Long-term incidence and risk of noncardiovascular and all-cause mortality in apparently healthy cats and cats with preclinical hypertrophic cardiomyopathy.

BACKGROUND: Epidemiologic knowledge regarding noncardiovascular and all-cause mortality in apparently healthy cats (AH) and cats with preclinical hypertrophic cardiomyopathy (pHCM) is limited, hindering development of evidence-based healthcare guidelines. OBJECTIVES: To characterize/compare incidence rates, risk, and survival associated with noncardiovascular and all-cause mortality in AH and pHCM cats. ANIMALS: A total of 1730 client-owned cats (722 AH, 1008 pHCM) from 21 countries. METHODS: Retrospective, multicenter, longitudinal, cohort study. Long-term health data were extracted by medical record review and owner/referring veterinarian interviews. RESULTS: Noncardiovascular death occurred in 534 (30.9%) of 1730 cats observed up to 15.2 years. Proportion of noncardiovascular death did not differ significantly between cats that at study enrollment were AH or had pHCM (P = .48). Cancer, chronic kidney disease, and conditions characterized by chronic weight-loss-vomiting-diarrhea-anorexia were the most frequently recorded noncardiovascular causes of death. Incidence rates/risk of noncardiac death increased with age in AH and pHCM. All-cause death proportions were greater in pHCM than AH (65% versus 40%, respectively; P < .001) because of higher cardiovascular mortality in pHCM cats. Comparing AH with pHCM, median survival (study entry to noncardiovascular death) did not differ (AH, 9.8 years; pHCM, 8.6 years; P = .10), but all-cause survival was significantly shorter in pHCM (P = .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: All-cause mortality was significantly greater in pHCM cats due to disease burden contributed by increased cardiovascular death superimposed upon noncardiovascular death.

Vitamin D is a regulator of endothelial nitric oxide synthase and arterial stiffness in mice.

The vitamin D hormone 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is essential for the preservation of serum calcium and phosphate levels but may also be important for the regulation of cardiovascular function. Epidemiological data in humans have shown that vitamin D insufficiency is associated with hypertension, left ventricular hypertrophy, increased arterial stiffness, and endothelial dysfunction in normal subjects and in patients with chronic kidney disease and type 2 diabetes. However, the pathophysiological mechanisms underlying these associations remain largely unexplained. In this study, we aimed to decipher the mechanisms by which 1,25(OH)2D3 may regulate systemic vascular tone and cardiac function, using mice carrying a mutant, functionally inactive vitamin D receptor (VDR). To normalize calcium homeostasis in VDR mutant mice, we fed the mice lifelong with the so-called rescue diet enriched with calcium, phosphate, and lactose. Here, we report that VDR mutant mice are characterized by lower bioavailability of the vasodilator nitric oxide (NO) due to reduced expression of the key NO synthesizing enzyme, endothelial NO synthase, leading to endothelial dysfunction, increased arterial stiffness, increased aortic impedance, structural remodeling of the aorta, and impaired systolic and diastolic heart function at later ages, independent of changes in the renin-angiotensin system. We further demonstrate that 1,25(OH)2D3 is a direct transcriptional regulator of endothelial NO synthase. Our data demonstrate the importance of intact VDR signaling in the preservation of vascular function and may provide a mechanistic explanation for epidemiological data in humans showing that vitamin D insufficiency is associated with hypertension and endothelial dysfunction.

Effects of treatment with ivabradine and atenolol on reproducibility of echocardiographic indices of left heart size and function in healthy cats.

OBJECTIVES: Data on reproducibility of echocardiographic indices in cats are commonly derived from studies in healthy, non-treated animals. However, medical treatment may alter reproducibility of such data possibly influencing interpretation of results of clinical trials assessing the effects of drugs on cardiovascular function. The objectives were therefore to investigate the effects of ivabradine and atenolol on reproducibility of echocardiographic indices of left heart function. ANIMALS: Eight healthy cats. METHODS: Repeated echocardiographic examinations were performed by two observers in mildly sedated cats at baseline and after four weeks of treatment (Group 1, ivabradine 0.3 mg/kg q12 h PO, n = 4; Group 2, atenolol 6.25 mg/cat q12 h PO, n = 4) in a prospective, double-blind, randomized study. Test reliability was determined by estimating measurement variability, within-day interobserver variability, and between-day intraobserver variability of all echocardiographic indices. Variability was expressed as coefficient of variation (CV) and the absolute value below which the difference between two measurements lay with 95% probability. Effects of treatments on variability were compared using linear mixed effects models ANOVA and Fisher's exact test. RESULTS: Overall, CVs ranged from 0.5 to 50.6% at baseline, 0.5-45.5% after ivabradine, and 0.5-23.3% after atenolol. Reproducibility of all variables determined did neither improve nor worsen consistently after either treatment although atenolol exhibited a tendency toward higher reliability with none of the CVs exceeding 24% as compared to ivabradine. CONCLUSIONS: Treatment of healthy cats with either atenolol or ivabradine had only minor effects on reproducibility of echocardiographic data. Whether these findings can be extrapolated to cats with hypertrophic cardiomyopathy deserves further study.

Effects of ivabradine on heart rate and left ventricular function in healthy cats and cats with hypertrophic cardiomyopathy.

OBJECTIVE: To evaluate the effects of the pacemaker funny current (I(f)) inhibitor ivabradine on heart rate (HR), left ventricular (LV) systolic and diastolic function, and left atrial performance in healthy cats and cats with hypertrophic cardiomyopathy (HCM). ANIMALS: 6 healthy cats and 6 cats with subclinical HCM. PROCEDURES: Anesthetized cats underwent cardiac catheterization and were studied over a range of hemodynamic states induced by treatment with esmolol (200 to 400 µg/kg/min, IV), esmolol and dobutamine (5 µg/kg/min, IV), ivabradine (0.3 mg/kg, IV), and ivabradine and dobutamine. Left ventricular systolic and diastolic function, cardiac output, and left atrial function were studied via catheter-based methods and echocardiography. RESULTS: Treatment with ivabradine resulted in a significant reduction of HR, rate-pressure product, and LV contractile function and a significant increase in LV end-diastolic pressure, LV end-diastolic wall stress, and LV relaxation time constant (tau) in cats with HCM. Concurrent administration of ivabradine and dobutamine resulted in a significant increase of LV contractility and lusitropy, with blunted chronotropic effects of the catecholamine. Left atrial performance was not significantly altered by ivabradine in cats with HCM. Regression analysis revealed an association between maximum rate of LV pressure rise and tau in cats with HCM. CONCLUSIONS AND CLINICAL RELEVANCE: Ivabradine had significant effects on several cardiovascular variables in anesthetized cats with HCM. Studies in awake cats with HCM are needed to clinically validate these findings.

Pharmacodynamic effects of ivabradine, a negative chronotropic agent, in healthy cats.

OBJECTIVE: To determine the pharmacodynamic effects of oral ivabradine in cats. ANIMALS: Eight healthy, adult domestic short hair cats. METHODS: Each cat underwent four study periods of 24 h, receiving either one dose of placebo or ivabradine (0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) in a single-blind randomized crossover study. Clinical tolerance was assessed hourly for the first 8 h, at 12 h, and at the end of the 24-h study period. Heart rate and blood pressure were monitored continuously for 18-24 h via radiotelemetry after each treatment. Response to stress (acoustic startle) was studied before (t = 0) and after treatment (t = 4 h). Statistical comparisons were made using a linear mixed models and 1-way and 2-way repeated measures ANOVA. RESULTS: Heart rate (min(-1)) decreased significantly (P < 0.05) in a dose-dependent manner with peak negative chronotropic effects observed 3 h after ivabradine (mean ± SD; placebo, 144 ± 20; ivabradine 0.1 mg/kg, 133 ± 22; ivabradine 0.3 mg/kg, 112 ± 20; and ivabradine 0.5 mg/kg, 104 ± 11). Heart rate (min(-1)) was still reduced (P < 0.05) 12 h after ivabradine (0.3 mg/kg; 128 ± 18 and 0.5 mg/kg; 124 ± 16) compared to placebo (141 ± 21). The tachycardic response to acoustic startle was significantly (P < 0.01) blunted at all 3 doses of ivabradine. Myocardial oxygen consumption estimated by the rate-pressure product was significantly reduced (P < 0.05) for all doses of ivabradine. No effect of ivabradine on systolic, diastolic, and mean blood pressure was identified and no clinically discernable side effects were observed. CONCLUSION: These findings indicate that a single oral dose of ivabradine predictably lowers heart rate, blunts the chronotropic response to stress, and is clinically well tolerated in healthy cats. This makes ivabradine potentially interesting in the treatment of feline heart disease where ischemia is of pathophysiologic importance.

Comparison of Doppler-derived aortic velocities obtained from various transducer sites in healthy dogs and cats.

In normal dogs and dogs with subaortic stenosis, it is known that the subcostal transducer site provides higher left ventricular ejection velocities than does the left apical site. We hypothesized that aortic flow velocities could also be obtained from the right parasternal long-axis view, optimized for the placement of the Doppler cursor as parallel as possible into the aortic root. In 15 healthy dogs and 13 healthy cats, high-pulsed repetition frequency Doppler flow velocity measurements in the proximal aorta were performed using two-dimensional echocardiographic guidance. The mean [ +/- standard error of the mean (SEM)] peak aortic flow velocities in healthy dogs were as follows: subcostal site 1.46 +/- 0.05 m/s; apical site 1.12 +/- 0.06 m/s; right parasternal long-axis site 1.09 +/- 0.05 m/s. In healthy cats, the following peak aortic flow velocities were observed: apical site 0.87 +/- 0.03m/s; right parasternal long-axis site 0.87 +/- 0.03 m/s. Aortic flow velocities obtained from the subcostal site were significantly higher in healthy dogs than those obtained from the left apical and right parasternal long-axis site (P< 0.001). There was no statistical difference between the peak aortic flow velocities obtained from right parasternal long-axis and left apical transducer position in all groups. We conclude therefore that right parasternal long-axis and left apical-derived aortic flow velocities are similar and may be used interchangeably in healthy dogs and cats.