Assessing left atrial size and pump function in ischemic stroke patients: Is cardiac MRI superior to transthoracic echocardiography?

OBJECTIVES: Current guidelines recommend transthoracic echocardiography (TTE) following an ischemic stroke as the primary technique to identify cardiac abnormalities associated with an increased risk of cerebral embolism. It is unclear whether cardiac magnetic resonance imaging (cMRI), a technique shown to provide increased imaging resolution, may also enhance the cardiac assessment of ischemic stroke patients. We compared cMRI with TTE in the evaluation of Left Atrial (LA) size and pump function in a cohort of 44 patients with ischemic stroke. MATERIALS AND METHODS: The biplane method was utilized to acquire LA diameters as well as area measurements in both TTE and cMRI. We calculated LA volume (LAV), LAV index (LAVI), LA Global Longitudinal Strain (GLS) and LA pump function. Results were compared using paired two sample for means t-test. Lin's concordance correlation coefficient (CCC) and Bland-Altman methods quantified the agreement of measurements obtained by TTE and cMRI. RESULTS: LAVI measurements by cMRI were significantly larger (34.97 v. 28.81; p = 0.001) than by TTE. The concordance correlation demonstrated only a weak agreement between LA size measured by cMRI and TTE (ρc = 0.397; p= 0.001, 95% CI 0.16 - 0.59), and the Bland-Altman plot demonstrated that LAVI measured by cMRI averaged 6.3 ml/m2 larger magnitude than those obtained by TTE. CONCLUSIONS: Using TTE alone leads to an underestimation of LA abnormalities important in the evaluation of ischemic stroke patients. Nearly one in every five ischemic stroke patients evaluated based on the current guidelines may have a missed potential source of cardiac embolism.

Suppression of Inflammatory Cardiac Cytokine Network in Rats with Untreated Obesity and Pre-Diabetes by AT2 Receptor Agonist NP-6A4.

Obesity affects over 42% of the United States population and exacerbates heart disease, the leading cause of death in men and women. Obesity also increases pro-inflammatory cytokines that cause chronic tissue damage to vital organs. The standard-of-care does not sufficiently attenuate these inflammatory sequelae. Angiotensin II receptor AT2R is an anti-inflammatory and cardiovascular protective molecule; however, AT2R agonists are not used in the clinic to treat heart disease. NP-6A4 is a new AT2R peptide agonist with an FDA orphan drug designation for pediatric cardiomyopathy. NP-6A4 increases AT2R expression (mRNA and protein) and nitric oxide generation in human cardiovascular cells. AT2R-antagonist PD123319 and AT2RSiRNA suppress NP-6A4-effects indicating that NP-6A4 acts through AT2R. To determine whether NP-6A4 would mitigate cardiac damage from chronic inflammation induced by untreated obesity, we investigated the effects of 2-weeks NP-6A4 treatment (1.8 mg/kg delivered subcutaneously) on cardiac pathology of male Zucker obese (ZO) rats that display obesity, pre-diabetes and cardiac dysfunction. NP-6A4 attenuated cardiac diastolic and systolic dysfunction, cardiac fibrosis and cardiomyocyte hypertrophy, but increased myocardial capillary density. NP-6A4 treatment suppressed tubulointerstitial injury marker urinary ß-NAG, and liver injury marker alkaline phosphatase in serum. These protective effects of NP-6A4 occurred in the presence of obesity, hyperinsulinemia, hyperglycemia, and hyperlipidemia, and without modulating blood pressure. NP-6A4 increased expression of AT2R (consistent with human cells) and cardioprotective erythropoietin (EPO) and Notch1 in ZO rat heart, but suppressed nineteen inflammatory cytokines. Cardiac miRNA profiling and in silico analysis showed that NP-6A4 activated a unique miRNA network that may regulate expression of AT2R, EPO, Notch1 and inflammatory cytokines, and mitigate cardiac pathology. Seventeen pro-inflammatory and pro-fibrotic cytokines that increase during lethal cytokine storms caused by infections such as COVID-19 were among the cytokines suppressed by NP-6A4 treatment in ZO rat heart. Thus, NP-6A4 activates a novel anti-inflammatory network comprised of 21 proteins in the heart that was not reported previously. Since NP-6A4's unique mode of action suppresses pro-inflammatory cytokine network and attenuates myocardial damage, it can be an ideal adjuvant drug with other anti-glycemic, anti-hypertensive, standard-of-care drugs to protect the heart tissues from pro-inflammatory and pro-fibrotic cytokine attack induced by obesity.

Minocycline reverses IL-17A/TRAF3IP2-mediated p38 MAPK/NF-κB/iNOS/NO-dependent cardiomyocyte contractile depression and death.

Minocycline, an FDA-approved second-generation semisynthetic tetracycline, exerts antioxidant, anti-apoptotic and anti-inflammatory effects, independent of its antimicrobial properties. Interleukin (IL)-17A is an immune and inflammatory mediator, and its sustained induction is associated with various cardiovascular diseases. Here we investigated (i) whether IL-17A induces cardiomyocyte contractile depression and death, (ii) whether minocycline reverses IL-17A's negative inotropic effects and (iii) investigated the underlying molecular mechanisms. Indeed, treatment with recombinant mouse IL-17A impaired adult cardiomyocyte contractility as evidenced by a 34% inhibition in maximal velocity of shortening and relengthening after 4 h (P < .01). Contractile depression followed iNOS induction at 2 h (2.13-fold, P < .01) and NO generation at 3 h (3.71-fold, P <.01). Further mechanistic investigations revealed that IL-17A-dependent induction of iNOS occurred via TRAF3IP2, TRAF6, TAK1, NF-κB, and p38MAPK signaling. 1400 W, a highly specific iNOS inhibitor, suppressed IL-17A-induced NO generation and contractile depression, where as the NO donors SNAP and PAPA-NONOate both suppressed cardiomyocyte contractility. IL-17A also stimulated cardiomyocyte IL-1ß and TNF-α secretion, however, their neutralization failed to modulate IL-17A-mediated contractile depression or viability. Further increases of IL-17A concentration and the duration of exposure enhanced IL-1ß and TNF-α secreted levels, buthad no impact on adult cardiomyocyte viability. However, when combined with pathophysiological concentrations of IL-1ß or TNF-α, IL-17A promoted adult cardiomyocyte death. Importantly, minocycline blunted IL-17A-mediated deleterious effects, indicating its therapeutic potential in inflammatory cardiac diseases.

Impact of Left Ventricular Hypertrophy on Peak Serum Troponin T Levels in Patients With Acute Myocardial Infarction.

Previous studies have reported that peak serum troponin I levels were disproportionately elevated in patients with acute anterior ST-segment elevation myocardial infarction (STEMI) and left ventricular (LV) hypertrophy (LVH) compared with those with normal LV mass. The purpose of this retrospective study was to assess the relation of peak serum troponin T levels in patients with normal LV mass and in subjects with mild, moderate, and severe LVH in patients with acute STEMI or non-ST segment elevation myocardial infarction (NSTEMI) when stratified on variables that might be expected to affect serum troponin T levels. The study population consisted of 262 patients; 91 with STEMI and 161 with NSTEMI. Serum troponin levels and 2-dimensional echocardiograms were obtained within the first 24 hours of hospitalization for STEMI or NSTEMI. There was no significant difference in serum troponin T levels in LV mass and/or LVH groups (p = 0.3210). There was no significant difference in serum troponin T levels in LV mass and/or LVH groups when these data were stratified on third variables including serum creatinine >1.2 mg/dl (p = 0.3681), LV ejection fraction <60% (p = 0.0978), STEMI (p = 0.2576), NSTEMI (p = 0.4994), and location of severe coronary stenosis (p = 0.1981). The results of this study suggest that there is no association between peak serum troponin T levels and LV mass and/or LVH groups when such groups are stratified on a third variable that may influence peak serum troponin T levels.

Multimodality detection of multiple left ventricular diverticula: A case report and brief review of the literature.

Left ventricular diverticula (LVD) are rare congenital anomalies usually detected incidentally in the adult population. Most commonly, they are found as a single left ventricular diverticulum in association with other congenital abnormalities but multiple LVD are exceedingly rare. We are describing a patient who was found to have multiple LVD on multimodality imaging studies. He had presented with a sudden cardiac arrest attributed to a combination of alcohol intoxication and QT interval prolongation from hypokalemia and antidepressant medications. The patient was managed conservatively and discharged with an implantable loop recorder for detecting any occult arrhythmias.

Reversible cardiac dysfunction in long-standing hypertension may be global variant of stress cardiomyopathy.

An adult man with long-standing poorly controlled cardiac risk factors presented with acute decompensated heart failure (ADHF). Echocardiogram, cardiac MRI and catheterisation suggested idiopathic dilated cardiomyopathy, severe systolic dysfunction, ejection fraction 25% with global left ventricular (LV) dilation and apical thrombus. He responded well to diuretics and gradual uptitration of lisinopril and carvedilol. Follow-up echocardiogram in 2 months demonstrated complete recovery of systolic function, normalisation of LV size and shape with severe LV hypertrophy. This presentation is potentially a global variant of stress cardiomyopathy with recovery of LV function, highlighting the importance of appropriate imaging, catheterisation and clinical monitoring in patients with ADHF.

A QS pattern in leads V1 and V2 is associated with septal scarring independent of scar etiology - A cardiac magnetic resonance imaging study.

BACKGROUND: Isolated septal myocardial infarction (MI) is traditionally characterized by the presence of pathological Q waves in leads V1 and V2 on the surface electrocardiogram (ECG). The purpose of this study was to determine the relation between this ECG pattern and septal scar on cardiac magnetic resonance (CMR) imaging. METHODS: We retrospectively reviewed the medical records of 996 consecutive patients who received both ECG and CMR. RESULTS: Nineteen patients had a Q wave in leads V1 and V2. Septal scar was present in all 19 patients. Based on CMR imaging criteria, septal scars were ischemic in 8 patients (42%) and non-ischemic in 11 patients (58%). CONCLUSION: The results suggest that the presence of a QS pattern in leads V1 and V2 on the surface ECG is highly predictive of the presence of a septal myocardial scar, but is not diagnostic for septal MI, even after excluding comorbidities known to produce a pseudo-septal MI pattern.

TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart.

Persistent inflammation promotes development and progression of heart failure (HF). TWEAK (TNF-Related WEAK Inducer Of Apoptosis), a NF-κB- and/or AP-1-responsive proinflammatory cytokine that signals via TWEAK receptor (TWEAKR), is expressed at high levels in human and preclinical models of HF. Since the adapter molecule TRAF3IP2 (TRAF3 Interacting Protein 2) is an upstream regulator of various proinflammatory pathways, including those activated by NF-κB and AP-1, we hypothesized that targeting TRAF3IP2 inhibits TWEAK-induced proinflammatory and pro-fibrotic responses in vitro and in vivo. Consistent with the hypothesis, forced expression of TRAF3IP2 upregulated TWEAK and its receptor expression in cultured adult mouse cardiac fibroblasts (CF). Further, exogenous TWEAK upregulated TRAF3IP2 expression in a time- and dose-dependent manner, suggesting a positive-feedback regulation of TRAF3IP2 and TWEAK. TWEAK also promoted TRAF3IP2 nuclear translocation. Confirming its critical role in TWEAK signaling, silencing TRAF3IP2 inhibited TWEAK autoregulation, TWEAKR upregulation, p38 MAPK, NF-κB and AP-1 activation, inflammatory cytokine expression, MMP and TIMP1 activation, collagen expression and secretion, and importantly, proliferation and migration. Recapitulating these in vitro results, continuous infusion of TWEAK for 7 days increased systolic blood pressure (SBP), upregulated TRAF3IP2 expression, activated p38 MAPK, NF-κB and AP-1, induced the expression of multiple proinflammatory and pro-fibrotic mediators, and interstitial fibrosis in hearts of wild type mice. These proinflammatory and pro-fibrotic changes occurred in conjunction with myocardial hypertrophy and contractile dysfunction. Importantly, genetic ablation of TRAF3IP2 inhibited these TWEAK-induced adverse cardiac changes independent of increases in SBP, indicating that TRAF3IP2 plays a causal role, and thus a therapeutic target, in chronic inflammatory and fibro-proliferative diseases.

Cardiovascular disease progression in female Zucker Diabetic Fatty rats occurs via unique mechanisms compared to males.

Population studies have shown that compared to diabetic men, diabetic women are at a higher risk of cardiovascular disease. However, the mechanisms underlying this gender disparity are unclear. Our studies in young murine models of type 2 diabetes mellitus (T2DM) and cardiovascular disease show that diabetic male rats develop increased cardiac fibrosis and suppression of intracardiac anti-fibrotic cytokines, while premenopausal diabetic female rats do not. This protection from cardiac fibrosis in female rats can be an estrogen-related effect. However, diabetic female rats develop early subclinical myocardial deformation, cardiac hypertrophy via elevated expression of pro-hypertrophic miR-208a, myocardial damage, and suppression of cardio-reparative Angiotensin II receptor 2 (Agtr2). Diabetic rats of both sexes exhibit a reduction in cardiac capillary density. However, diabetic female rats have reduced expression of neuropilin 1 that attenuates cardiomyopathy compared to diabetic male rats. A combination of cardiac hypertrophy and reduced capillary density likely contributed to increased myocardial structural damage in diabetic female rats. We propose expansion of existing cardiac assessments in diabetic female patients to detect myocardial deformation, cardiac hypertrophy and capillary density via non-invasive imaging, as well as suggest miR-208a, AT2R and neuropilin 1 as potential therapeutic targets and mechanistic biomarkers for cardiac disease in females.

Inulin oligofructose attenuates metabolic syndrome in high-carbohydrate, high-fat diet-fed rats.

Prebiotics alter bacterial content in the colon, and therefore could be useful for obesity management. We investigated the changes following addition of inulin oligofructose (IO) in the food of rats fed either a corn starch (C) diet or a high-carbohydrate, high-fat (H) diet as a model of diet-induced metabolic syndrome. IO did not affect food intake, but reduced body weight gain by 5·3 and 12·3 % in corn starch+inulin oligofructose (CIO) and high-carbohydrate, high-fat with inulin oligofructose (HIO) rats, respectively. IO reduced plasma concentrations of free fatty acids by 26·2 % and TAG by 75·8 % in HIO rats. IO increased faecal output by 93·2 %, faecal lipid excretion by 37·9 % and weight of caecum by 23·4 % and colon by 41·5 % in HIO rats. IO improved ileal morphology by reducing inflammation and improving the density of crypt cells in HIO rats. IO attenuated H diet-induced increases in abdominal fat pads (C 275 (sem 19), CIO 264 (sem 40), H 688 (sem 55), HIO 419 (sem 32) mg/mm tibial length), fasting blood glucose concentrations (C 4·5 (sem 0·1), CIO 4·2 (sem 0·1), H 5·2 (sem 0·1), HIO 4·3 (sem 0·1) mmol/l), systolic blood pressure (C 124 (sem 2), CIO 118 (sem 2), H 152 (sem 2), HIO 123 (sem 3) mmHg), left ventricular diastolic stiffness (C 22·9 (sem 0·6), CIO 22·9 (sem 0·5), H 27·8 (sem 0·5), HIO 22·6 (sem 1·2)) and plasma alanine transaminase (C 29·6 (sem 2·8), CIO 32·1 (sem 3·0), H 43·9 (sem 2·6), HIO 33·6 (sem 2·0) U/l). IO attenuated H-induced increases in inflammatory cell infiltration in the heart and liver, lipid droplets in the liver and plasma lipids as well as impaired glucose and insulin tolerance. These results suggest that increasing soluble fibre intake with IO improves signs of the metabolic syndrome by decreasing gastrointestinal carbohydrate and lipid uptake.

Cardiac Effects of Obesity: PATHOPHYSIOLOGIC, CLINICAL, AND PROGNOSTIC CONSEQUENCES-A REVIEW.

Obesity produces various hemodynamic alterations and changes in cardiac morphology that predispose to ventricular dysfunction and heart failure (HF). Obesity may serve as a risk factor for or the primary cause of HF. Obesity is also associated with impairment of cardiorespiratory fitness. An obesity paradox exists with respect to mortality in those with HF wherein overweight and mildly to moderately obese individuals have a better prognosis than underweight or normal weight persons. Cardiorespiratory fitness is an important determinant of the prognosis in obesity. Many of the alterations in cardiac structure and function as well as the clinical manifestations of HF are reversible with substantial weight loss in moderately to severely obese individuals.

Effect of weight loss on ventricular repolarization in normotensive severely obese patients with and without heart failure.

BACKGROUND: Obesity has been reported to be associated with delayed ventricular repolarization. The purpose of this study was to assess ventricular repolarization in normotensive severely obese subjects with and without heart failure (HF) and to assess the effect of weight loss on ventricular repolarization in such patients. METHODS: Twenty-eight patients with and 39 patients without HF (body mass index ≥ 40 kg/m(2)) were studied before and after weight loss from bariatric surgery. Corrected QT interval (QTc) was measured on 12-lead electrocardiograms using Bazett's formula. QTc dispersion was calculated by subtracting the minimum from the maximum QTc on each 12-lead electrocardiogram. Electrocardiograms and transthoracic echocardiograms were performed preoperatively and at the nadir of postoperative weight loss. RESULTS: Mean QTc and QTc dispersion were significantly longer/greater in subjects with HF than in those without HF (P < 0.0001). Weight loss produced significant reductions in mean QTc and QTc dispersion in both subgroups (P < 0.0001). Pre-weight loss left ventricular (LV) mass/height and presence or absence of HF independently predicted pre-weight loss QTc and QTc dispersion (P < 0.0001). Weight loss-induced decrease in LV mass/height independently predicted weight loss-induced decreases in QTc and QTc dispersion (P < 0.0001). CONCLUSIONS: HF independently predicts QTc and QTc dispersion in normotensive severely obese patients. Decrease in the LV mass resulting from weight loss independently predicts reduction in QTc and QTc dispersion in such patients.

Obesity and heart failure: epidemiology, pathophysiology, clinical manifestations, and management.

Obesity is a risk factor for heart failure (HF) in both men and women. The mortality risk of overweight and class I and II obese adults with HF is lower than that of normal weight or underweight adults with HF of comparable severity, a phenomenon referred to as the obesity paradox. Severe obesity produces hemodynamic alterations that predispose to changes in cardiac morphology and ventricular function, which may lead to the development of HF. The presence of systemic hypertension, sleep apnea, and hypoventilation, comorbidities that occur commonly with severe obesity, may contribute to HF in such patients. The resultant syndrome is known as obesity cardiomyopathy. Substantial weight loss in severely obese persons is capable of reversing most obesity-related abnormalities of cardiac performance and morphology and improving the clinical manifestations of obesity cardiomyopathy.

Heart failure and obesity in adults: pathophysiology, clinical manifestations and management.

Obesity is both a risk factor and a direct cause of heart failure (HF) in adults. Severe obesity produces hemodynamic alterations that predispose to changes in left ventricular morphology and function, which, over time, may lend to the development of HF (obesity cardiomyopathy). Certain neurohormonal and metabolic abnormalities as well as cardiovascular co-morbidities may facilitate this process. Substantial purposeful weight loss is capable of reversing most of the alterations in cardiac performance and morphology and may improve functional capacity and quality of life in patents with obesity cardiomyopathy.

Responses to oleic, linoleic and α-linolenic acids in high-carbohydrate, high-fat diet-induced metabolic syndrome in rats.

We investigated the changes in adiposity, cardiovascular and liver structure and function, and tissue fatty acid compositions in response to oleic acid-rich macadamia oil, linoleic acid-rich safflower oil and α-linolenic acid-rich flaxseed oil (C18 unsaturated fatty acids) in rats fed either a diet high in simple sugars and mainly saturated fats or a diet high in polysaccharides (cornstarch) and low in fat. The fatty acids induced lipid redistribution away from the abdomen, more pronounced with increasing unsaturation; only oleic acid increased whole-body adiposity. Oleic acid decreased plasma total cholesterol without changing triglycerides and nonesterified fatty acids, whereas linoleic and α-linolenic acids decreased plasma triglycerides and nonesterified fatty acids but not cholesterol. α-Linolenic acid improved left ventricular structure and function, diastolic stiffness and systolic blood pressure. Neither oleic nor linoleic acid changed the left ventricular remodeling induced by high-carbohydrate, high-fat diet, but both induced dilation of the left ventricle and functional deterioration in low fat-diet-fed rats. α-Linolenic acid improved glucose tolerance, while oleic and linoleic acids increased basal plasma glucose concentrations. Oleic and α-linolenic acids, but not linoleic acid, normalized systolic blood pressure. Only oleic acid reduced plasma markers of liver damage. The C18 unsaturated fatty acids reduced trans fatty acids in the heart, liver and skeletal muscle with lowered stearoyl-CoA desaturase-1 activity index; linoleic and α-linolenic acids increased accumulation of their C22 elongated products. These results demonstrate different physiological and biochemical responses to primary C18 unsaturated fatty acids in a rat model of human metabolic syndrome.

Variability in the origin of the obturator artery.

INTRODUCTION: General surgeons dealing with laparoscopic herniorrhaphy should be aware of the aberrant obturator artery that crosses the superior pubic ramus and is susceptible to injuries during dissection of the Bogros space and mesh stapling onto Cooper's ligament. The obturator artery is usually described as a branch of the anterior division of the internal iliac artery, although variations have been reported. MATERIALS AND METHODS: The present study was conducted on 98 pelvic halves of embalmed cadavers, and the origin and course of the obturator artery were traced and noted. RESULTS: In 79% of the specimens, the obturator artery was a branch of the internal iliac artery. It branched off at different levels either from the anterior division or posterior division, individually or with other named branches. In 19% of the cases, the obturator artery branched off from the external iliac artery as a separate branch or with the inferior epigastric artery. However, in the remaining 2% of the specimens, both the internal and the external iliac arteries branched to form an anastomotic structure within the pelvic cavity. CONCLUSION: The data obtained in this study show that it is more common to find an abnormal obturator artery than was reported previously, and this observation has implications for pelvic surgeons and is of academic interest to anatomists. Surgeons dealing with direct, indirect, femoral, or obturator hernias need to be aware of these variations and their close proximity to the femoral ring.

Variability in the origin of the obturator artery

INTRODUCTION: General surgeons dealing with laparoscopic herniorrhaphy should be aware of the aberrant obturator artery that crosses the superior pubic ramus and is susceptible to injuries during dissection of the Bogros space and mesh stapling onto Cooper's ligament. The obturator artery is usually described as a branch of the anterior division of the internal iliac artery, although variations have been reported. MATERIALS AND METHODS: The present study was conducted on 98 pelvic halves of embalmed cadavers, and the origin and course of the obturator artery were traced and noted. RESULTS: In 79 percent of the specimens, the obturator artery was a branch of the internal iliac artery. It branched off at different levels either from the anterior division or posterior division, individually or with other named branches. In 19 percent of the cases, the obturator artery branched off from the external iliac artery as a separate branch or with the inferior epigastric artery. However, in the remaining 2 percent of the specimens, both the internal and the external iliac arteries branched to form an anastomotic structure within the pelvic cavity. CONCLUSION: The data obtained in this study show that it is more common to find an abnormal obturator artery than was reported previously, and this observation has implications for pelvic surgeons and is of academic interest to anatomists. Surgeons dealing with direct, indirect, femoral, or obturator hernias need to be aware of these variations and their close proximity to the femoral ring.