Records of 127 cats with arterial thromboembolism (ATE) were reviewed. Abyssinian, Birman, Ragdoll, and male cats were overrepresented. Tachypnea (91%), hypothermia (66%), and absent limb motor function (66%) were common. Of 90 cats with diagnostics performed, underlying diseases were hyperthyroidism (12), cardiomyopathy (dilated [8], unclassified [33], hypertrophic obstructive [5], hypertrophic [19]), neoplasia (6), other (4), and none (3). Common abnormalities were left atrial enlargement (93%), congestive heart failure (CHF, 44%), and arrhythmias (44%). Of cats without CHF, 89% were tachypneic. Common biochemical abnormalities were hyperglycemia, azotemia, and abnormally high serum concentrations of muscle enzymes. Of 87 cats treated for acute limb ATE, 39 (45%) survived to be discharged. Significant differences were found between survivors and nonsurvivors for temperature (P < .00001), heart rate (P = .038), serum phosphorus concentration (P = .024), motor function (P = .008), and number of limbs affected (P = .001). No significant difference was found between survivors and nonsurvivors when compared by age, respiratory rate, other biochemical analytes, or concurrent CHE A logistic regression model based on rectal temperature predicted a 50% probability of survival at 98.9 degrees F (37.2 degrees C). Median survival time (MST) for discharged cats was 117 days. Eleven cats had ATE recurrences, and 5 cats developed limb problems. Cats with CHF (MST: 77 days) had significantly shorter survival than cats without CHF (MST: 223 days; P = .016). No significant difference was found in survival or recurrence rate between cats receiving high-dose aspirin (> or = 40 mg/cat q72h) and cats receiving low-dose aspirin (5 mg/cat q72h). Adverse effects were less frequent and milder for the lower dosage.

Records of 127 cats with arterial thromboembolism (ATE) were reviewed. Abyssinian, Birman, Ragdoll, and male cats were overrepresented. Tachypnea (91%), hypothermia (66%), and absent limb motor function (66%) were common. Of 90 cats with diagnostics performed, underlying diseases were hyperthyroidism (12), cardiomyopathy (dilated [8], unclassified [33], hypertrophic obstructive [5], hypertrophic [19]), neoplasia (6), other (4), and none (3). Common abnormalities were left atrial enlargement (93%), congestive heart failure (CHF, 44%), and arrhythmias (44%). Of cats without CHF, 89% were tachypneic. Common biochemical abnormalities were hyperglycemia, azotemia, and abnormally high serum concentrations of muscle enzymes. Of 87 cats treated for acute limb ATE, 39 (45%) survived to be discharged. Significant differences were found between survivors and nonsurvivors for temperature (P < .00001), heart rate (P = .038), serum phosphorus concentration (P = .024), motor function (P = .008), and number of limbs affected (P = .001). No significant difference was found between survivors and nonsurvivors when compared by age, respiratory rate, other biochemical analytes, or concurrent CHE A logistic regression model based on rectal temperature predicted a 50% probability of survival at 98.9 degrees F (37.2 degrees C). Median survival time (MST) for discharged cats was 117 days. Eleven cats had ATE recurrences, and 5 cats developed limb problems. Cats with CHF (MST: 77 days) had significantly shorter survival than cats without CHF (MST: 223 days; P = .016). No significant difference was found in survival or recurrence rate between cats receiving high-dose aspirin (> or = 40 mg/cat q72h) and cats receiving low-dose aspirin (5 mg/cat q72h). Adverse effects were less frequent and milder for the lower dosage.

Duchenne muscular dystrophy (DMD) affects both skeletal and cardiac muscle. It is currently unclear whether the strategies developed for skeletal muscle can ameliorate cardiomyopathy. Synthetic mini-/micro-dystrophin genes have yielded impressive skeletal muscle protection in animal models. The 6-kb ΔH2-R19 minigene is particularly promising because it completely restores skeletal muscle force to wild-type levels. Here, we examined whether expressing this minigene in the heart, but not skeletal muscle, could normalize cardiac function in the mdx model of DMD cardiomyopathy. Transgenic mdx mice were generated to express the ΔH2-R19 minigene under the control of the α-myosin heavy-chain promoter. Heart structure and function were examined in adult and very old mice. The ΔH2-R19 minigene enhanced cardiomyocyte sarcolemmal strength and prevented myocardial fibrosis. It also restored the dobutamine response and enhanced treadmill performance. Surprisingly, heart-restricted ΔH2-R19 minigene expression did not completely normalize electrocardiogram and hemodynamic abnormalities. Overall, systolic function and ejection fraction were restored to normal levels but stroke volume and cardiac output remained suboptimal. Our results demonstrate that the skeletal muscle–proven ΔH2-R19 minigene can correct cardiac histopathology but cannot fully normalize heart function. Novel strategies must be developed to completely restore heart function in DMD.

The identification of mutations in PTPN11 (encoding the protein tyrosine phosphatase Shp2) in families with congenital heart disease has facilitated mechanistic studies of various cardiovascular defects. However, the roles of normal and mutant Shp2 in the developing heart are still poorly understood. Furthermore, it remains unclear how Shp2 loss-of-function (LOF) mutations cause LEOPARD Syndrome (also termed Noonan Syndrome with multiple lentigines), which is characterized by congenital heart defects such as pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). In normal hearts, Shp2 controls cardiomyocyte size by regulating signaling through protein kinase B (Akt) and mammalian target of rapamycin (mTOR). We hypothesized that Shp2 LOF mutations dysregulate this pathway, resulting in HCM. For our studies, we chose the Shp2 mutation Q510E, a dominant-negative LOF mutation associated with severe early onset HCM. Newborn mice with cardiomyocyte-specific overexpression of Q510E-Shp2 starting before birth displayed increased cardiomyocyte sizes, heart-to-body weight ratios, interventricular septum thickness, and cardiomyocyte disarray. In 3-mo-old hearts, interstitial fibrosis was detected. Echocardiographically, ventricular walls were thickened and contractile function was depressed. In ventricular tissue samples, signaling through Akt/mTOR was hyperactivated, indicating that the presence of Q510E-Shp2 led to upregulation of this pathway. Importantly, rapamycin treatment started shortly after birth rescued the Q510E-Shp2-induced phenotype in vivo. If rapamycin was started at 6 wk of age, HCM was also ameliorated. We also generated a second mouse model in which cardiomyocyte-specific Q510E-Shp2 overexpression started after birth. In contrast to the first model, these mice did not develop HCM. In summary, our studies establish a role for mTOR signaling in HCM caused by Q510E-Shp2. Q510E-Shp2 overexpression in the cardiomyocyte population alone was sufficient to induce the phenotype. Furthermore, the pathomechanism was triggered pre- but not postnatally. However, postnatal rapamycin treatment could still reverse already established HCM, which may have important therapeutic implications.