231 research outputs found
Cardiomyocyte-Specific Deletion of β-catenin Protects Mouse Hearts from Ventricular Arrhythmias After Myocardial Infarction
No full textWnt/β-catenin signaling is activated in the heart after myocardial infarction (MI). This study aims to investigate if β-catenin deletion affects post-MI ion channel gene alterations and ventricular tachycardias (VT). MI was induced by permanent ligation of left anterior descending artery in wild-type (WT) and cardiomyocyte-specific β-catenin knockout (KO) mice. KO mice showed reduced susceptibility to VT (18% vs. 77% in WT) at 8 weeks after MI, associated with reduced scar size and attenuated chamber dilation. qPCR analyses of both myocardial tissues and purified cardiomyocytes demonstrated upregulation of Wnt pathway genes in border and infarct regions after MI, including Wnt ligands (such as Wnt4) and receptors (such as Fzd1 and Fzd2). At 1 week after MI, cardiac sodium channel gene (Scn5a) transcript was reduced in WT but not in KO hearts, consistent with previous studies showing Scn5a inhibition by Wnt/β-catenin signaling. At 8 weeks after MI when Wnt genes have declined, Scn5a returned to near sham levels and K⁺ channel gene downregulations were not different between WT and KO mice. This study demonstrated that VT susceptibility in the chronic phase after MI is reduced in mice with cardiomyocyte-specific β-catenin deletion primarily through attenuated structural remodeling, but not ion channel gene alterations
Plasminogen Activator Inhibitor-1, Diabetes, and Vascular Disease
No full textPatients with established coronary artery disease (CAD) remain at elevated risk of major adverse cardiac events (MACE). Specifically, stented coronary artery remains the highest-risk coronary lesion with annualized adverse event rates as high as 8-12% in the following year largely due to in-stent restenosis (ISR) and stent thrombosis. Plasminogen activator inhibitor-1 (PAI-1), an anti-fibrinolytic protein, has previously been associated with CAD with known mechanism of action to regulate the pathophysiological changes associated with in-stent restenosis and stent thrombosis. Moreover, extracellular vesicles (EVs) originating from circulating blood and vascular cells are increasingly being utilized as biomarkers and mediators of vascular disease. We first demonstrate the analytical and biochemical performance of plasma PAI-1 in patients with established CAD. Specifically, PAI-1 performs similarly to established biomarkers including C-reactive protein and NT-proBNP with an analytical (CVa = 4.1%), intra-individual (CVi = 44.0%), and inter-individual (CVg = 118.6%) coefficients of variation. Following this, we demonstrate that plasma PAI-1 is not associated with MACE in one-year follow-up, but reduced levels of PAI-1 remain associated with unplanned revascularization. Subsequently, we sought to evaluate the relationship between PAI-1 and EVs in humans with platelets being a common source of origin. In the largest study of EV to-date in CAD (n=489), we demonstrate the strong predictive ability of PAI-1 platelet-derived EVs (PAI-1+ PEV) with MACE following revascularization. Patients with high circulating levels of PAI-1+ PEV had higher rates of MACE (262.3 vs. 103.0 events per 1,000 person-years; hazard ratio (HR) 2.19; 95% CI, 1.07-4.52; and HR 2.67; 95% CI, 1.22-5.84, discovery and validation cohorts, respectively). Furthermore, we reveal that high PAI-1+ PEV fractions did not enhance thrombogenicity but promoted a pro-inflammatory vascular smooth muscle cell (VSMC) state by enhancing proliferation and migration, through up-regulation of pro-inflammatory genes such as KLF4. Inhibition of the PAI-1-LRP-1 interaction by TM5275 dampened the pro-inflammatory VSMC response, whereas inhibition of the PAI-1-vitronectin interaction by tiplaxtinin had no such effect. Our data reveals the potential of PAI-1+ PEV as a biomarker in the post-revascularization population and postulates the mechanism in an in vitro model of VSMCs. Accordingly, our data demonstrates the potential of PAI-1 PEV as a strong biomarker following revascularization and PAI-1 inhibition by TM5275 is a promising strategy to reduce the pro-inflammatory VSMC state associated with ISR
Impact of Glycemic Therapy on Myocardial Sympathetic Neuronal Integrity and Left Ventricular Function in Insulin Resistant Diabetic Rats: Serial Evaluation by 11C-meta-Hydroxyephedrine Positron Emission Tomography
No full textDiagnosis of diabetes mellitus, presence of hyperglycemia, and/or insulin resistance confer cardiovascular risk, particularly for diastolic dysfunction. Diabetes is associated with elevated myocardial norepinephrine (NE) content, enhanced sympathetic nervous system (SNS) activity, altered resting heart rate, and depressed heart rate variability. Positron emission tomography (PET) using the NE analogue [11C]meta-hydroxyephedrine ([11C]HED) provides an index of myocardial sympathetic neuronal integrity at the NE reuptake transporter (NET). The hypothesis of this project is that (i) hyperglycemia imparts heightened sympathetic tone and NE release, leading to abnormal sympathetic neuronal function in the hearts of diabetic rats, and (ii) these abnormalities may be reversed or prevented by treatments to normalize glycemia. Sprague Dawley rats were rendered insulin resistant by high fat feeding and diabetic by a single dose of streptozotocin (STZ). Diabetic rats were treated for 8 weeks with insulin, metformin or rosiglitazone, starting from either 1 week (prevention) or 8 weeks (reversal) after STZ administration. Sympathetic neuronal integrity was evaluated longitudinally by [11C]HED PET. Echocardiography measures of systolic and diastolic function were completed at serial timepoints. Plasma NE levels were evaluated serially and expression of NET and β-adrenoceptors were tested at the terminal endpoints. Diabetic rats exhibited a 52-57% reduction of [11C]HED standardized uptake value (SUV) at 8 weeks after STZ, with a parallel 2.5-fold elevation of plasma NE and a 17-20% reduction in cardiac NET expression. These findings were confirmed by ex vivo biodistribution studies. Transmitral pulse wave Doppler echocardiography established an extension of mitral valve deceleration time and elevated early to atrial velocity ratio, suggesting diastolic dysfunction. Subsequent treatment with insulin but not metformin restored glycemia, reduced plasma NE by 50%, normalized NET expression, and recovered [11C]HED SUV towards non-diabetic age-matched control. Diastolic dysfunction in these rats persisted. By contrast, early treatment with insulin, metformin, or rosiglitazone delayed the progression of diastolic dysfunction, but had no effect on elevated NE and reduced [11C]HED SUV in diabetic rats, potentially owing to a latent decrease in blood glucose. In conclusion, diabetes is associated with heightened circulating and tissue NE levels which can be effectively reversed by lowering glycemia with insulin. Noninvasive interrogation of sympathetic neuronal integrity using [11C]HED PET may have added value in the stratification of cardiovascular risk among diabetic patients and in determining the myocardial effects of glycemic therapy
The Impact of Diabetes Mellitus on Territory-Specific Myocardial Flow Reserve in the Presence of Epicardial Coronary Disease
No full textImpact of Glycemic Therapy on Myocardial Sympathetic Neuronal Integrity and Left Ventricular Function in Insulin Resistant Diabetic Rats: Serial Evaluation by 11C-meta-Hydroxyephedrine Positron Emission Tomography
No full textDiagnosis of diabetes mellitus, presence of hyperglycemia, and/or insulin resistance confer cardiovascular risk, particularly for diastolic dysfunction. Diabetes is associated with elevated myocardial norepinephrine (NE) content, enhanced sympathetic nervous system (SNS) activity, altered resting heart rate, and depressed heart rate variability. Positron emission tomography (PET) using the NE analogue [11C]meta-hydroxyephedrine ([11C]HED) provides an index of myocardial sympathetic neuronal integrity at the NE reuptake transporter (NET). The hypothesis of this project is that (i) hyperglycemia imparts heightened sympathetic tone and NE release, leading to abnormal sympathetic neuronal function in the hearts of diabetic rats, and (ii) these abnormalities may be reversed or prevented by treatments to normalize glycemia. Sprague Dawley rats were rendered insulin resistant by high fat feeding and diabetic by a single dose of streptozotocin (STZ). Diabetic rats were treated for 8 weeks with insulin, metformin or rosiglitazone, starting from either 1 week (prevention) or 8 weeks (reversal) after STZ administration. Sympathetic neuronal integrity was evaluated longitudinally by [11C]HED PET. Echocardiography measures of systolic and diastolic function were completed at serial timepoints. Plasma NE levels were evaluated serially and expression of NET and β-adrenoceptors were tested at the terminal endpoints. Diabetic rats exhibited a 52-57% reduction of [11C]HED standardized uptake value (SUV) at 8 weeks after STZ, with a parallel 2.5-fold elevation of plasma NE and a 17-20% reduction in cardiac NET expression. These findings were confirmed by ex vivo biodistribution studies. Transmitral pulse wave Doppler echocardiography established an extension of mitral valve deceleration time and elevated early to atrial velocity ratio, suggesting diastolic dysfunction. Subsequent treatment with insulin but not metformin restored glycemia, reduced plasma NE by 50%, normalized NET expression, and recovered [11C]HED SUV towards non-diabetic age-matched control. Diastolic dysfunction in these rats persisted. By contrast, early treatment with insulin, metformin, or rosiglitazone delayed the progression of diastolic dysfunction, but had no effect on elevated NE and reduced [11C]HED SUV in diabetic rats, potentially owing to a latent decrease in blood glucose. In conclusion, diabetes is associated with heightened circulating and tissue NE levels which can be effectively reversed by lowering glycemia with insulin. Noninvasive interrogation of sympathetic neuronal integrity using [11C]HED PET may have added value in the stratification of cardiovascular risk among diabetic patients and in determining the myocardial effects of glycemic therapy
Ex Vivo Evaluation of Myocardial Beta-Adrenergic Receptors in High-Fat Fed STZ and ZDF Models of Diabetes Using [3H]-CGP12177
No full textDiabetes mellitus (DM) and hyperglycemia contribute to sympathetic nervous system (SNS) activation and cardiovascular dysfunction. SNS activation and increased norepinephrine levels downregulate cardiac β-adrenergic receptors (β-AR). The ADMIRE-HF trial identified reduced cardiac SNS innervation as an independent prognostic marker in heart failure. The β-AR antagonist [3H]-CGP12177 was used to quantify cardiac β-AR in ex vivo biodistribution studies in streptozotocin (STZ)-treated rats after 8 weeks of sustained hyperglycemia, and in the Zucker Diabetic Fatty (ZDF) rat model of type-2 diabetes at the onset of hyperglycemia (10 weeks of age) and after a sustained period of hyperglycemia (16 weeks of age). In some STZ rats, insulin was provided at the onset of hyperglycemia, or after a sustained period of hyperglycemia. Insulin treatment at both time points prevented reduced [3H]-CGP12177 binding (33-38% compared to controls) observed in STZ hyperglycemics. ZDF β-ARs were intact at 10 weeks but became reduced (16-25% relative to the Zucker leans) following 6 weeks of hyperglycemia. This work supports that cardiac β-AR are reduced in models of DM and that restoring insulin signalling to maintain glycemic control can normalize β-AR density whether provided early or after a period of sustained hyperglycemia
Risk Factors, Mechanisms and Therapeuthic for Right Heart Failure Associated with Pulmonary Hypertension
No full textRight ventricular function (RV) is one of the most important predictors of prognosis in
many cardiovascular disease states. Despite the significance of RV function to survival, there are
no therapies that directly nor selectively improve RV function. As well, the basis for RV failure
is poorly understood. This is particularly relevant for patients with pulmonary arterial
hypertension (PAH), where RV failure in the setting of pressure overload is the leading cause of
death. PAH will be introduced in the 2nd chapter of this thesis by comparing and refining
contemporary mortality risk assessment strategies. I will then explore 1) RV neurohormonal
function and, 2) RV energetics, two molecular pathways thought to be involved in the
pathogenesis and progression of maladaptive RV failure. I employed small animal molecular
imaging using positron emission tomography (PET) to non-invasively investigate these
pathways. The PET imaging techniques employed in this thesis have the unique potential for
translation to human studies, to further explore disease mechanisms
Ex Vivo Evaluation of Myocardial Beta-Adrenergic Receptors in High-Fat Fed STZ and ZDF Models of Diabetes Using [3H]-CGP12177
No full textDiabetes mellitus (DM) and hyperglycemia contribute to sympathetic nervous system (SNS) activation and cardiovascular dysfunction. SNS activation and increased norepinephrine levels downregulate cardiac β-adrenergic receptors (β-AR). The ADMIRE-HF trial identified reduced cardiac SNS innervation as an independent prognostic marker in heart failure. The β-AR antagonist [3H]-CGP12177 was used to quantify cardiac β-AR in ex vivo biodistribution studies in streptozotocin (STZ)-treated rats after 8 weeks of sustained hyperglycemia, and in the Zucker Diabetic Fatty (ZDF) rat model of type-2 diabetes at the onset of hyperglycemia (10 weeks of age) and after a sustained period of hyperglycemia (16 weeks of age). In some STZ rats, insulin was provided at the onset of hyperglycemia, or after a sustained period of hyperglycemia. Insulin treatment at both time points prevented reduced [3H]-CGP12177 binding (33-38% compared to controls) observed in STZ hyperglycemics. ZDF β-ARs were intact at 10 weeks but became reduced (16-25% relative to the Zucker leans) following 6 weeks of hyperglycemia. This work supports that cardiac β-AR are reduced in models of DM and that restoring insulin signalling to maintain glycemic control can normalize β-AR density whether provided early or after a period of sustained hyperglycemia
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