猫肥厚型心肌病与心肌纤维化

肥厚型心肌病是猫最常见的原发性心脏疾病,典型特征为心脏左心室肥厚。心肌纤维化是猫肥厚型心肌病的标志性病理变化,其可导致心脏功能障碍和节律异常,是心肌病患猫预后不良的重要因素。对于猫肥厚型心肌病与心肌纤维化,目前缺乏针对性治疗,新型治疗方法亟需开发。本综述总结了猫肥厚型心肌病的病理特征以及目前关于猫心肌纤维化发病机制的研究进展,拟通过探索心肌纤维化的发病机制,从而为猫肥厚型心肌病新型治疗药物的开发寻找突破点。     

Hypertrophic Cardiomyopathy. Clinical and Pathologic Correlates

Hypertrophic cardiomyopathy is a primary myocardial disease with a wide range of clinical and morphologic characteristics. It is characterized by increased cardiac mass associated with a non-dilated, hypertrophied left ventricle. Phenotypic variability is substantial and includes both diffuse and segmental forms of left ventricular hypertrophy. Histopathologic features consist of myofiber disorganization, intramural arteriosclerosis, and pathologic fibrosis and matrix connective tissue. Associated functional derangements include dynamic obstruction to left and right ventricular outflow and diastolic dysfunction, including heart failure.     

Transient Myocardial Thickening in Cats Associated with Heart Failure

Background

Cats with hypertrophic cardiomyopathy (HCM) and congestive heart failure (CHF) can have resolution of both left ventricular hypertrophy and CHF.

Objectives

To describe the clinical characteristics of cats with transient myocardial thickening (TMT) and CHF compared with a control population of cats without resolution of HCM.

Animals

A total of 21 cats with TMT, 21 cats with HCM.

Methods

Retrospective study. Clinical records at 4 veterinary centers were searched for TMT cases and a control group of cats with HCM and CHF. TMT was defined as initial maximal left ventricular wall thickness (LVWT) ≥6 mm with left‐sided CHF, with subsequent resolution of CHF, reduction in left atrium/aorta (LA/Ao), and LVWT<5.5 mm. HCM was defined as persistent LVWT ≥6 mm.

Results

Cats with TMT were younger (2 [0.4–11.4] years) than cats with HCM (8 [1.6–14] years) (P < 0.0001), and antecedent events were more common (15/21 versus 6/21, respectively) (P = 0.01). In cats with TMT, LVWT normalized from 6.8 [6.0–9.7] mm to 4.8 [2.8–5.3] mm and LA/Ao decreased from 1.8 [1.6–2.3] to 1.45 [1.2–1.7] after a mean interval of 3.3 (95% CI: 1.8–4.7) months. CHF recurred in 1 of 21 TMT and 15 of 21 cats with HCM. Cardiac treatment was discontinued in 20 of 21 cats with TMT and 0 of 21 HCM cats. All cats with TMT survived, whereas 8 of 19 cats with HCM died during the study period.

Conclusions and Clinical Importance

TMT occurs in younger cats, and antecedent events are common. The prognosis is better in cats with CHF associated with TMT than HCM.     

Analysis of 8 Sarcomeric Candidate Genes for Feline Hypertrophic Cardiomyopathy Mutations in Cats with Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats. Causative mutations have been identified in the Maine Coon (MC) and Ragdoll breed in the cardiac myosin binding protein C gene (MYBPC3). HCM is thought to be inherited in other breeds.
Hypothesis: That a causative mutation for HCM in the British Shorthair (BSH), Norwegian Forest (NWF), Siberian, Sphynx, or MC cats would be identified in the exonic and splice site regions of 1 of 8 genes associated with human familial HCM.
Animals: Three affected BSH, NWF, Siberians, Sphynx, 2 MC (without the known MC mutation), and 2 Domestic Shorthair cats (controls) were studied.
Methods: Prospective, observational study. Exonic and splice site regions of the genes encoding the proteins cardiac troponin I, troponin T, MYBPC3, cardiac essential myosin light chain, cardiac regulatory myosin light chain, α tropomyosin, actin, and β–myosin heavy chain were sequenced. Sequences were compared for nucleotide changes between affected cats, the published DNA sequences, and control cats. Changes were considered to be causative for HCM if they involved a conserved amino acid and changed the amino acid to a different polarity, acid-base status, or structure.
Results: A causative mutation for HCM was not identified, although several single nucleotide polymorphisms were detected.
Conclusions and Clinical Importance: Mutations within these cardiac genes do not appear to be the only cause of HCM in these breeds. Evaluation of additional cardiac genes is warranted to identify additional molecular causes of this feline cardiac disease.     

Symmetric Dimethylarginine in Cats with Hypertrophic Cardiomyopathy and Diabetes Mellitus

Background

Symmetric dimethylarginine (SDMA) has been increasingly used as a marker of early chronic kidney disease (CKD) in cats, but little is known about the influence of comorbidities on SDMA in this species.

Hypothesis

Hypertrophic cardiomyopathy (HCM) and diabetes mellitus (DM), independently of CKD, are associated with changes in serum SDMA.

Animals

Ninety‐four cats (17 with CKD, 40 with HCM, 17 with DM, and 20 healthy controls).

Methods

Case‐control study. Clinical examination, echocardiography, ECG, blood pressure, CBC, biochemistry, thyroxine, and SDMA measurement were performed. Urinalysis was performed in controls and cats with CKD and DM. Analysis of variance was used to compare overall differences in the log‐transformed SDMA data among groups. A random forest algorithm was applied to explore which clinical and other factors influenced serum SDMA.

Results

Median (range) serum SDMA for the renal group (positive control) was 19 (10–93) μg/dL, whereas for the control group (negative control), it was 10 (5–15) μg/dL. For the cardiac and diabetic groups, serum SDMA was 9 (4–24) μg/dL and 7 (3–11) μg/dL, respectively. The renal group had significantly higher SDMA concentrations and the diabetic group significantly lower SDMA concentrations compared to all other groups.

Conclusions and Clinical Importance

Serum SDMA concentrations in cats with HCM were not significantly different from those of healthy control cats. Cats with DM, however, had significantly lower SDMA concentrations than controls, a finding that needs further investigation and should be kept in mind when evaluating renal function of cats with this endocrinopathy.     

Cardiac Biomarkers in Hyperthyroid Cats

Background

Hyperthyroidism has substantial effects on the circulatory system. The cardiac biomarkers NT‐proBNP and troponin I (cTNI) have proven useful in identifying cats with myocardial disease but have not been extensively investigated in hyperthyroidism.

Hypothesis

Plasma NT‐proBNP and cTNI concentrations are higher in cats with primary myocardial disease than in cats with hyperthyroidism and higher in cats with hyperthyroidism than in healthy control cats.

Animals

Twenty‐three hyperthyroid cats, 17 cats with subclinical hypertrophic cardiomyopathy (HCM), and 19 euthyroid, normotensive healthy cats ≥8 years of age. Fourteen of the hyperthyroid cats were re‐evaluated 3 months after administration of radioiodine (¹³¹I).

Methods

Complete history, physical examination, complete blood count, serum biochemistries, urinalysis, blood pressure measurement, serum T4 concentration, plasma concentrations of NT‐proBNP and cTNI, and echocardiogram were obtained prospectively from each cat.

Results

Hyperthyroid cats and cats with HCM had plasma NT‐proBNP and cTNI concentrations that were significantly higher than those of healthy cats, but there was no significant difference between hyperthyroid cats and cats with HCM with respect to the concentration of either biomarker. In hyperthyroid cats that were re‐evaluated 3 months after ¹³¹I treatment, plasma NT‐proBNP and cTNI concentrations as well as ventricular wall thickness had decreased significantly.

Conclusions and Clinical Importance

Although there may be a role for NT‐proBNP in monitoring the cardiac response to treatment of hyperthyroidism, neither NT‐proBNP nor cTNI distinguish hypertrophy associated with hyperthyroidism from primary HCM. Therefore, the thyroid status of older cats should be ascertained before interpreting NT‐proBNP and cTNI concentrations.     

Immunohistochemical Expression of Potential Therapeutic Targets in Canine Thyroid Carcinoma

Background

Thyroid carcinoma is a common endocrine tumor in the dog. Local invasive growth frequently precludes surgical excision and, in up to 38% of dogs, the tumor has already metastasized by the time of diagnosis. Therefore, it is important to investigate new treatment modalities that may be useful for the large number of dogs with inoperable tumors or metastatic disease.

Hypothesis/Objectives

To investigate the immunohistochemical expression of potential therapeutic targets in canine thyroid tumors.

Animals

74 dogs with thyroid neoplasia.

Methods

Immunohistochemistry was performed for thyroglobulin, calcitonin, vascular endothelial growth factor (VEGF), p53, cycloxygenase‐2 (cox‐2), and P‐glycoprotein (P‐gp).

Results

Fifty‐four (73%) tumors were classified as follicular cell thyroid carcinomas (FTCs) and 20 (27%) as medullary thyroid carcinomas (MTCs). Eighty percent of FTCs and all MTCs had a high percentage (76–100%) of neoplastic cells immunopositive for VEGF. Thirteen percent of FTCs and 50% of MTCs expressed cox‐2. Seven percent of FTCs and 70% of MTCs expressed P‐gp. No tumor was immunopositive for p53 expression. Expression of VEGF (P = .034), cox‐2 (P = .013), and P‐gp (P < .001) was significantly higher in MTCs compared to FTCs.

Conclusions and Clinical Importance

VEGF is a potential therapeutic target in both FTC and MTC in dogs. Cox‐2 and P‐gp may be useful molecular targets in canine MTC.     

Acute Effects of Ivabradine on Dynamic Obstruction of the Left Ventricular Outflow Tract in Cats with Preclinical Hypertrophic Cardiomyopathy

Background

Ivabradine is a negative chronotropic drug with minimal effects on central hemodynamics. Its effect on dynamic obstruction of the left ventricular outflow tract (LVOT) in cats with hypertrophic cardiomyopathy (HCM) remains unknown.

Hypothesis/Objectives

Ivabradine reduces dynamic obstruction of the LVOT in cats with HCM.

Animals

Twenty‐eight client‐owned cats with preclinical HCM and dynamic LVOT obstruction.

Methods

Randomized, double‐blind, active‐control single dose study. Cats received a single dose of either ivabradine (0.3 mg/kg PO) or atenolol (2 mg/kg PO). Heart rate, echocardiographic variables, and systolic blood pressure (SBP) were recorded before and 3 hours after drug administration. Statistical comparisons were made using ANCOVA.

Results

Peak velocity in the LVOT was significantly decreased compared to baseline for both drugs; however, the effect was more prominent with atenolol (mean reduction 2.53 m/s; 95% CI 2.07–3.13 m/s) compared to ivabradine (mean reduction 0.32 m/s; 95% CI −0.04 to 0.71 m/s; P < .0001). Echocardiographic indices of systolic function were largely unchanged by ivabradine, but significantly reduced by atenolol.

Conclusions and Clinical Importance

A single dose of ivabradine decreases dynamic LVOT obstruction in cats with HCM, but the clinical effect is negligible and inferior compared to that achieved by atenolol.     

Cardiac Troponin I and T as Prognostic Markers in Cats with Hypertrophic Cardiomyopathy

Background

Myocardial injury detected by cardiac troponin I and T (cTnI and cTnT) in cardiac disease is associated with increased risk of death in humans and dogs.

Hypothesis

Presence of myocardial injury predicts long‐term death in cats with hypertrophic cardiomyopathy (HCM), and ongoing myocardial injury reflects change in left ventricular wall thickness over time.

Animals

Thirty‐six cats with primary HCM.

Methods

Prospective cohort study. Cats with HCM were included consecutively and examined every 6 months. Echocardiography, ECG, blood pressure, and serum cTnI and cTnT were evaluated at each visit. Cox proportional hazards regression analysis was performed to evaluate prognostic potential of serum troponin concentrations at admission and subsequent examinations. Correlations were used to examine associations between troponin concentrations and cardiac hypertrophy.

Results

Troponin concentrations at admission were median [range] 0.14 [0.004–1.02] ng/mL for cTnI, and 13 [13–79.5] ng/L for cTnT. Both were prognostic for death (P = .032 and .026) as were the last available concentrations of each (P = .016 and .003). The final cTnT concentration was a significant predictor of death even when adjusting for the admission concentration (P = .043). In a model containing both markers, only cTnT remained significant (P = .043). Left ventricular free wall thickness at end‐diastole (LVFWd) at admission was correlated with cTnI at admission (r = 0.35, P = .035), however no significant correlations (r = 0.2–0.31, P = .074–.26) were found between changes in troponin concentrations and left ventricular thickness over time.

Conclusions and Clinical Importance

Myocardial injury is part of the pathophysiology leading to disease progression and death. Low sensitivities and specificities prevent outcome prediction in individual cats.     

Plasma Cardiac Troponin I Concentration and Cardiac Death in Cats with Hypertrophic Cardiomyopathy

Background

The use of cardiac biomarkers to assist in the diagnosis of occult and symptomatic hypertrophic cardiomyopathy (HCM) in cats has been established. There is limited data describing their prognostic utility in cats with HCM.

Hypothesis

Circulating concentrations of N‐terminal B‐type natriuretic peptide (NTproBNP) and cardiac troponin I (cTnI) predict cardiac death in cats with HCM.

Animals

Forty‐one cats diagnosed with HCM at a veterinary teaching hospital, between February 2010 and May 2011.

Methods

Prospective investigational study. Plasma samples were collected from cats diagnosed with HCM and concentrations of NTproBNP and cTnI were analyzed at a commercial laboratory. Echocardiographic measurements from the day of blood sampling were recorded. Long‐term outcome data were obtained. Associations with time to cardiac death were analyzed using Cox proportional hazards models.

Results

When controlling for the presence/absence of heart failure and echocardiographic measures of left atrial size and function, cTnI > 0.7 ng/mL was independently associated with time to cardiac death. In univariable analysis, NTproBNP > 250 pmol/L was associated with cardiac death (P = .023), but this did not remain significant (P = .951) when controlling for the effect of clinical signs or left atrial size/function.

Conclusions and Clinical Importance

Plasma concentration of cTnI (cutoff >0.7 ng/mL) is a predictor of cardiac death in cats with HCM that is independent of the presence of heart failure or left atrial dilatation.     

A Randomized Study Assessing the Effect of Diet in Cats with Hypertrophic Cardiomyopathy

Background

Diet might influence progression of hypertrophic cardiomyopathy (HCM).

Objective

To investigate whether diet composition could alter clinical, biochemical, or echocardiographic variables in cats with HCM.

Animals

Twenty‐nine cats with HCM (International Small Animal Cardiac Health Council stage 1b) examined at a university teaching hospital.

Methods

Randomized, placebo‐controlled trial. After physical examination, echocardiogram, and blood collection, cats were randomized to 1 of 3 diets, which varied in carbohydrate and fat content and ingredients. Measurements were repeated after 6 months.

Results

There were no significant differences among the 3 groups at baseline. After 6 months, there were no significant changes in the primary endpoints, left ventricular free wall (Group A, P = .760; Group B, P = .475; Group C, P = .066) or interventricular septal thickness in diastole (Group A, P = .528; Group B, P = .221; Group C, P = .097). Group A had significant increases in BUN (P = .008) and cholesterol (P = .021), while Group B had significant increases in BUN (P = .008), cholesterol (P = .007), and triglycerides (P = .005), and significant decreases in NT‐proBNP (P = .013) and hs‐troponin I (P = .043). Group C had significant decreases in body weight (P = .021), left atrial dimension (P = .035), interventricular septal thickness in systole (P = .038), and liver enzymes (P = .034–.038).

Conclusions and Clinical Importance

These data suggest that diet might influence some clinical, biochemical, and echocardiographic variables in cats with HCM.     

Detection of Clinically Relevant Pain Relief in Cats with Degenerative Joint Disease Associated Pain

Background

Detection of clinically relevant pain relief in cats with degenerative joint disease (DJD) is complicated by a lack of validated outcome measures and a placebo effect.

Hypothesis/Objectives

To evaluate a novel approach for detection of pain relief in cats with DJD.

Animals

Fifty‐eight client‐owned cats.

Methods

Prospective, double‐masked, placebo‐controlled, stratified, randomized, clinical study. Enrolled cats were 6–21 years of age, with owner‐observed mobility impairment, evidence of pain in at least 2 joints during orthopedic examination, and overlapping radiographic evidence of DJD, and underwent a 2‐week baseline period, 3‐week treatment period with placebo or meloxicam, and 3‐week masked washout period. Outcome measures were evaluated at days 0, 15, 36, and 57.

Results

Both groups significantly improved after the treatment period (day 36) on client‐specific outcome measures (CSOM) and feline musculoskeletal pain index (FMPI) (P < .0001 for both); there was no difference between the groups on CSOM or FMPI score improvement. After the masked washout period, more cats that received meloxicam during the treatment period had a clinically relevant decrease in CSOM score (P = .048) and FMPI score (P = .021) than cats that received placebo.

Conclusions and Clinical Importance

Using both a client‐specific and a general clinical metrology instrument, owners of cats with DJD were able to detect evident recurrence of clinical signs after withdrawal of active medication than after withdrawal of placebo, and that this study design might be a novel and useful way to circumvent the placebo effect and detect the efficacy of pain‐relieving medications.     

Quality of Life Measurement in Prospective Studies of Cancer Treatments in Dogs and Cats

Background

Quality of life (QOL) is an important consideration in healthcare decision‐making for pets with cancer. To determine the effect of disease and treatment on pet QOL, this important variable should be objectively measured as an outcome in veterinary cancer studies.

Objectives

To determine the prevalence and methodology of QOL measurement in a sample of recently published reports of prospective studies evaluating cancer treatments in client‐owned dogs and cats; to characterize reporting of QOL outcomes and to identify article characteristics associated with QOL measurement.

Methods

English‐language reports of prospective studies of cancer treatments in dogs and cats published from 2008 to 2013 were identified using medical research databases combined with a hand‐searching strategy. Data pertaining to general article characteristics and QOL measurement were abstracted and summarized.

Results

Reports of 144 eligible studies were identified. QOL was measured in 16 (11.1%) studies, with 8 (5.6%) reporting the results. All studies that measured QOL reported using unvalidated instruments, or did not report how QOL was assessed. Only 1 study provided sufficient information for QOL measurements to be replicated. Recently published articles (2011–2013) were significantly more likely to report measuring QOL, compared with earlier articles.

Conclusions

Quality of life of pets undergoing cancer treatment is largely unreported and cannot be meaningfully compared across treatments or disease states using the existing literature. Reliable, validated instruments are needed to facilitate the measurement and comparison of pet QOL in veterinary cancer research. Consistent reporting practices could improve transparency and interpretation of QOL results.     

Renal biomarkers in cats: A review of the current status in chronic kidney disease

Serum creatinine concentration, the classical biomarker of chronic kidney disease (CKD) in cats, has important limitations that decrease its value as a biomarker of early CKD. Recently, serum symmetric dimethylarginine concentration was introduced as a novel glomerular filtration rate biomarker for the early detection of CKD in cats. However, data on its specificity are still limited. The limitations of conventional biomarkers and the desire for early therapeutic intervention in cats with CKD to improve outcomes have prompted the discovery and validation of novel renal biomarkers to detect glomerular or tubular dysfunction. Changes in the serum or urinary concentrations of these biomarkers may indicate early kidney damage or predict the progression of kidney before changes in conventional biomarkers are detectable. This review summarizes current knowledge on renal biomarkers in CKD in cats, a field that has progressed substantially over the last 5 years.