), cardiac output (CO), and maximum left ventricular elastance (E (max)) may also be monitored. To evaluate the technique, we measured aortic pressure waveforms, reference EF and EDV via standard echocardiography, and other cardiovascular variables from six dogs during various pharmacological influences and total intravascular volume changes. Our results showed overall EF and calibrated EDV root-mean-squared-errors of 5.6% and 4.1 mL, and reliable estimation of relative E (max) and beat-to-beat CO changes. These results demonstrate, perhaps for the first time, the feasibility of estimating EF from only a blood pressure waveform.

Cardiac events, including heart failure and arrhythmias, are the leading cause of death in patients with beta thalassemia. Although cardiac arrhythmias in humans are believed to result from iron overload, excluding confounding factors in the human population is difficult. The goal of the current study was to determine whether cardiac arrhythmias occurred in the guinea pig model of secondary iron overload. Electrocardiograms were recorded by using surgically implanted telemetry devices in guinea pigs loaded intraperitoneally with iron dextran (test animals) or dextran alone (controls). Loading occurred over approximately 6 wk. Electrocardiograms were recorded for 1 wk prior to loading, throughout loading, and for approximately 4 wk after loading was complete. Cardiac and liver iron concentrations were significantly increased in the iron-loaded animals compared with controls and were in the range of those reported for humans with thalassemia. Arrhythmias were rare in both iron-loaded and control guinea pigs. No life-threatening arrhythmias were detected in either group. These data suggest that iron alone may be insufficient to cause cardiac arrhythmias in the iron-loaded guinea pig model and that arrhythmias detected in human patients with iron overload may be the result of a complex interplay of factors.

Polycystic ovary syndrome (PCOS), a leading cause of infertility, affects ∼10% of women of reproductive age. The etiology and pathophysiology of PCOS are poorly understood. PCOS is multifaceted and includes reproductive abnormalities and components of the metabolic syndrome such as insulin resistance, obesity, dyslipidemia, and hypertension. Exposure to excess testosterone (T) during the prenatal period may predispose individuals to PCOS phenotype. The goal of this study was to determine whether hypertension and dyslipidemia occur in a well-characterized model of PCOS produced by prenatal treatment of sheep with T. Radiotelemetry was used to measure blood pressure over a 24-h period in conscious, undisturbed animals. To normalize circulating estradiol levels across treatment, control ( n = 4) and prenatal T-treated (100 mg T propionate im twice weekly from days 30 to 90 of fetal life, n = 4) 2-yr-old females were ovariectomized, instrumented with a radiotelemetry transmitter, and clamped with early follicular phase levels of estrogen using an implant. Six days later, a 24-h recording period commenced. Prenatal T-treated sheep were hypertensive compared with control sheep, and heart rate tended to be higher. T-treated sheep had hyperglycemia, insulin resistance, hypernatremia, and hyperchloremia, and both total and LDL cholesterol tended to be higher. Plasma aldosterone and epinephrine were significantly lower in T-treated sheep, whereas norepinephrine was unchanged. This first-ever use of radiotelemetric blood pressure recordings in sheep demonstrates that mild hypertension, a risk factor reported in some women with PCOS, is also a feature of the sheep model of PCOS produced by prenatal T treatment.

Background: Accurate detection of drug-induced QT interval changes is often confounded by concurrent heart rate changes. Application of heart rate correction formulas has been the traditional approach to account for heart rate–induced QT interval changes, and thereby identify the direct effect of the test article on cardiac repolarization. Despite numerous recent studies identifying the imprecision of these formulas they continue to be applied. Methods: Using a chronic atrioventricular dissociated His-paced canine model, heart rate correction methods were evaluated for their ability to generate a corrected QT interval independent of original heart rate. Additionally, His bundle pacing at a heart rate of 60 beats/min allowed calculation of the magnitude of error introduced by application of heart rate correction formulas. Results: Of the fixed parameter heart rate correction formulas, only Van de Water was able to predict corrected QT values independent of the original heart rate. The magnitude of error discovered by application of heart rate correction formulas varied, but in many cases was very large. Bazett's formula was associated with a mean overcorrection of 67.9 ms; Fridericia's 28.7 ms. Van de Water was the best fixed parameter formula with a mean error of 10.8 ms. As expected, group and individual corrections derived from linear regression of the HR-QT data offered improvement over the traditional formulas. Both were able to predict QTc values independent of the heart rate. However, errors of the magnitude of 10 and 6 ms, respectively, were still introduced. Conclusion: Van de Water and linear regression correction methods were superior to others in this study, but all methods generated QTc errors equal to or much greater than the magnitude of interest for drug safety evaluation.

Introduction: Terfenadine, cisapride, and E-4031, three drugs that prolong ventricular repolarization, were selected to evaluate the sensitivity of the conscious chronic atrioventricular node—ablated, His bundle-paced Dog for defining drug induced cardiac repolarization prolongation. A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation was generated from these data. Methods: Three male beagle dogs underwent radiofrequency AV nodal ablation, and placement of a His bundlepacing lead and programmable pacemaker under anesthesia. Each dog was restrained in a sling for a series of increasing dose infusions of each drug while maintained at a constant heart rate of 80 beats/min. RT interval, a surrogate for QT interval in His bundle-paced dogs, was recorded throughout the experiment. Results: E-4031 induced a statistically significant RT prolongation at the highest three doses. Cisapride resulted in a dose-dependent increase in RT interval, which was statistically significant at the two highest doses. Terfenadine induced a dose-dependent RT interval prolongation with a statistically significant change occurring only at the highest dose. The relationship between drug concentration and RT interval change was described by a sigmoid Emax model with an effect site. Maximum RT change (Emax), free drug concentration at half of the maximum effect (EC50), and free drug concentration associated with a 10 ms RT prolongation (EC10 ms) were estimated. A linear correlation between EC10 ms and HERG IC50 values was identified. Discussion: The conscious dog with His bundle-pacing detects delayed cardiac repolarization related to IKr inhibition, and detects repolarization change induced by drugs with activity at multiple ion channels. A clinically relevant sensitivity and a linear correlation with in vitro HERG data make the conscious His bundle-paced dog a valuable tool for detecting repolarization effect of new chemical entities.

Following AVN ablation, eight dogs were surgically instrumented for chronic (continuous) HIS-bundle pacing. For data collection, implanted pacemakers were transiently programmed to pace in stepwise ascending ramps at rates from 50 to 200 beats/min in 30-beat/min steps. Each rate was held for 60 seconds. At each rate, ECG signals were collected from conscious dogs for measurements of QT intervals during the last 10 seconds of each paced rate to construct a QT-HR ramp. This QT-HR ramp was repeated twice on each day of study 10 minutes apart. Dogs were randomly assigned to two groups and studied weekly for a minimum of 6 weeks. Group 1 dogs had pacemakers programmed to a rate of 80 beats/min for the duration of the study. Group 2 dogs were paced at 80 beats/min for weeks 1-3, then increased to 140 beats/min for weeks 4-6. The difference between paired QT-HR ramps within 1 day was

Introduction: QT interval prolongation following drug exposure is considered a marker for increased risk of drug-induced arrhythmias. QT interval measurements are common components of the safety pharmacology assessment of new therapeutic compounds but are potentially confounded by concurrent changes in heart rate that also alter QT intervals. We describe an anesthetized canine model of AV dissociation with His-bundle pacing that overcomes the confounding effects of a change in heart rate. Methods and Results: Transvenous radiofrequency ablation of the AV node was performed in isoflurane-anesthetized dogs and followed by open chest implantation of bipolar pacing electrodes in the vicinity of the His bundle. Pace rates were adjusted from 50 to 190 in steps of 20 beats/min, holding each step for 30 seconds. At each paced rate, QT intervals were measured manually to the nearest 1 ms to construct paced QT interval-heart rate (QT-HR) relationships. Paired QT-HR relationships using identical ascending ramps of pace rates were compared to paired QT-HR relationships with an ascending and descending pace ramp to evaluate short-term reproducibility and hysteresis effects. For proof of concept, an additional QT-HR relationship was constructed in three dogs after intravenous administration of a compound known to alter QT intervals: one dog received terfenadine (0.48 mg/kg bolus followed by 0.017 mg/kg/min infusion), one dog received quinidine (20 mg/kg), and the third dog received sotalol (1 and 3 mg/kg). Substantial interdog variation was found for QT-HR, although short-term reproducibility was high within one dog (average absolute difference for paired ascending ramps

Cardiac events, including heart failure and arrhythmias, are the major cause of death in patients with b-thalassemia. Although cardiac arrhythmias in humans are believed to result from iron overload, excluding confounding factors in the human population is difficult. The purpose of these studies was to evaluate the development of cardiac arrhythmias using the guinea pig model of secondary iron overload. Electrocardiograms were recorded via surgically implanted telemetry devices in guinea pigs loaded intraperitoneally with iron dextran and controls. Cardiac and liver iron concentrations were significantly elevated in the iron loaded animals when compared to control, and were in the range of those reported for humans with thalassemia. Arrhythmias were noted infrequently in both iron loaded and control guinea pigs. No life threatening arrhythmias were detected in either group. These data suggest that iron alone may be insufficient to cause cardiac arrhythmias, and that arrhythmias detected in individuals with iron overload may be the result of a complex interplay of factors.

Systolic myocardial function was assessed in 16 dogs with severe congestive heart failure due to chronic mitral valve fibrosis. End-systolic diameters were measured on echocardiograms and end-systolic volume indices were calculated. Thirteen of the 16 dogs (81%) had normal or only mildly abnormal myocardial function. These data suggested that myocardial failure is not a prominent factor contributing to signs of heart failure in dogs with mitral regurgitation. Because of these data, the routine use of digitalis glycosides to increase cardiac contractility is seriously questioned in dogs with heart failure secondary to chronic mitral regurgitation.