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Basu R, Oudit GY, Wang X, Zhang L, Ussher JR, Lopaschuk GD, Kassiri Z. Type 1 diabetic cardiomyopathy in the Akita (Ins[2.sup.WT/C96Y]) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function. Am J Physiol Heart Circ Physiol 297: H2096-H2108, 2009. First published October 2, 2009; doi: 10.1152/ajpheart.00452.2009.--Diabetic cardiomyopathy is an important contributor to diastolic and systolic heart failure. We examined the nature and mechanism of the cardiomyopathy in Akita (Ins[2.sup.WT/C96Y]) mice, a model of genetic nonobese type 1 diabetes that recapitulates human type 1 diabetes. Cardiac function was evaluated in male Ins[2.sup.WT/C96Y] and their littermate control (Ins[2.sup.WT/WT]) mice using echocardiography and tissue Doppler imaging, in vivo hemodynamic measurements, as well as ex vivo working heart preparation. At 3 and 6 mo of age, Ins[2.sup.WT/C96Y] mice exhibited preserved cardiac systolic function compared with Ins[2.sup.WT/WT] mice, as evaluated by ejection fraction, fractional shortening, left ventricular (LV) end-systolic pressure and maximum rate of increase in LV pressure in vivo, cardiac work, cardiac power, and rate-pressure product ex vivo. Despite the unaltered systolic function, Ins[2.sup.WT/C96Y] mice exhibited significant and progressive diastolic dysfunction at 3 and 6 mo of age compared with Ins[2.sup.WT/WT] mice as assessed by tissue and pulse Doppler imaging (E-wave velocity, isovolumetric relaxation time) and by in vivo hemodynamic measurements (LV end-diastolic pressure, time constant of LV relaxation, and maximum rate of decrease in LV pressure). We found no evidence of myocardial hypertrophy or fibrosis in the Ins[2.sup.WT/C96Y] myocardium. Consistent with the lack of fibrosis, expression of procollagen-[alpha] type I, procollagen-[alpha] type III, and fibronectin were not increased in these hearts. Ins[2.sup.WT/C96Y] hearts showed significantly reduced sarcoplasmic reticulum [Ca.sup.2+]-ATPase 2a (cardiac sarcoplasmic reticulum [Ca.sup.2+] pump) levels, elevated [beta]-myosin heavy chain isoform, increased long-chain fatty acids, and triacylglycerol with evidence of lipotoxicity, as indicated by a significant rise in ceramide, diacylglycerol, and lipid deposits in the myocardium. Consistent with metabolic perturbation, and a switch to fatty acid oxidation from glucose oxidation in Ins[2.sup.WT/C96Y] hearts, expression of mitochondrial long-chain acyl-CoA dehydrogenase and pyruvate dehydrogenase kinase isoform 4 were increased. Insulin treatment reversed the diastolic dysfunction, the elevated B-type natriuretic peptide and [beta]-myosin heavy chain, and the reduced sarcoplasmic reticulum [Ca.sup.2+]-ATPase 2a levels with abolition of cardiac lipotoxicity. We conclude that early type 1 diabetic cardiomyopathy is characterized by diastolic dysfunction associated with lipotoxic cardiomyopathy with preserved systolic function in the absence of interstitial fibrosis and hypertrophy. insulin; fibrosis; hypertrophy; sarco(endo)plasmic reticulum calcium-ATPase 2a doi: 10.1152/ajpheart.00452.2009

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2004.10.006 Byline: Hossein Ardehali (a), David L. Howard (a), Arvin Hariri (a), Atif Qasim (a), Joshua M. Hare (a), Kenneth L. Baughman (b), Edward K. Kasper (a) Abstract: Sarcoidosis is a systemic granulomatous disorder of unknown etiology. In patients with cardiomyopathy, the diagnosis of sarcoidosis has important treatment implications. We studied the prognostic implications of a cardiac biopsy diagnosis of sarcoidosis in patients with unexplained cardiomyopathy. Author Affiliation: (a) Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Md (b) Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Mass Article History: Received 31 March 2004; Accepted 15 October 2004

Women with a history of peripartum cardiomyopathy who become pregnant have a high risk of heart failure and death. Peripartum cardiomyopathy is a heart disease that occurs during pregnancy or in the postpartum period. Most women recover partially or completely.

The prognosis of patients with cardiomyopathy depends on the underlying condition that is causing the disease. Cardiomyopathy is the medical term for disease of the heart muscle. It can be caused by coronary artery disease and by many other conditions, including HIV infection, pregnancy, hypertension, substance abuse, connective tissue disease, and treatment with doxorubicin. In a study of 1,230 people with cardiomyopathy from various causes, women with pregnancy-related cardiomyopathy had the best prognosis and those with HIV infection, doxorubicin treatment, or infiltrative heart muscle diseases had the worst prognosis.

Dilated cardiomyopathy is a condition of unknown cause characterized by an enlarged and poorly functioning heart. The course of the disease and the risk factors associated with dilated cardiomyopathy have not been adequately described in children. To describe more fully the development and prognosis of cardiomyopathy in a pediatric population, the records of 25 patients (average age 9.6 years) diagnosed some time after the age of two with dilated cardiomyopathy were reviewed. Patients were categorized into those who died less than one year after diagnosis and those who survived longer than a year. Based on this classification, two factors seemed to distinguish survivors from nonsurvivors at the time of diagnosis: cardiothoracic ratio (the ratio of heart size to the size of the chest cavity) was significantly smaller in surviving patients, and the left ventricular ejection fraction (the percentage of blood in the left ventricle that is ejected during maximal contraction, a measure of heart function) was significantly greater. In spite of various combinations of medical therapy, including digitalis (a drug that increases cardiac output), vasodilators (which relax the blood vessels), anticoagulants (which dissolve clots) and antiarrhythmic agents (which restore proper electrical conduction), prognosis was poor. Fifty-nine percent of the patients died within one year of diagnosis; 80 percent died within three years. In light of the extremely poor survival rate in young patients with dilated cardiomyopathy, alternate forms of therapy, such as heart transplant, should be considered. (Consumer Summary produced by Reliance Medical Information, Inc.)

People who recover from cardiac arrest are at risk of suffering a recurrent episode. A subset of this group (60 to 80 percent) exhibits abnormalities in heart function during electrocardiogram (ECG) testing; these patients respond well to medication that alleviates the abnormalities. This improvement appears to prevent recurrence of cardiac arrest. The remaining 20 to 40 percent of patients show no abnormalities during ECG testing; this group is thought to be at a particularly high risk for sudden cardiac death. Seventy-one survivors of a single episode of cardiac arrest were evaluated. During testing, 26 of these patients had no inducible ECG abnormalities, such as ventricular tachycardia (abnormally rapid patterns of contraction of the ventricle). After a 16-month follow-up, 11 of the 26 patients suffered recurrent cardiac arrest, and 10 of these patients died. Analysis of the clinical data pertaining to these patients revealed that several variables were more likely to be associated with recurrent cardiac arrest. Among the 11 patients who suffered a recurrence, 55 percent had dilated cardiomyopathy (a defect in the functioning of the heart muscle), and 64 percent experienced premature ventricular contractions. Twenty-four-hour ambulatory ECG-guided therapy (wearing a portable ECG machine) did not improve the survival rate for these patients. Further studies are needed to determine the optimal treatment strategy for this high-risk group of patients. (Consumer Summary produced by Reliance Medical Information, Inc.)

In coronary artery disease the coronary arteries do not provide adequate blood flow to the heart muscle, often because of fatty plaques lining the vessels. Idiopathic dilated cardiomyopathy is characterized by enlargement of the heart, poor function of the heart muscle, and congestive heart failure (inadequate heart contractions, leading to lung congestion). Eighty patients with coronary artery disease and 53 with idiopathic dilated cardiomyopathy were followed for an average of 29 months to determine which disease characteristics are associated with outcomes. These patients had been referred because of failure to respond adequately to treatments, and were representative of patients who might be candidates for heart transplant. Among these patients, the fraction of blood successfully ejected during a contraction of the heart, the so-called left-ventricular ejection fraction, did not correlate with poor prognosis. This is in sharp contrast to other studies, which have reported that this factor had significant prognostic value. The primary factors which contributed to mortality were a resting systolic blood pressure (during heart contraction) less than 120 millimeters of mercury (mm Hg), X-ray evidence of heart congestion, age over 64, and evidence of coronary artery disease. The patients were given a questionnaire that asked about common symptoms and the performance of everyday chores. It is worthy of note that for patients with dilated cardiomyopathy, this questionnaire proved to be a more effective predictor of survival than any of the more objective factors analyzed. For patients with ischemic heart problems resulting from coronary artery disease, the questionnaire had no such predictive power. Although blood pressure monitoring is recommended because of its high prognostic value, it is uncertain to what degree health improvements might be achieved through management of hypertension. The subjective self-appraisal of patients with idiopathic dilated cardiomyopathy should be considered quite seriously, as this seems to be a better predictor of outcome than more objective measures. (Consumer Summary produced by Reliance Medical Information, Inc.)

Identifying the cause of cardiomyopathy may allow doctors to estimate a patient's prognosis. Cardiomyopathy is a disease of the heart muscle and it has many different causes. The most common causes are hypertension and coronary artery disease. However, it can also occur during or after pregnancy, in HIV patients, and in people exposed to certain drugs. A study published in 2000 found that the prognosis of cardiomyopathy depended on the underlying cause of the disease. Women who developed the disease during pregnancy had the best prognosis compared to other groups.

Although numerous studies have evaluated the relationship between arrhythmia (irregular or abnormal heart beat) and the development of cardiac complications and stroke, little is known about the sorts of conditions which might contribute to the development of the arrhythmias themselves. In a study of 77 patients, the presence of arrhythmias was compared to the extent and distribution of cardiac hypertrophy. Hypertrophic cardiomyopathy is a condition of generally uncertain cause which results in an increase in the mass of the heart muscle and a corresponding decrease in the effectiveness of its contraction. Of the 77 patients studied, the hypertrophy was extensive in 38 patients. In 34 it was limited to the septum between the chambers of the heart, and in six patients the hypertrophy was apical, that is, limited to the pointed end of the heart. When the patients were evaluated for ventricular arrhythmias, 37 percent were found to have grade I or II, which are less severe. Grade III arrhythmias were found in 21 percent and 29 percent were found to have grade IV arrhythmias. When these findings were correlated with the muscular hypertrophy, it was found that the worst arrhythmias, i.e. grade III or IV, were more likely among patients with extensive hypertrophy and those with septal hypertrophy. Chronic atrial fibrillation (rapid, uncoordinated contraction of the atrium) was also found to be more common among the patients with extensive hypertrophy, as well. During an average follow-up of 2.6 years, three patients had died. All three were from the extensive hypertrophy group. Two had ventricular arrhythmias and one had chronic atrial fibrillation. The results indicate that a finding of extensive hypertrophy of the heart muscle be regarded as suggestive of the possibility of serious arrhythmias and a potentially poorer prognosis. (Consumer Summary produced by Reliance Medical Information, Inc.)