Lipotoxic heart disease in obese rats: Implications for human obesity

To determine the mechanism of the cardiac dilatation and reduced contractility of obese Zucker Diabetic Fatty rats, myocardial triacylglycerol (TG) was assayed chemically and morphologically. TG was high because of underexpression of fatty acid oxidative enzymes and their transcription factor, peroxisome proliferator-activated receptor-α. Levels of ceramide, a mediator of apoptosis, were 2–3 times those of controls and inducible nitric oxide synthase levels were 4 times greater than normal. Myocardial DNA laddering, an index of apoptosis, reached 20 times the normal level. Troglitazone therapy lowered myocardial TG and ceramide and completely prevented DNA laddering and loss of cardiac function. In this paper, we conclude that cardiac dysfunction in obesity is caused by lipoapoptosis and is prevented by reducing cardiac lipids.

Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice

Tissue kallikrein is a serine protease thought to be involved in the generation of bioactive peptide kinins in many organs like the kidneys, colon, salivary glands, pancreas, and blood vessels. Low renal synthesis and urinary excretion of tissue kallikrein have been repeatedly linked to hypertension in animals and humans, but the exact role of the protease in cardiovascular function has not been established largely because of the lack of specific inhibitors. This study demonstrates that mice lacking tissue kallikrein are unable to generate significant levels of kinins in most tissues and develop cardiovascular abnormalities early in adulthood despite normal blood pressure. The heart exhibits septum and posterior wall thinning and a tendency to dilatation resulting in reduced left ventricular mass. Cardiac function estimated in vivo and in vitro is decreased both under basal conditions and in response to βadrenergic stimulation. Furthermore, flow-induced vasodilatation is impaired in isolated perfused carotid arteries, which express, like the heart, low levels of the protease. These data show that tissue kallikrein is the main kinin-generating enzyme in vivo and that a functional kallikrein–kinin system is necessary for normal cardiac and arterial function in the mouse. They suggest that the kallikrein–kinin system could be involved in the development or progression of cardiovascular diseases.

Oxygen deprivation causes suspended animation in the zebrafish embryo

Continuous exposure to oxygen is essential for nearly all vertebrates. We found that embryos of the zebrafish Danio rerio can survive for 24 h in the absence of oxygen (anoxia, 0% O2). In anoxia, zebrafish entered a state of suspended animation where all microscopically observable movement ceased, including cell division, developmental progression, and motility. Animals that had developed a heartbeat before anoxic exposure showed no evidence of a heartbeat until return to terrestrial atmosphere (normoxia, 20.8% O2). In analyzing cell-cycle changes of rapidly dividing blastomeres exposed to anoxia, we found that no cells arrested in mitosis. This is in sharp contrast to similarly staged normoxic embryos that consistently contain more than 15% of cells in mitosis. Flow cytometry analysis revealed that blastomeres arrested during the S and G2 phases of the cell cycle. This work indicates that survival of oxygen deprivation in vertebrates involves the reduction of diverse processes, such as cardiac function and cell-cycle progression, thus allowing energy supply to be matched by energy demands.

Targeted disruption of the mouse beta1-adrenergic receptor gene: developmental and cardiovascular effects.

At least three distinct beta-adrenergic receptor (beta-AR) subtypes exist in mammals. These receptors modulate a wide variety of processes, from development and behavior, to cardiac function, metabolism, and smooth muscle tone. To understand the roles that individual beta-AR subtypes play in these processes, we have used the technique of gene targeting to create homozygous beta 1-AR null mutants (beta 1-AR -/-) in mice. The majority of beta 1-AR -/- mice die prenatally, and the penetrance of lethality shows strain dependence. Beta l-AR -/- mice that do survive to adulthood appear normal, but lack the chronotropic and inotropic responses seen in wild-type mice when beta-AR agonists such as isoproterenol are administered. Moreover, this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice. These findings occur despite persistent cardiac beta 2-AR expression, demonstrating the importance of beta 1-ARs for proper mouse development and cardiac function, while highlighting functional differences between beta-AR subtypes.

Atrial-like phenotype is associated with embryonic ventricular failure in retinoid X receptor alpha -/- mice.

We have recently characterized a cardiac model of ventricular chamber defects in retinoid X receptor alpha (RXR alpha) homozygous mutant (-/-) gene-targeted mice. These mice display generalized edema, ventricular chamber hypoplasia, and muscular septal defects, and they die at embryonic day 15. To substantiate our hypothesis that the embryos are dying of cardiac pump failure, we have used digital bright-field and fluorescent video microscopy and in vivo microinjection of fluorescein-labeled albumin to analyze cardiac function. The affected embryos showed depressed ventricular function (average left ventricular area ejection fraction, 14%), ventricular septal defects, and various degrees of atrioventricular block not seen in the RXR alpha wild-type (+/+) and heterozygous (+/-) littermates (average left ventricular area ejection fraction, 50%). The molecular mechanisms involved in these ventricular defects were studied by evaluating expression of cardiac-specific genes known to be developmentally regulated. By in situ hybridization, aberrant, persistent expression of the atrial isoform of myosin light chain 2 was identified in the ventricles. We hypothesize that retinoic acid provides a critical signal mediated through the RXR alpha pathway that is required to allow progression of development of the ventricular region of the heart from its early atrial-like form to the thick-walled adult ventricle. The conduction system disturbances found in the RXR alpha -/- embryos may reflect a requirement of the developing conduction system for the RXR alpha signaling pathway, or it may be secondary to the failure of septal development.

Les mécanismes sous-jacents aux effets pathologiques cardiaques de l’angiotensine II dans le remodelage électrique et contractile entre les sexes

L’insuffisance cardiaque (IC) est associée à un taux de mortalité et d’hospitalisations élevé causant un fardeau économique important. Les deux causes majeures de décès de l’IC sont les arythmies ventriculaires létales et les sidérations myocardiques. Il est maintenant reconnu que l’angiotensine II (ANGII) est l'un des principaux médiateurs de l’IC. Ses effets délétères découlent de l’activation du récepteur de type 1 de l’ANGII (AT1) et entraînent le développement d’hypertrophie. Toutefois, son rôle dans la genèse d’arythmies demeure incompris. De ce fait, l'étude des mécanismes électriques et contractiles sous-jacents aux effets pathologiques de l’ANGII s’avère essentielle afin de mieux comprendre et soigner cette pathologie. Il est souvent perçu que les femmes sont protégées envers les maladies cardiovasculaires. Cependant, le nombre total de femmes décédant d’IC est plus grand que le nombre d’hommes. Également, l’impact des facteurs de risque diffère entre chaque sexe. Ces différences existent, mais les mécanismes sous-jacents sont encore peu connus. De plus, les femmes reçoivent fréquemment un diagnostic ou un traitement inapproprié en raison d’un manque d’information sur les différences entre les sexes dans la manifestation d’une pathologie. Ce manque de données peut découler du fait que les sujets de sexe féminin sont souvent sous-représentés dans les essais cliniques ou la recherche fondamentale ce qui a grandement limité l’avancement de nos connaissances sur ~50 % de la population. Ainsi, il semble plus que nécessaire d’approfondir notre compréhension des différences entre les sexes, notamment dans la progression de l’IC. L’utilisation d’un modèle de souris transgénique surexprimant le récepteur AT1 (souris AT1R) a permis d’étudier les changements électriques, structurels et contractiles avant et après le développement d’hypertrophie. Premièrement, chez les souris AT1R mâles, un ralentissement de la conduction ventriculaire a été observé indépendamment de l’hypertrophie. Ce résultat était expliqué par une réduction de la densité du courant Na+, mais pas de l’expression du canal. Ensuite, le rôle des protéines kinases C (PKC) dans la régulation du canal Na+ par l’ANGII a été exploré. Les évidences ont suggéré que la PKCα était responsable de la modulation de la diminution du courant Na+ chez les souris AT1R mâles et dans les cardiomyocytes humains dérivés de cellules souches induites pluripotentes (hiPSC-CM) en réponse à un traitement chronique à l’ANGII. Ensuite, les différences entre les sexes ont été comparées chez la souris AT1R. Une plus grande mortalité a été constatée chez les femelles AT1R suggérant qu’elles sont plus sensibles à la surexpression de AT1R. Le remodelage électrique ventriculaire a donc été comparé entre les souris AT1R des deux sexes. Les courants ioniques étaient altérés de façon similaire entre les sexes excluant ainsi leur implication dans la mortalité plus élevée chez les femelles. Ensuite, l’homéostasie calcique et la fonction cardiaque ont été étudiées. Il a été démontré que les femelles développaient une hypertrophie et une dilatation ventriculaire plus sévère que les mâles. De plus, les femelles AT1R avaient de petits transitoires calciques, une extrusion du Ca2+ plus lente ainsi qu’une augmentation de la fréquence des étincelles Ca2+ pouvant participer à des troubles contractiles et à la venue de post-dépolarisations précoces. En conclusion, l’ANGII est impliquée dans le remodelage électrique, structurel et calcique associé à l'émergence de l’IC. De surcroît, ces altérations affectent plus sévèrement les femelles soulignant la présence de différences entre les sexes dans le développement de l’IC.

Homocysteine-lowering therapy in renal disease

Hyperhomocysteinemia is a potential risk factor for vascular disease and is associated with endothelial dysfunction, a predictor of adverse cardiovascular events. Renal patients (end-stage renal failure (ESRF) and transplant recipients (RTR)) exhibit both hyperhomocysteinemia and endothelial dysfunction with increasing evidence of a causative link between the 2 conditions. The elevated homocysteine appears to be due to altered metabolism in the kidney (intrarenal) and in the uremic circulation ( extrarenal). This review will discuss 18 supplementation studies conducted in ESRF and 6 in RTR investigating the effects of nutritional therapy to lower homocysteine. The clinical significance of lowering homocysteine in renal patients will be discussed with data on the effects of B vitamin supplementation on cardiovascular outcomes such as endothelial function presented. Folic acid is the most effective nutritional therapy to lower homocysteine. In ESRF patients, supplementation with folic acid over a wide dose range ( 2 - 20 mg/day) either individually or in combination with other B vitamins will decrease but not normalize homocysteine. In contrast, in RTR similar doses of folic acid normalizes homocysteine. Folic acid improves endothelial function in ESRF patients, however this has yet to be investigated in RTR. Homocysteine-lowering therapy is more effective in ESRF patients than RTR.

Alterations of left ventricular myocardial characteristics associated with obesity

Background-Obesity is associated with heart failure, but an effect of weight, independent of comorbidities, on cardiac structure and function is not well established. We sought whether body mass index (BMI) and insulin levels were associated with subclinical myocardial disturbances. Methods and Results-Transthoracic echocardiography, myocardial Doppler-derived systolic (sm) and early diastolic velocity ( em), strain and strain rate imaging and tissue characterization with cyclic variation (CVIB), and calibrated integrated backscatter (cIB) were obtained in 109 overweight or obese subjects and 33 referents (BMI35) and the referent patients (P

The role of growth hormone replacement in a growth hormone deficient patient with underlying cardiomyopathy and severe congestive heart failure

It has been reported that-growth hormone (GH) deficiency induced cardiomyopathy responds to growth hormone replacement therapy. We describe the case of a middle-aged male with cardiomyopathic heart failure and growth hormone deficiency of the adult secondary to surgical panhypopituitarism. We demonstrate clinical and hemodynamic improvement of cardiac function with growth hormone replacement therapy despite underlying structural heart disease. Copyright (C) 2005 by the International Society for Heart and Lung Transplantation.

Determinants of exercise capacity in patients with type 2 diabetes

OBJECTIVE - Type 2 diabetes is associated with reduced exercise capacity, but the cause of this association is unclear. We sought the associations of impaired exercise capacity in type 2 diabetes. RESEARCH DESIGN AND METHODS - Subclinical left ventricular (LV) dysfunction was sought from myocardial strain rate and the basal segmental diastolic velocity (Em) of each wall in 170 patients with type 2 diabetes (aged 56 +/- 10 years, 91 men), good quality echocardiographic images, and negative exercise echocardiograms. The same measurements were made in 56 control subjects (aged 53 +/- 10 years, 29 men). Exercise capacity was calculated in metabolic equivalents, and heart rate recovery (HRR) was measured as the heart rate difference between peak and 1 min after exercise. In subjects with type 2 diabetes, exercise capacity was correlated with clinical, therapeutic, biochemical, and echocardiographic variables, and significant independent associations were sought using a multiple linear regression model. RESULTS - Exercise capacity, strain rate, Em, and HRR were significantly reduced in type 2 diabetes. Exercise capacity was associated with age (r- = -0.37, P < 0.001), male sex (r = 0.26, P = 0.001), BMI (r = -0.19, P = 0.012), HbA(1c) (AlC; r = -0.22, P = 0.009), Em (r = 0.43, P < 0.001), HRR (r = 0.42, P < 0.001), diabetes duration (r = -0.18, P = 0.021), and hypertension history (r = -0.28, P < 0.001). Age (P < 0.001), male sex (P = 0.007), BMI (P = 0.001), Em (P = 0.032), HRR (P = 0.013), and AlC (P = 0.0007) were independent predictors of exercise capacity. CONCLUSIONS - Reduced exercise capacity in patients with type 2 diabetes is associated with diabetes control, subclinical LV dysfunction, and impaired HRR.

Determinants of subclinical diabetic heart disease

Aims/hypothesis: Subclinical left ventricular (LV) dysfunction has been shown by tissue Doppler and strain imaging in diabetic patients in the absence of coronary disease or LV hypertrophy, but the prevalence and aetiology of this finding remain unclear. This study sought to identify the prevalence and the determinants of subclinical diabetic heart disease. Methods: A group of 219 unselected patients with type 2 diabetes without known cardiac disease underwent resting and stress echocardiography. After exclusion of coronary artery disease or LV hypertrophy, the remaining 120 patients ( age 57 +/- 10 years, 73 male) were studied with tissue Doppler imaging. Peak systolic strain of each wall and systolic (Sm) and diastolic ( Em) velocity of each basal segment were measured from the three apical views and averaged for each patient. Significant subclinical LV dysfunction was identified according to Sm and Em normal ranges adjusted by age and sex. Strain and Em were correlated with clinical, therapeutic, echocardiographic and biochemical variables, and significant independent associations were sought using a multiple linear regressionmodel. Results: Significant subclinical LV dysfunction was present in 27% diabetic patients. Myocardial systolic dysfunction by peak strain was independently associated with glycosylated haemoglobin level ( p< 0.001) and lack of angiotensin- converting enzyme inhibitor treatment ( p= 0.003). Myocardial diastolic function ( Em) was independently predicted by age ( p= 0.013), hypertension ( p= 0.001), insulin ( p= 0.008) and metformin ( p= 0.01) treatment. Conclusions/ interpretation: In patients with diabetes mellitus, subclinical LV dysfunction is common and associated with poor diabetic control, advancing age, hypertension and metformin treatment; ACE inhibitor and insulin therapies appear to be protective.

Multi-centre Phase II trial of the polyamine synthesis inhibitor SAM486A (CGP48664) in patients with metastatic melanoma

Purpose: To determine the activity and tolerability of SAM496A, an inhibitor of S-adenosylmethionine decarboxylase (SAMDC), in patients with metastatic melanoma who had not received prior chemotherapy. Selected patients were offered participation in two sub-studies examining early changes in tumor metabolism with FDG-PET and changes in tumor polyamine content. Patients and methods: Fifteen patients with measurable metastatic melanoma, normal cardiac function, and no known CNS metastases were eligible and received SAM486A by 1-hour IV infusion daily for 5 days every 3 weeks. Response was assessed by SWOG criteria. Results: No patient had a confirmed partial response. Fatigue/lethargy, myalgia and neutropenia were the main toxicities but no febrile neutropenia or grade 4 non-hematological toxicity occurred. Five patients had PET scans pre-treatment and on days 8-12 of cycle 1. No patient had reduction of tumor metabolism. Serial biopsy in one patient showed alterations in polyamines consistent with SAMDC inhibition. Conclusions: Using the present dose and schedule of administration, SAM486A does not have significant therapeutic potential in patients with metastatic melanoma.

Measurement of strain and strain rate by echocardiography - Ready for prime time?

Strain and strain rate (SR) are measures of deformation that are basic descriptors of both the nature and the function of cardiac tissue. These properties may now be measured using either Doppler or two-dimensional ultrasound techniques. Although these measurements are feasible in routine clinical echocardiography, their acquisition and analysis nonetheless presents a number of technical challenges and complexities. Echocardiographic strain and SR imaging has been applied to the assessment of resting ventricular function, the assessment of myocardial viability using low-dose dobutamine infusion, and stress testing for ischemia. Resting function assessment has been applied in both the left and the fight ventricles, and may prove particularly valuable for identifying myocardial diseases and following up the treatment response. Although the evidence base is limited, SR imaging seems to be feasible and effective for the assessment of myocardial viability. The use of the technique for the detection of ischemia during stress echocardiography is technically challenging and likely to evolve further. The clinical availability of strain and SR measurement may offer a solution to the ongoing need for quantification of regional and global cardiac function. Nonetheless, these techniques are susceptible to artifact, and further technical development is necessary.

The role of BNP testing in heart failure

Brain natriuretic peptide (BNP) levels are simple and objective measures of cardiac function. These measurements can be used to diagnose heart failure, including diastolic dysfunction, and using them has been shown to save money in the emergency department setting. The high negative predictive value of BNP tests is particularly helpful for ruling out heart failure. Treatment with angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, spironolactone, and diuretics reduces BNP levels, suggesting that BNP testing may have a role in monitoring patients with heart failure. However, patients with treated chronic stable heart failure may have levels in the normal range (i.e., BNP less than 100 pg per mL and N-terminal proBNP less than 125 pg per mL in patients younger than 75 years). Increases in BNP levels may be caused by intrinsic cardiac dysfunction or may be secondary to other causes such as pulmonary or renal diseases (e.g., chronic hypoxia). BNP tests are correlated with other measures of cardiac status such as New York Heart Association classification. BNP level is a strong predictor of risk of death and cardiovascular events in patients previously diagnosed with heart failure or cardiac dysfunction.

Altered blood vessel responses in the eye and finger in coronary artery disease

Cardiac function, such as heart rate variability, is abnormal in coronary artery disease, but its relation with the function of ocular and nail-fold blood vessels is unknown. The hypothesis was that there is abnormal retinal and peripheral microvascular endothelial function compared with large blood vessel and cardiac function. Twenty-four patients with coronary artery disease (CAD) and 30 healthy, age- and sex-matched control subjects were enrolled in the study.