A 9-year-old 28-kg (62-lb) spayed female Dalmatian was referred to our hospital for evaluation of progressive pelvic limb paraparesis and signs of thoracolumbar pain of 2 months' duration. The dog had a history of urinary incontinence, which was diagnosed when the dog was approximately 5 months old and had been controlled since that time with PPAa (mean dosage, 1.8 mg/kg [0.8 mg/lb], PO, q 12 h). The dog had also received estrogen-based medications at various times, but they did not adequately control the urinary incontinence. Shortly after the onset of the neurologic signs, the referring veterinarian performed a serum biochemical analysis and urinalysis (free-catch sample). Remarkable findings from those tests included abnormally increased BUN (42 mg/dL; reference range, 6 to 31 mg/dL) and creatinine (2.6 mg/dL; reference range, 0.5 to 1.6 mg/dL) concentrations, bacteriuria, and proteinuria (2+). A bacterial urinary tract infection was suspected, and the dog was prescribed sulfadimethoxine-ormetoprim (32 mg/kg [14.5 mg/lb], PO, q 24 h). Two weeks later, the BUN (36 mg/dL) and creatinine (2.0 mg/dL) concentrations were still above the upper limit of the respective reference ranges, and notable urinalysis (free-catch sample) results included hyposthenuria (urine specific gravity, 1.009; reference value, > 1.035), bacteriuria, and proteinuria. The antimicrobial treatment regimen was changed to ciprofloxacin (20 mg/kg [9 mg/lb], PO, q 12 h for 4 weeks), after which the bacteriuria had resolved.
At the time of the initial examination at our hospital, general physical examination findings were unremarkable; heart rate and rhythm and results of cardiac auscultation were considered clinically normal. Results of a serum biochemical analysis revealed that BUN (37 mg/dL) and creatine (2.1 mg/dL) concentrations were still abnormally increased. Remarkable results of a urinalysis (free-catch sample) included hyposthenuria (urine specific gravity, 1.013) and proteinuria (4+). A neurologic examination revealed mild pelvic limb paraparesis with moderately delayed proprioception in both pelvic limbs. Signs of pain were elicited during palpation of the thoracolumbar junction. On the basis of those findings, T3-L3 myelopathy was suspected, and the patient was admitted to the hospital for MRI examination of the thoracolumbar region of the vertebral column, which was scheduled for the next day. Phenylpropanolamine administration was discontinued the night prior to hospitalization, and urinary incontinence was not observed during the intervening period.
The next morning, the dog was premedicated with hydromorphone (0.1 mg/kg [0.045 mg/lb], IM). Anesthesia was induced with propofol (2 mg/kg [0.9 mg/lb], IV) and lidocaine (2 mg/kg, IV) and maintained with isoflurane following tracheal intubation. While anesthetized for the MRI procedure, the dog became hypotensive (MAP, 40 to 50 mm Hg; reference range, 60 to 100 mm Hg). The dog received boluses of a crystalloidb (10 mL/kg [4.5 mL/lb], IV) and hetastarch (4 mL/kg [1.8 mL/lb], IV), which resulted in little improvement in the MAP. The dog then received 2 successive doses of ephedrine (0.09 mg/kg [0.04 mg/lb], IV), after which the MAP remained between 70 and 80 mm Hg for the remaining duration of anesthesia.
The MRI sequences revealed the presence of Hansen type II intervertebral disk disease at T12–13, and a right-sided partial corpectomy and laminectomy were immediately performed while the dog was still anesthetized. Throughout the MRI procedure, the dog's heart had a normal sinus rhythm and the heart rate had remained at 120 bpm. Shortly after initiation of surgery, the heart rate increased to 140 bpm, which was interpreted as a pain response. Ketamine (0.5 mg/kg [0.2 mg/lb], IV) was administered, followed by a CRI of a solution of morphine (0.3 mg/kg/min [0.14 mg/lb/min]), lidocaine (50 μg/kg/min [23 μg/lb/min]), and ketamine (20 μg/kg/min). The heart continued to have a normal sinus rhythm, and the heart rate decreased and remained between 80 and 120 bpm for the remaining duration of the otherwise uneventful procedure.
Anesthesia was discontinued following completion of the surgical procedure, and the dog was moved to the ICU, where it was allowed to recover. While in the ICU, it received a CRI of fentanyl (2 to 5 μg/kg/h [0.9 to 2.3 μg/lb/h]) and had a transdermal fentanyl patch (75 μg) applied for analgesia. Early in the recovery period, the dog became dysphoric and was administered a CRI of dexmedetomidine (1 μg/kg/h [0.45 μg/lb/h]) for 8 hours, during which it was continuously instrumented with an ECG monitor for detection of dexmedetomidine-induced bradycardia. No heart rate or rhythm abnormalities were detected by ECG during that period.
The next morning, the patient appeared comfortable and began eating, so all injectable medications were discontinued. Continued analgesia was supplied via the transdermal fentanyl patch, and the dog was moved from the ICU to a canine ward for continued monitoring. The dog did not receive PPA while hospitalized.
A physical examination was performed on the dog twice daily while it was hospitalized. During the first 2 days after surgery, signs of pain appeared to be well controlled and the dog had gradual improvement in ambulation, although mild pelvic limb paraparesis persisted. No abnormalities were reported following cardiopulmonary auscultation. On the third day after surgery, a tachyarrhythmia (heart rate, 200 bpm) with pulse deficits was detected; however, no clinical signs associated with the arrhythmia were observed. A previously unrecognized grade 2/6 systolic murmur with a point of maximal intensity at the left apex was also heard, which prompted consultation with the cardiology service.
Because the dog had an excitable temperament, it was sedated with buprenorphine (0.0075 mg/kg [0.003 mg/lb], IV) and acepromazine (0.03 mg/kg [0.013 mg/lb], IV) to facilitate acquisition of thoracic radiographs, a 6-lead ECG tracing, blood pressure measurement, and an echocardiographic examination. No cardiopulmonary abnormalities were observed on thoracic radiographs. The ECG tracing revealed a heart rate of 200 bpm with monomorphic ventricular couplets and paroxysmal ventricular tachycardia (Figure 1). The dog was administered lidocaine (2 mg/kg, IV), after which the ventricular tachyarrhythmia converted to a normal sinus rhythm and the heart rate decreased to approximately 128 to 130 bpm. The systolic blood pressure was 96 mm Hg (as determined with Doppler echocardiography) following sedation and lidocaine administration.
Portion of an ECG tracing (leads I, II, and III) obtained from a 9-year-old spayed female Dalmatian that developed tachyarrhythmia (heart rate, 200 bpm) with pulse deficits and a grade 2/6 systolic heart murmur with a point of maximal intensity at the left apex 3 days after it underwent a right-sided partial corpectomy and laminectomy for the treatment of T12–13 intervertebral disk disease, which led to the cardiologic examination during which this tracing was acquired. The dog had a history of receiving PPA (mean dosage, 1.8 mg/kg [0.8 mg/lb], PO, q 12 h) for almost 8.5 years to treat urinary incontinence. At the time this tracing was obtained, the dog had not received PPA for approximately 3 days. The tracing includes frequent ventricular couplets and paroxysmal ventricular tachycardia (bracket); heart rate = 200 bpm. Paper speed = 25 mm/s; 1 cm = 1 mV.
Citation: Journal of the American Veterinary Medical Association 253, 11; 10.2460/javma.253.11.1452
Echocardiography revealed marked concentric LV and septal hypertrophy with reduced LV cavity size as well as mild RV free-wall and interatrial septal hypertrophy (Figure 2; Table 1). Mitral valve leaflets were mildly thickened in a manner consistent with degenerative valve disease, and color flow Doppler echocardiography revealed evidence of mitral regurgitation. The aortic root appeared prominent, but its measurements were within normal prediction limits and there was no evidence of aortic valve insufficiency.1 Left atrial and right heart chamber dimensions were within reference limits. Left ventricular systolic function was also with reference limits, and there was no evidence of a dynamic LV outflow obstruction. Results of spectral Doppler echocardiography suggested mild LV diastolic dysfunction, with reversal of the trans-mitral mitral E and A wave peak velocities. A mild dynamic RV outflow obstruction was also observed (peak velocity, 2.5 m/s). At that time, it was unclear whether the ventricular hypertrophy represented primary (idiopathic) HCM or was secondary to other factors. Results of a cursory ocular fundic examination were unremarkable. A consultation with the ophthalmology service was recommended to evaluate the patient for subtle evidence of systemic hypertension but was declined by the owner. Serum thyroxine concentration (1.1 μg/dL; reference range, 1.0 to 3.0 μg/dL) was within reference limits.
Representative 2-D echocardiographic images obtained from the right parasternal short axis (A) and long axis (B) at the end of diastole for the dog of Figure 1. Notice that the LV wall (LVW) is hypertrophied in both panels; the interatrial septum (IVS) is also thickened in panel B. The simultaneously recorded ECG (lead III) appears at the bottom of each image. LA = Left atrium. P = Papillary muscle. RA = Right atrium. RVW = RV wall.
Citation: Journal of the American Veterinary Medical Association 253, 11; 10.2460/javma.253.11.1452
Echocardiographic M-mode measurements for a 9-year-old spayed female Dalmatian at the time of and at 5 and 10 months after diagnosis of LV hypertrophy.
| Time of diagnosis | 5-month recheck | 10-month recheck | Reference limit* | |||||
|---|---|---|---|---|---|---|---|---|
| Measurement | Diastole | Systole | Diastole | Systole | Diastole | Systole | Diastole | Systole |
| RV wall (cm) | 0.53 | 0.65 | 0.34 | 0.68 | 0.36 | 0.78 | Approx 1/3 of the reference value for the LV wall | — |
| RV internal diameter (cm) | 0.42 | 0.42 | 1.05 | 0.56 | 0.74 | 0.28 | — | — |
| Interventricular septum (cm) | 1.63 | 1.90 | 1.24 | 1.60 | 1.45 | 1.91 | 0.9 (0.6–1.3) | 1.3 (1.0–1.8) |
| LV internal diameter (cm) | 2.52 | 1.60 | 4.05 | 2.61 | 3.60 | 1.59 | 4.0 (3.4–4.9) | 2.7 (2.0–3.6) |
| LV posterior wall (cm) | 1.96 | 2.37 | 1.30 | 1.78 | 1.55 | 2.44 | 0.9 (0.6–1.3) | 1.3 (1.0–1.8) |
| Heart rate (bpm)† | 128–130 | 105–110 | 118–120 | — | ||||
A cardiologic examination was performed after the dog developed tachyarrhythmia (heart rate, 200 bpm) with pulse deficits and a grade 2/6 systolic heart murmur with a point of maximal intensity at the left apex 3 days after it underwent a right-sided partial corpectomy and laminectomy for the treatment of T12–13 intervertebral disk disease. It had a history of receiving PPA (mean dosage, 1.8 mg/kg [0.8 mg/lb], PO, q 12 h) for almost 8.5 years for the treatment of urinary incontinence. Administration of PPA was discontinued prior to surgery approximately 3 days before the cardiologic examination and was not resumed until shortly after the 5-month recheck examination. At the time of the 10-month recheck examination, PPA administration had been resumed, albeit at a lower dosage (1 mg/kg [0.45 mg/lb], PO, q 24 h) than before.
Unless otherwise specified, the reference limit represents the predicted value (95% prediction interval) based on allometric scaling for a 28-kg (62 lb) dog as described.1
Approximate heart rate during recording of the M-mode echocardiographic frames used for ventricular measurements.
— = Not calculated.
Owing to the severe LV hypertrophy and rapid ventricular tachyarrhythmia, administration of sotalol (1.5 mg/kg [0.7 mg/lb], PO, q 12 h) was initiated. The dog was transferred back to the ICU for continuous ECG monitoring. Tachyarrhythmia was not observed during the subsequent 48 hours. The transdermal fentanyl patch was removed 5 days after surgery, and the dog appeared to remain comfortable.
The dog was discharged from the hospital 1 week after it was admitted, with instructions for the owner to continue sotalol (1.5 mg/kg, PO, q 12 h) administration and restrict exercise. The owner was advised not to administer PPA to the dog, but rather to try an estrogen compound if urinary incontinence recurred. Acepromazine (recommended dose, 2.6 mg/kg [1.2 mg/lb], PO) was dispensed to help control the dog's excitement and anxiety during stressful situations and was to be used at the owner's discretion.
Over the next 5 months, the dog was returned to the referring veterinarian for periodic recording of a resting ECG; 24-hour Holter monitoring was declined. Estriolc (1 mg, PO, q 24 h) was initiated for recurrence of urinary incontinence and resulted in only partial control of signs. All neurologic deficits resolved, and the dog resumed its normal activity, although restriction of moderate exercise was prescribed.
The dog was returned to our hospital 5 months after surgery for a recheck appointment. At that time, the dog appeared clinically normal, although the grade 2/6 left-sided systolic murmur was still present. An ECG revealed sinus arrhythmia with a heart rate of 90 bpm. Doppler-measured systolic blood pressure (175 mm Hg) was above the upper reference limit; however, the dog was very excited at the time it was measured. Echocardiography revealed that the LV cavity size was within reference limits, and there was marked improvement of the myocardial hypertrophy and subjective improvement in interatrial septal hypertrophy (Figure 3; Table 1). On the basis of those findings and the fact that the dog appeared clinically normal, the sotalol dosage was decreased to 0.75 mg/kg (0.34 mg/lb), PO, every 12 hours, with the intention of discontinuing its administration in 10 days unless an arrhythmia recurred. No arrhythmias were identified by the referring veterinarian during periodic recording of resting ECGs over the next 10 days, and sotalol was discontinued.
Representative 2-D echocardiographic image of the right parasternal short axis at the end of diastole for the dog of Figure 1 obtained 5 months after LV hypertrophy was diagnosed and before PPA administration was resumed. Notice that the LV hypertrophy has almost completely resolved. See Figure 2 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 253, 11; 10.2460/javma.253.11.1452
The dog was returned to our hospital 10 months after surgery. The owner reported that the dog had been clinically normal except for persistence of uri- nary incontinence. Administration of PPA had been reinitiated 5 months previously, albeit at a lower dosage (1 mg/kg, PO, q 24 h) than that prior to surgery because administration of estriol (0.5 mg, PO, q 12 h) alone was inadequate for controlling the signs of urinary incontinence. Concurrent administration of those 2 medications provided satisfactory control of the incontinence. Estriol was last administered 12 hours and PPA was last administered 4 hours prior to the recheck examination. The left-sided systolic murmur (ie, mitral regurgitation) was still present. Heart rate was 140 bpm, and intermittent premature heartbeats were evident. Doppler-measured systolic blood pressure was 226 mm Hg, although the dog was markedly excited, and it was unclear whether that was an accurate measurement. Electrocardiography revealed a sinus arrhythmia with intermittent uniform ventricular premature complexes. Echocardiography revealed that ventricular hypertrophy had recurred, but it was not as severe as it was at the time of the initial examination (Table 1). A mild RV dynamic outflow tract obstruction was also noted. The owners were again advised to discontinue PPA administration and to have the blood pressure measured and another ECG recording obtained by the referring veterinarian in 3 days. If the arrhythmia and systemic hypertension persisted at that time, additional medical treatment was recommended. Reevaluation of serum creatinine and electrolyte concentrations was recommended, but the owner preferred to have those tests performed by the referring veterinarian.
The dog was reexamined by the referring veterinarian 10 days later. The arrhythmia had resolved, but Doppler-measured systolic blood pressure was 180 mm Hg. The dog was quite calm when blood pressure was measured; therefore, the measurement was considered accurate and not an excitement-induced artifact. Enalapril (0.5 mg/kg, PO, q 24 h) was prescribed for management of hypertension.
One month later (11.5 months after surgery), the dog was again examined by the referring veterinarian. The dog had reportedly had no clinical problems at home. Doppler-measured systolic blood pressure was 160 mm Hg. All electrolyte concentrations were within the respective reference ranges. Unfortunately, BUN and creatinine concentrations were not evaluated.
The dog was reexamined by the referring veterinarian periodically over the next 12 months. No arrhythmias were documented, and the Dopplermeasured systolic blood pressure was consistently between 160 and 170 mm Hg. The dog developed severe azotemia (BUN, 97 mg/dL; creatine, 5.8 mg/dL) 18 months after surgery, which was managed by the referring veterinarian. The dog was not reevaluated at our hospital and was subsequently lost to follow-up.
Discussion
Hypertrophic heart disease can develop as a primary or secondary condition. Primary (idiopathic) HCM is defined as LV hypertrophy in the absence of identifiable causes of concentric hypertrophy, including systemic hypertension, hyperthyroidism, aortic stenosis, or acromegaly.2 Primary HCM is rare in dogs. The etiology is unknown, although a genetic basis is suspected and a heritable form has been identified in Pointer breeds.d Secondary myocardial hypertrophy develops subsequent to conditions that cause an increase in ventricular systolic pressure or cardiac metabolic rate and oxygen consumption.3
The dog of the present report had no evidence of an LV outflow obstruction or hyperthyroidism. Serum growth hormone concentration was not measured, but the improvement of cardiac hypertrophy after discontinuation of PPA and absence of other signs of acromegaly suggested that growth hormone aberrations were not responsible for the cardiac abnormalities. Phenylpropanolamine administration can cause systemic hypertension, and chronic systemic hypertension can result in LV hypertrophy. Given that the dog of this report had received PPA for approximately 8.5 years prior to detection of the cardiac abnormalities, it seems reasonable to suspect that PPA might have contributed to the development of LV hypertrophy. Generally, systemic hypertension does not cause RV hypertrophy unless there is concurrent clinically relevant PH. It is unknown whether PPA causes PH in dogs, especially when it is administered at doses within or only slightly above the recommended range. The dog of this report had no evidence of PH.
Unfortunately, for the dog of the present report, systolic blood pressure was not measured prior to it being anesthetized at our hospital for the MRI procedure. Blood pressure was within reference limits during the initial cardiology consultation; however, the dog was sedated for the cardiologic examination and had not received PPA for 3 days at that time. Blood pressure was moderately increased (175 mm Hg) when the dog was rechecked at our hospital 5 months after surgery, but the dog was very excited during that examination and that might have artificially increased blood pressure. At that time, PPA administration had not been resumed, and there was marked regression of LV hypertrophy. If the LV hypertrophy was the result of chronic systemic hypertension independent of PPA administration, it is unlikely that the condition would have regressed in the absence of PPA administration. Thus, we strongly believe that systemic hypertension caused by chronic PPA administration contributed to the LV hypertrophy in this dog. Additionally, it is possible that chronic PPA administration led to downregulation of some adrenergic receptors, which could have contributed to the unexpected development of hypotension when the dog was anesthetized for the MRI procedure (1.5 days after discontinuation of PPA administration). Therefore, it might have been prudent to taper the dose of PPA administered prior to anesthesia.
For the dog of the present report, chronic catechol amine stimulation was thought to be an important contributing factor for the myocardial hypertrophy that affected both ventricles, although increases in ventricu lar afterload were presumably involved as well. Unfortunately, the dog's temperament and lack of information regarding its blood pressure prior to referral to our hospital made it difficult to determine whether, or how persistently, chronic PPA administration was associated with systemic hypertension. In veterinary patients, PPA is primarily used to control urinary incontinence associated with primary urethral sphincter incompetence.4 The precise mechanism by which PPA controls urinary incontinence is not completely understood; however, it is believed to involve direct stimulation of adrenergic (primarily α1) receptors and indirect stimulation of both α- and β-adrenergic receptors subsequent to an increase in the release of norepinephrine.5,6 In human patients, adverse effects associated with PPA administration include headache, dizziness, tachycardia, cardiac arrhythmias, myocardial infarction or necrosis, hypertension, acute renal failure, intracranial hemorrhage, and hemorrhagic stroke.5–10 In veterinary patients, only limited adverse effects (anorexia, vomiting, restlessness, and urine retention) have been associated with administration of PPA at the dosage (1.1 mg/kg [0.5 mg/lb], PO, q 8 h) recommended for control of urinary incontinence.5 Dogs that receive a single large dose of PPA (46 to 69 mg/kg [21 to 31 mg/lb], PO) occasionally develop more serious adverse effects, such as tachycardia, serious cardiac arrhythmias, myocardial infarction, and systemic hypertension, but those events are rare.6,10–12 The dose of PPA (1.8 mg/kg, PO) administered to the dog of this report for years was only slightly higher than the recommended dose, but the dosing interval (every 12 hours vs every 8 hours) was 1.5 times as long.
High concentrations of PPA can inhibit monoamine oxidase activity in addition to its direct and indirect effects on adrenergic receptors. Inhibition of monoamine oxidase slows the metabolism of catecholamines, which potentiates their effects.12 Chronic neurohormonal stimulation subsequent to catecholamine release and cardiomyocyte α- and β-receptor activation can initiate cardiac remodeling and result in pathological hypertrophy.13–15 Norepinephrine increases cardiac contractility, heart rate, and myocardial oxygen consumption, and the increase in cardiac work induced by norepinephrine has been implicated as a stimulus for myocardial hypertrophy.3 Norepinephrine may also have a direct trophic effect on the myocardium. In dogs, results of multiple experimental studies3,16,17 indicate that a chronic abnormally increased plasma norepinephrine concentration is positively associated with the development of cardiac hypertrophy. In another study,18 the LV weight and wall thickness increased over time in conscious dogs that received IV infusions of subhypertensive doses (ie, doses that did not increase heart rate or arterial blood pressure) of norepinephrine for 6 to 63 weeks.
The role of β1-adrenergic receptor activation in the pathogenesis of cardiac disease is well understood. Although acute activation of β1-adrenergic receptors enhances cardiac contractility, sustained activation of those receptors leads to cardiac contractility dysfunction, ventricular arrhythmias and hypertrophy, and interstitial fibrosis.15 Synthesis of myocardial proteins is enhanced by sustained activation of β-adrenergic receptors and mediated by induction of cardiac oxidative stress, stimulation of myocardial growth factors, and upregulation of nuclear proto-oncogenes along with activation of phosphatidylinositol 3-kinase.19 As heart failure progresses, signaling of β1-adrenergic receptors becomes compromised and the proportion of α1-adrenergic receptors in the myocardium increases.14 Stimulation of these myocardial α1-adrenergic receptors leads to a positive inotropic effect and has been implicated in the development of cardiac hypertrophy.12 We believed that the pathophysiologic mechanisms resulting from chronic catecholamine activation induced by long-term PPA administration were responsible for the development of severe cardiac hypertrophy in the dog of the present report. Concentric ventricular hypertrophy attributed to excessive catecholamine activation has been described in dogs with pheochromocytoma.20 Likewise, some human patients with pheochromocytoma develop concentric ventricular hypertrophy similar to HCM, whereas others develop dilated or tachycardia-induced cardiomyopathy.20
Although persistent systemic hypertension associated with long-term PPA administration was not documented for the dog of the present report, we believe it was likely and contributed to the development of LV hypertrophy. In the human medical literature, results of a meta-analysis7 indicate that oral ingestion of PPA causes a significant increase in systolic, diastolic, and mean blood pressure. Hypertension (systolic blood pressure, > 180 mm Hg) has also been reported in dogs following ingestion of PPA, either as a result of acute intoxication11,12 or in experimental settings.21,22 High vascular resistance causes an increase in cardiac afterload, to which the myocardium adapts by the development of concentric LV hypertrophy.23 In a study24 in which echocardiographic measurements were compared between 30 dogs with untreated systemic hypertension and 28 age-and body weight–matched healthy dogs, 14 (47%) hyper- tensive dogs had diastolic and systolic LV free-wall and interventricular septum thicknesses that were significantly greater than those of healthy dogs, whereas the remaining 16 hypertensive dogs had no evidence of LV hypertrophy. Interestingly, the magnitude of LV hypertrophy for the dog of the present report was substantially greater than that described for any of the hypertensive dogs of that study.24
The dog of the present report was not hypertensive at the time LV hypertrophy was diagnosed; however, PPA administration had been discontinued several days prior to that diagnosis. At the recheck examination 5 months later, the systolic blood pressure was 175 mm Hg, which was considered normal in light of the dog's excitable demeanor, and the myocardial hypertrophy had almost completely resolved. It is important to note that the dog did not receive PPA during the 5 months after hospital discharge, but PPA administration was resumed, albeit at a lower dosage (1 mg/kg, PO, q 24 h), shortly after the 5-month recheck appointment. At the recheck examination 10 months after diagnosis (approx 5 months following resumption of PPA administration), the dog had severe systemic hypertension (systolic blood pressure, 226 mm Hg), and the thickness of both the right ventricle and LV was greater than that measured at the 5-month recheck appointment. Phenylpropanolamine has a half-life of approximately 6 hours5 and was administered to the dog 4 hours before the 10-month recheck appointment. Therefore, the dog likely still had plasma PPA concentrations that might (in addition to its excitable nature) have contributed to the hypertension, and the hypertension likely contributed to recurrence of the LV hypertrophy.
Chronic renal disease could have also contributed to the development of hypertension in the dog of the present report. In veterinary patients, the relationship between renal disease and hypertension is ill-defined and likely multifactorial, with alterations in renal processing of sodium and the renin-angiotensin-aldosterone axis likely causative factors in the development of hypertension.25 Glomerular hypertension can lead to protein loss through the glomerular capillaries, and prolonged glomerular hypertension and proteinuria gradually impair renal function, thereby providing a feedback loop for further exacerbation of hypertension.25 The dog of this report had a history of abnormally increased BUN and creatinine concentrations prior to referral to our hospital. Also, the referring veterinarian had treated the dog for a presumptive ascending urinary tract infection on the basis of bacteriuria and proteinuria in a free-catch urine sample, a diagnosis that was not confirmed by bacterial culture and susceptibility testing results. Because 40% to 87% of dogs and cats with renal disease are hypertensive,26,e it is possible that the dog of this report had hypertension induced by renal disease, particularly given that it was proteinuric prior to referral to our hospital. Phenylpropanolamine is renally excreted; therefore, its effects might have been potentiated or prolonged if the dog had impaired renal function. Unfortunately, the dog's renal function was not evaluated following referral for evaluation and management of the pelvic limb para-aresis and subsequent diagnosis of LV hypertrophy. The dog developed marked azotemia 1.5 years after diagnosis of LV hypertrophy, which was managed by the referring veterinarian. However, it seems unlikely that systemic hypertension induced by renal disease was the sole cause of LV hypertrophy in this dog, especially because the myocardial changes had largely resolved at the time of the 5-month recheck appointment without the dog receiving any treatments specific for chronic renal disease.
The dog of the present report did not have a documented history of any arrhythmia prior to diagnosis of LV hypertrophy, despite having received PPA for almost its entire life. However, there was no way for us to rule out that the dog did not have intermittent arrhythmias prior to diagnosis of cardiac disease. The ventricular tachyarrhythmia detected while the dog was hospitalized was likely associated with excessive catecholamine release and myocardial hypertrophy. The myocardium becomes more sensitive to adrenergic stimulation and susceptible to ischemic injury as hypertrophy progresses.12 During the hemilaminectomy procedure, the dog became hypotensive and received 2 doses of ephedrine and ketamine as an adjunct analgesic. Ephedrine causes the release of norepinephrine, which indirectly stimulates α- and β-adrenergic receptors and leads to vasoconstriction and an increase in heart rate, coronary blood flow, and blood pressure.27 Tachycardia increases myocardial oxygen demand, which increases the risk of an arrhythmia. Ephedrine is not recommended for patients with cardiovascular disease or hypertension because it can exacerbate those conditions.27,28 Ketamine is an N-methyl-d-aspartate receptor antagonist and, as such, increases cardiac output and heart rate secondary to an increase in sympathetic tone and myocardial oxygen consumption. Thus, ketamine is likewise not recommended for patients with underlying cardiovascular disease.29 The dog of the present report had no history or evidence of compromised cardiovascular function prior to its being anesthetized for the MRI procedure; therefore, the attending anesthetist had no reason to avoid administration of ephedrine or ketamine to the patient. In fact, the residual effects of those 2 medications might have aided the detection of cardiac disease because the arrhythmias presumably developed secondary to an increase in the workload of a severely hypertrophied myocardium. Other factors that might have contributed to the arrhythmia include alterations in the number or sensitivity of adrenergic receptors, catecholamine-induced myocardial cellular damage, underlying structural heart disease, and local electrolyte abnormalities. Myocardial injury or infarction could not be ruled out because cardiac biomarkers were not measured for this dog.
For the dog of the present report, hypertrophic cardiac disease was believed to be the result of chronic catecholamine stimulation from long-term PPA administration on the basis of the extent of LV hypertrophy as well as the increase in the thickness of the RV wall and interatrial septum. Systemic hypertension induced by PPA might have also contributed to the LV hypertrophy. Regardless of the mechanism, the fact that the LV hypertrophy almost completely resolved when PPA adminis- tration was discontinued and then recurred after it was resumed strongly suggested the drug was an important contributing factor to the cardiac disease of this patient. In retrospect, because PPA has the potential to down-regulate adrenergic receptors, tapering the dosage of the drug prior to its discontinuation may have been advisable to minimize abrupt changes in physiologic processes. To our knowledge, the present report was the first to describe severe cardiac structural changes and arrhythmias associated with chronic PPA administration in a dog. Given our experience with this dog, we recommend that, for patients receiving PPA on a long-term basis, the dosing schedule should be reviewed and blood pressure should be monitored frequently. Such patients should also undergo periodic echocardio-graphic evaluation to monitor for myocardial hypertrophy. The use of other adrenergic agonists should also be avoided for patients receiving PPA.
Acknowledgments
The authors thank Dr. Andrew Linklater for assistance with manuscript preparation.
ABBREVIATIONS
| bpm | Beats per minute |
| CRI | Constant rate infusion |
| HCM | Hypertrophic cardiomyopathy |
| ICU | Intensive care unit |
| LV | Left ventricular or ventricle |
| MAP | Mean arterial pressure |
| PH | Pulmonary hypertension |
| PPA | Phenylpropanolamine |
| RV | Right ventricular |
Footnotes
Proin, PRN Pharmacal, Pensacola, Fla.
Plasmalyte-A, Baxter Healthcare, Deerfield, Ill.
Incurin, Merck Animal Health, Madison, NJ.
Sisson DD. Heritability of idiopathic myocardial hypertrophy and dynamic subaortic stenosis in Pointer dogs (abstr). J Vet Intern Med 1995;9:118.
Francey T, Cowgill LD. Hypertension in dogs with severe acute renal failure (abstr). J Vet Intern Med 2004;18:418.
References
1. Cornell CC, Kittleson MD, Della Torre P, et al. Allometric scaling of M-mode cardiac measurements in normal adult dogs. J Vet Intern Med 2004;18:311–321.
2. Fox P. Feline cardiomyopathies. In: Fox P, Sisson D, Moise N, eds. Textbook of canine and feline cardiology principles and clinical practice. 2nd ed. Philadelphia: Saunders-Elsevier, 1999;624–641.
3. Patel MB, Loud AV, King BD, et al. Global myocardial hypertrophy in conscious dogs with chronic elevation of plasma norepinephrine levels. J Mol Cell Cardiol 1989;21(suppl 5):49–61.
4. Claeys S, Rustichelli F, Noël S. Clinical evaluation of a single daily dose of phenylpropanolamine in the treatment of urethral sphincter mechanism incompetence in the bitch. Can Vet J 2011;52:501–505.
5. Plumb DC. Phenylpropanolamine. In: Plumb's veterinary drug handbook. 7th ed. Stockholm, Wis: Pharma Vet Inc, 2008;726–727.
6. Crandell JM, Ware WA. Cardiac toxicity from phenylpropanolamine overdose in a dog. J Am Anim Hosp Assoc 2005;41:413–420.
7. Salerno SM, Jackson JL, Berbano EP. The impact of oral phenylpropanolamine on blood pressure: a meta-analysis and review of the literature. J Hum Hypertens 2005;19:643–652.
8. Barst RJ, Abenhaim L. Fatal pulmonary arterial hypertension associated with phenylpropanolamine exposure. Heart 2004;90:e42.
9. Thomas SH, Clark CK, Allen R, et al. A comparison of the cardiovascular effects of phenylpropanolamine and phenylephrine containing proprietary cold remedies. Br J Clin Pharmacol 1991;32:705–711.
10. Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000;343:1826–1832.
11. Peterson KL, Lee JA, Hovda LR. Phenylpropanolamine toxicosis in dogs: 170 cases (2004–2009). J Am Vet Med Assoc 2011;239:1463–1469.
12. Ginn JA, Bentley E, Stepien RL. Systemic hypertension and hypertensive retinopathy following PPA overdose in a dog. J Am Anim Hosp Assoc 2013;49:46–53
13. Long KM, Kirby R. An update on cardiovascular adrenergic receptor physiology and potential pharmacological applications in veterinary critical care. J Vet Emerg Crit Care 2008;18:2–25.
14. Woodcock EA, Du XJ, Reichelt ME, et al. Cardiac α-1 adrenergic drive in pathological remodeling. Cardiovasc Res 2008;77:452–462.
15. Vidal M, Wieland T, Lohse MJ, et al. β-Adrenergic receptor stimulation causes cardiac hypertrophy via Gβγ/ERK-dependent pathway. Cardiovasc Res 2012;96:255–264.
16. King BD, Sack D, Kichuck M, et al. Absence of hypertension despite chronic marked elevations in plasma norepinephrine in conscious dogs. Hypertension 1987;9:582–590.
17. Stewart JM, Patel MB, Wang J, et al. Chronic elevation of norepinephrine in conscious dogs produces hypertrophy with no loss of LV reserve. Am J Physiol 1992;262:H331–H339
18. Laks MM, Morady F, Swan HJ. Myocardial hypertrophy produced by chronic infusion of subhypertensive doses of norepinephrine in the dog. Chest 1973;64:75–78.
19. Osadchii OE. Cardiac hypertrophy induced by sustained β-adrenoreceptor activation: pathophysiological aspects. Heart Fail Rev 2007;12:66–86.
20. Edmondson EF, Bright JM, Halsey CH, et al. Pathologic and cardiovascular characterization of pheochromocytoma-associated cardiomyopathy in dogs. Vet Pathol 2015;52:338–343.
21. Vick J, Weiss L, Ellis S. Cardiovascular studies of phenylpropanolamine. Arch Int Pharmacodyn Ther 1994;327:13–24.
22. Carofiglio F, Hamaide AJ, Farnir F, et al. Evaluation of the urodynamic and hemodynamic effects of orally administered phenylpropanolamine and ephedrine in female dogs. Am J Vet Res 2006;67:723–730.
23. Atkins C. Cardiac manifestations of systemic and metabolic disease. In: Fox P, Sisson D, Moise N, eds. Textbook of canine and feline cardiology principles and clinical practice. 2nd ed. Philadelphia: Saunders-Elsevier, 1999;757–759.
24. Misbach C, Gouni V, Tissier RI. Echocardiographic and tissue Doppler imaging alterations associated with spontaneous canine systemic hypertension. J Vet Intern Med 2011;25:1025–1035.
25. Stepien RL. Pathophysiology of systemic hypertension and blood pressure assessment. In: Ettinger SG, Feldman EC, eds. Textbook of veterinary internal medicine. 7th ed. St Louis: Saunders-Elsevier, 2010;577–582.
26. Panteleo V, Francey T, Fischer JR, et al. Application of hemodialysis for the management of acute uremia in cats: 119 cases (1993–2003). J Vet Intern Med 2004;18:418.
27. Plumb DC. Ephedrine. In: Plumb's veterinary drug handbook. 7th ed. Stockholm, Wis: Pharma Vet Inc, 2008;510–512.
28. Adamson PB, Suarez J, Ellis E, et al. Ephedrine increases ventricular arrhythmias in conscious dogs after myocardial infarction. J Am Coll Cardiol 2004;44:1675–1678.
29. Plumb DC. Ketamine. In: Plumb's veterinary drug handbook. 7th ed. Stockholm, Wis: Pharma Vet Inc, 2008;762–768.
