COVID19-associated cardiomyocyte dysfunction, arrhythmias and the effect of Canakinumab.

BACKGROUND: Cardiac injury associated with cytokine release frequently occurs in SARS-CoV-2 mediated coronavirus disease (COVID19) and mortality is particularly high in these patients. The mechanistic role of the COVID19 associated cytokine-storm for the concomitant cardiac dysfunction and associated arrhythmias is unclear. Moreover, the role of anti-inflammatory therapy to mitigate cardiac dysfunction remains elusive. AIMS AND METHODS: We investigated the effects of COVID19-associated inflammatory response on cardiac cellular function as well as its cardiac arrhythmogenic potential in rat and induced pluripotent stem cell derived cardiomyocytes (iPS-CM). In addition, we evaluated the therapeutic potential of the IL-1ß antagonist Canakinumab using state of the art in-vitro confocal and ratiometric high-throughput microscopy. RESULTS: Isolated rat ventricular cardiomyocytes were exposed to control or COVID19 serum from intensive care unit (ICU) patients with severe ARDS and impaired cardiac function (LVEF 41±5%; 1/3 of patients on veno-venous extracorporeal membrane oxygenation; CK 154±43 U/l). Rat cardiomyocytes showed an early increase of myofilament sensitivity, a decrease of Ca2+ transient amplitudes and altered baseline [Ca2+] upon exposure to patient serum. In addition, we used iPS-CM to explore the long-term effect of patient serum on cardiac electrical and mechanical function. In iPS-CM, spontaneous Ca2+ release events were more likely to occur upon incubation with COVID19 serum and nuclear as well as cytosolic Ca2+ release were altered. Co-incubation with Canakinumab had no effect on pro-arrhythmogenic Ca2+ release or Ca2+ signaling during excitation-contraction coupling, nor significantly influenced cellular automaticity. CONCLUSION: Serum derived from COVID19 patients exerts acute cardio-depressant and chronic pro-arrhythmogenic effects in rat and iPS-derived cardiomyocytes. Canakinumab had no beneficial effect on cellular Ca2+ signaling during excitation-contraction coupling. The presented method utilizing iPS-CM and in-vitro Ca2+ imaging might serve as a novel tool for precision medicine. It allows to investigate cytokine related cardiac dysfunction and pharmacological approaches useful therein.

Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice.

Increasing evidence indicates the involvement of myocardial oxidative injury and mitochondrial dysfunction in the pathophysiology of heart failure (HF). Alpha-ketoglutarate (AKG) is an intermediate metabolite of the tricarboxylic acid (TCA) cycle that participates in different cellular metabolic and regulatory pathways. The circulating concentration of AKG was found to decrease with ageing and is elevated after acute exercise and resistance exercise and in HF. Recent studies in experimental models have shown that dietary AKG reduces reactive oxygen species (ROS) production and systemic inflammatory cytokine levels, regulates metabolism, extends lifespan and delays the occurrence of age-related decline. However, the effects of AKG on HF remain unclear. In the present study, we explored the effects of AKG on left ventricular (LV) systolic function, the myocardial ROS content and mitophagy in mice with transverse aortic constriction (TAC). AKG supplementation inhibited pressure overload-induced myocardial hypertrophy and fibrosis and improved cardiac systolic dysfunction; in vitro, AKG decreased the Ang II-induced upregulation of ß-MHC and ANP, reduced ROS production and cardiomyocyte apoptosis, and repaired Ang II-mediated injury to the mitochondrial membrane potential (MMP). These benefits of AKG in the TAC mice may have been obtained by enhanced mitophagy, which cleared damaged mitochondria. In summary, our study suggests that AKG improves myocardial hypertrophy remodelling, fibrosis and LV systolic dysfunction in the pressure-overloaded heart by promoting mitophagy to clear damaged mitochondria and reduce ROS production; thus, AKG may have therapeutic potential for HF.

Water-soluble alkaloids extracted from Aconiti Radix lateralis praeparata protect against chronic heart failure in rats via a calcium signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Many studies have shown the beneficial effects of aconite water-soluble alkaloid extract (AWA) in experimental models of heart disease, which have been ascribed to the presence of aconine, hypaconine, talatisamine, fuziline, neoline, and songorine. This study evaluated the effects of a chemically characterized AWA by chemical content, evaluated its effects in suprarenal abdominal aortic coarctation surgery (AAC)-induced chronic heart failure (CHF) in rats, and revealed the underlying mechanisms of action by proteomics. METHODS: Rats were distributed into different groups: sham, model, and AWA-treated groups (10, 20, and 40 mg/kg/day). Sham rats received surgery without AAC, whereas model rats an AWA-treated groups underwent AAC surgery. after 8 weeks, the treatment group was fed AWA for 4 weeks, and body weight was assessed weekly. At the end of the treatment, heart function was tested by echocardiography. AAC-induced chronic heart failure, including myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis, was evaluated in heart tissue and plasma by RT-qPCR, ELISA, hematoxylin and eosin (H&E) staining, Masson's trichrome staining, TUNEL staining, and immunofluorescence staining of α-SMA, Col Ⅰ, and Col Ⅲ. Then, a proteomics approach was used to explore the underlying mechanisms of action of AWA in chronic heart failure. RESULTS: AWA administration reduced body weight gain, myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis, and rats showed improvement in cardiac function compared to model group. The extract significantly ameliorated the AAC-induced altered expression of heart failure markers such as ANP, NT-proBNP, and ß-MHC, as well as fibrosis, hypertrophy markers MMP-2 and MMP-9, and other heart failure-related factors including plasma levels of TNF-α and IL-6. Furthermore, the extract reduced the protein expression of α-SMA, Col Ⅰ, and Col Ⅲ in the left ventricular (LV), thus inhibiting the LV remodeling associated with CHF. In addition, proteomics characterization of differentially expressed proteins showed that AWA administration inhibited left ventricular remodeling in CHF rats via a calcium signaling pathway, and reversed the expression of RyR2 and SERCA2a. CONCLUSIONS: AWA extract exerts beneficial effects in an AAC-induced CHF model in rats, which was associated with an improvement in LV function, hypertrophy, fibrosis, and apoptotic status. These effects may be related to the regulation of calcium signaling by the altered expression of RyR2 and SERCA2a.

Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure.

BACKGROUND: Accumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and that increasing cardiac ketone delivery ameliorates cardiac dysfunction. As an initial step toward development of ketone therapies, we investigated the effect of chronic oral ketone ester (KE) supplementation as a prevention or treatment strategy in rodent heart failure models. METHODS: Two independent rodent heart failure models were used for the studies: transverse aortic constriction/myocardial infarction (MI) in mice and post-MI remodeling in rats. Seventy-five mice underwent a prevention treatment strategy with a KE comprised of hexanoyl-hexyl-3-hydroxybutyrate KE (KE-1) diet, and 77 rats were treated in either a prevention or treatment regimen using a commercially available ß-hydroxybutyrate-(R)-1,3-butanediol monoester (DeltaG; KE-2) diet. RESULTS: The KE-1 diet in mice elevated ß-hydroxybutyrate levels during nocturnal feeding, whereas the KE-2 diet in rats induced ketonemia throughout a 24-hour period. The KE-1 diet preventive strategy attenuated development of left ventricular dysfunction and remodeling post-transverse aortic constriction/MI (left ventricular ejection fraction±SD, 36±8 in vehicle versus 45±11 in KE-1; P=0.016). The KE-2 diet therapeutic approach also attenuated left ventricular dysfunction and remodeling post-MI (left ventricular ejection fraction, 41±11 in MI-vehicle versus 61±7 in MI-KE-2; P<0.001). In addition, ventricular weight, cardiomyocyte cross-sectional area, and the expression of ANP (atrial natriuretic peptide) were significantly attenuated in the KE-2-treated MI group. However, treatment with KE-2 did not influence cardiac fibrosis post-MI. The myocardial expression of the ketone transporter and 2 ketolytic enzymes was significantly increased in rats fed KE-2 diet along with normalization of myocardial ATP levels to sham values. CONCLUSIONS: Chronic oral supplementation with KE was effective in both prevention and treatment of heart failure in 2 preclinical animal models. In addition, our results indicate that treatment with KE reprogrammed the expression of genes involved in ketone body utilization and normalized myocardial ATP production following MI, consistent with provision of an auxiliary fuel. These findings provide rationale for the assessment of KEs as a treatment for patients with heart failure.

Comparison of exercise training and estrogen supplementation on mast cell-mediated doxorubicin-induced cardiotoxicity.

Cardiac inflammation has been proposed as one of the primary mechanisms of anthracycline-induced acute cardiotoxicity. A reduction in cardiac inflammation might also reduce cardiotoxicity. This study aimed to evaluate the potential of estrogen therapy and regular exercise on attenuating cardiac inflammation in the context of doxorubicin-induced cardiomyopathy. Ovariectomized rats were randomly allocated into estrogen supplementation, exercise training, and mast cell stabilizer treatment groups. Eight weeks after ovariectomy, rats received six cumulative doses of doxorubicin for two weeks. Echocardiography demonstrated a progressive decrease in ejection fraction in doxorubicin-treated rats without hypertrophic effect. This systolic defect was completely prevented by either estrogen supplementation or mast cell stabilizer treatment but not by regular exercise. As a heart disease indicator, increased ß-myosin heavy chain expression induced by doxorubicin could only be prevented by estrogen supplementation. Decrease in shortening and intracellular Ca2+ transients of cardiomyocytes were due to absence of female sex hormones without further effects of doxorubicin. Again, estrogen supplementation and mast cell stabilizer treatment prevented these changes but exercise training did not. Histological analysis indicated that the hyperactivation of cardiac mast cells in ovariectomized rats was augmented by doxorubicin. Estrogen supplementation and mast cell stabilizer treatment completely prevented both increases in mast cell density and degranulation, whereas exercise training partially attenuated the hyperactivation. Our results, therefore, suggest that estrogen supplementation acts similarly to mast cell stabilizers in attenuating the effects of doxorubicin. Ineffectiveness of regular exercise in preventing the acute cardiotoxicity of doxorubicin might be due to a lesser effect on preventing cardiac inflammation.

Therapeutic Modulation of the Immune Response in Arrhythmogenic Cardiomyopathy.

BACKGROUND: Inflammation is a prominent feature of arrhythmogenic cardiomyopathy (ACM), but whether it contributes to the disease phenotype is not known. METHODS: To define the role of inflammation in the pathogenesis of ACM, we characterized nuclear factor-κB signaling in ACM models in vitro and in vivo and in cardiac myocytes from patient induced pluripotent stem cells. RESULTS: Activation of nuclear factor-κB signaling, indicated by increased expression and nuclear accumulation of phospho-RelA/p65, occurred in both an in vitro model of ACM (expression of JUP2157del2 in neonatal rat ventricular myocytes) and a robust murine model of ACM (homozygous knock-in of mutant desmoglein-2 [Dsg2mut/mut]) that recapitulates the cardiac manifestations seen in patients with ACM. Bay 11-7082, a small-molecule inhibitor of nuclear factor-κB signaling, prevented the development of ACM disease features in vitro (abnormal redistribution of intercalated disk proteins, myocyte apoptosis, release of inflammatory cytokines) and in vivo (myocardial necrosis and fibrosis, left ventricular contractile dysfunction, electrocardiographic abnormalities). Hearts of Dsg2mut/mut mice expressed markedly increased levels of inflammatory cytokines and chemotactic molecules that were attenuated by Bay 11-7082. Salutary effects of Bay 11-7082 correlated with the extent to which production of selected cytokines had been blocked. Nuclear factor-κB signaling was also activated in cardiac myocytes derived from a patient with ACM. These cells produced and secreted abundant inflammatory cytokines under basal conditions, and this was also greatly reduced by Bay 11-7082. CONCLUSIONS: Inflammatory signaling is activated in ACM and drives key features of the disease. Targeting inflammatory pathways may be an effective new mechanism-based therapy for ACM.

Oxidative stress induces different tissue dependent effects on Mutyh-deficient mice.

8-oxoguanine (8-oxoG) is one of the most prevalent genotoxic lesions, and it is generated in DNA attacked by reactive oxygen species (ROS). Adenine misincorporated opposite to 8-oxoG during replication is excised by MutY homolog (MUTYH), an important protein of the base excision repair (BER) system. Mutyh plays an important role in the maintenance of genomic integrity, but the functional consequences of Mutyh deficiency are not fully understood. In the current study, we investigated the histological and functional changes of five tissues (hippocampus, heart, liver, kidney and lung) and their molecular basis in Mutyh-/- and wild-type mice exposed to D-galactose (D-gal). Our data indicated that Mutyh deficiency hindered the weight gain of experimental mice and induced substantial alterations of 8-oxoG content and superoxide dismutase (SOD) activity, but no significant histological and functional impairment appeared in the investigated tissues of Mutyh- deficient mice without D-gal exposure. Under low-dose D-gal exposure, Mutyh deficiency altered expression of genes involved in mitochondrial unfolded protein response (UPRmt) in the heart, liver and lung, and caused an enhanced expression of mitochondrial dynamics proteins (MDPs) in hippocampus and liver. The stress responses could maintain mitochondrial proteostasis and function. However, such responses were not noted when experiencing excessive damage burden induced by high-dose D-gal exposure, in which Mutyh deficiency increased accumulation of 8-oxoG and aggravated mitonuclear protein imbalance, as well as histological lesions in heart, liver and kidney. A higher sensitivity to ROS-induced cardiotoxicity with high-dose D-gal exposure was noticed in Mutyh-/- mice. However, no differences in learning and memory impairments were observed between Mutyh-/- and wild-type mice with high-dose D-gal exposure. In conclusion, our data demonstrated that Mutyh deficiency has different impacts on various tissues based on the degree of oxidative stress.

Pretreatment with fish oil attenuates heart ischaemia consequences in rats.

NEW FINDINGS: What is the central question of this study? We investigated whether pretreatment with fish oil could prevent the major consequences of ischaemic injury to the heart. What is the main finding and its importance? Fish oil pretreatment attenuated the consequences of ischaemic injury as indicated by the small infarction area and the preservation of systolic function and coronary blood flow. These findings support the use of fish oil in order to reduce the impact of heart ischaemia. ω-3 Polyunsaturated fatty acid (ω-3 PUFA)-rich fish oil supplementation has protective effects on heart ischaemic injury. Left ventricular (LV) ischaemia was induced in rats by permanent ligation of the left descending coronary artery. Saline, fish oil or soybean oil was administered daily by gavage [3 g (kg body weight)-1 ] for 20 days before inducing ischaemia. Outcomes were assessed 24 h after left descending coronary artery ligation. Pretreatment with fish oil decreased the ω-6/ω-3 fatty acid ratio in the LV. A reduction in infarct size and in the intensity of ventricular systolic dysfunction was found in the fish oil group compared with the saline or soybean oil groups through echocardiographic evaluation. Before infarction, LV glycogen concentrations were decreased in the fish oil group compared with the saline group. Soybean oil pretreatment led to a further increase in the LV levels of CINC-2/αß, IL-1ß and TNF-α induced by the heart infarction. In heart-infarcted rats, fish oil pretreatment decreased creatine kinase and caspase-3 activities; prevented the decrease in the coronary blood flow; increased LV contents of ATP and lactate; increased the mRNA levels of iNOS, eNOS, HIF1α, GLUT1, VEGF-α and p53 in the LV as measured by RT-PCR; and did not change LV pro-inflammatory cytokine concentrations compared with the control group. Fish oil protected the heart from ischaemia, as indicated by the decrease in the heart infarction area and systolic dysfunction associated with increased LV ATP concentrations and maintenance of the coronary blood flow with no change in pro-inflammatory cytokine levels.

Proanthocyanidins block aldosterone-dependent up-regulation of cardiac gamma ENaC and Nedd4-2 inactivation via SGK1.

Aldosterone plays a central role in the development of cardiac pathological states involving ion transport imbalances, especially sodium transport. We have previously demonstrated a cardioprotective effect of proanthocyanidins in aldosterone-treated rats. Our objective was to investigate for the first time the effect of proanthocyanidins on serum and glucocorticoid-regulated kinase 1 (SGK1), epithelial Na+ channel (γ-ENaC), neuronal precursor cells expressed developmentally down-regulated 4-2 (Nedd4-2) and phosphoNedd4-2 protein expression in the hearts of aldosterone-treated rats. Male Wistar rats received aldosterone (1mg kg-1day-1)+1% NaCl for 3weeks. Half of the animals in each group were simultaneously treated with the proanthocyanidins-rich extract (80% w/w) (PRO80, 5mg kg-1day-1). Hypertension and diastolic dysfunction induced by aldosterone were abolished by treatment with PRO80. Expression of fibrotic, inflammatory and oxidative mediators were increased by aldosterone-salt administration and blunted by PRO80. Antioxidant capacity was improved by PRO80. The up-regulated aldosterone mediator SGK1, ENaC and p-Nedd4-2/total Nedd4-2 ratio were blocked by PRO80. PRO80 blunted aldosterone-mineralocorticoid-mediated up-regulation of ENaC provides new mechanistic insight of the beneficial effect of proanthocyanidins preventing the cardiac alterations induced by aldosterone excess.

Diffuse fibrosis leads to a decrease in unipolar voltage: Validation in a swine model of premature ventricular contraction-induced cardiomyopathy.

BACKGROUND: Frequent premature ventricular contractions (PVCs) may lead to dilated cardiomyopathy. A leftward shift in the unipolar voltage distribution in patients with cardiomyopathy has also been described and attributed to increased fibrosis. OBJECTIVES: We established a swine model of PVC-induced cardiomyopathy and assessed (1) whether an increase in left ventricular fibrosis occurs and (2) whether increased fibrosis leads to a leftward shift in the unipolar voltage distribution. METHODS: Ten swine underwent implantation of ventricular pacemakers; 6 programmed to deliver a 50% PVC burden and 4 controls without pacing. Voltage maps were acquired at baseline and after 14 weeks of ventricular bigeminy. RESULTS: In the PVC group, left ventricular ejection fraction decreased from 67% ± 7% to 44% ± 15% (P < .05) with no change in controls (71% ± 6% to 73% ± 4%; P = .56). The fifth percentile of the bipolar and unipolar voltage distribution at baseline was 1.63 and 5.36 mV, respectively. In the control group, after 14 weeks of pacing there was no significant change in % bipolar voltage <1.5 mV (pre 1.2% vs post 2.2%; P = .34) or % unipolar voltage <5.5 mV (pre 4.0% vs post 3.5%; P = .20). In the PVC group, there was a significant increase in % unipolar voltage <5.5 mV (5.4% vs 12.6%; P < .01), with a leftward shift in the unipolar voltage distribution. Histologically, % fibrosis was increased in the PVC group (control 1.8% ± 1.3% vs PVC 3.4% ± 2.6%; P < .01). CONCLUSION: PVC-induced cardiomyopathy in swine leads to an increase in interstitial fibrosis and a leftward shift in the unipolar voltage distribution. These findings are consistent with findings in humans with PVC-induced cardiomyopathy.

Evaluation of Cardiovascular Risk Factors in the Wistar Audiogenic Rat (WAR) Strain.

INTRODUCTION: Risk factors for life-threatening cardiovascular events were evaluated in an experimental model of epilepsy, the Wistar Audiogenic Rat (WAR) strain. METHODS: We used long-term ECG recordings in conscious, one year old, WAR and Wistar control counterparts to evaluate spontaneous arrhythmias and heart rate variability, a tool to assess autonomic cardiac control. Ventricular function was also evaluated using the pressure-volume conductance system in anesthetized rats. RESULTS: Basal RR interval (RRi) was similar between WAR and Wistar rats (188 ± 5 vs 199 ± 6 ms). RRi variability strongly suggests that WAR present an autonomic imbalance with sympathetic overactivity, which is an isolated risk factor for cardiovascular events. Anesthetized WAR showed lower arterial pressure (92 ± 3 vs 115 ± 5 mmHg) and exhibited indices of systolic dysfunction, such as higher ventricle end-diastolic pressure (9.2 ± 0.6 vs 5.6 ± 1 mmHg) and volume (137 ± 9 vs 68 ± 9 µL) as well as lower rate of increase in ventricular pressure (5266 ± 602 vs 7320 ± 538 mmHg.s-1). Indices of diastolic cardiac function, such as lower rate of decrease in ventricular pressure (-5014 ± 780 vs -7766 ± 998 mmHg.s-1) and a higher slope of the linear relationship between end-diastolic pressure and volume (0.078 ± 0.011 vs 0.036 ± 0.011 mmHg.µL), were also found in WAR as compared to Wistar control rats. Moreover, Wistar rats had 3 to 6 ventricular ectopic beats, whereas WAR showed 15 to 30 ectopic beats out of the 20,000 beats analyzed in each rat. CONCLUSIONS: The autonomic imbalance observed previously at younger age is also present in aged WAR and, additionally, a cardiac dysfunction was also observed in the rats. These findings make this experimental model of epilepsy a valuable tool to study risk factors for cardiovascular events in epilepsy.

Therapeutic targeting of oxidative stress with coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of diabetes with diminished PI3K(p110α) signaling.

Diabetes-induced cardiac complications include left ventricular (LV) dysfunction and heart failure. We previously demonstrated that LV phosphoinositide 3-kinase p110α (PI3K) protects the heart against diabetic cardiomyopathy, associated with reduced NADPH oxidase expression and activity. Conversely, in dominant negative PI3K(p110α) transgenic mice (dnPI3K), reduced cardiac PI3K signaling exaggerated diabetes-induced cardiomyopathy, associated with upregulated NADPH oxidase. The goal was to examine whether chronic supplementation with the antioxidant coenzyme Q(10) (CoQ(10)) could attenuate LV superoxide and diabetic cardiomyopathy in a setting of impaired PI3K signaling. Diabetes was induced in 6-week-old nontransgenic and dnPI3K male mice via streptozotocin. After 4 weeks of diabetes, CoQ(10) supplementation commenced (10 mg/kg ip, 3 times/week, 8 weeks). At study end (12 weeks of diabetes), markers of LV function, cardiomyocyte hypertrophy, collagen deposition, NADPH oxidase, oxidative stress (3-nitrotyrosine), and concentrations of CoQ(9) and CoQ(10) were determined. LV NADPH oxidase (Nox2 gene expression and activity, and lucigenin-enhanced chemiluminescence), as well as oxidative stress, were increased by diabetes, exaggerated in diabetic dnPI3K mice, and attenuated by CoQ(10). Diabetes-induced LV diastolic dysfunction (prolonged deceleration time, elevated end-diastolic pressure, impaired E/A ratio), cardiomyocyte hypertrophy and fibrosis, expression of atrial natriuretic peptide, connective tissue growth factor, and ß-myosin heavy chain were all attenuated by CoQ(10). Chronic CoQ(10) supplementation attenuates aspects of diabetic cardiomyopathy, even in a setting of reduced cardiac PI3K protective signaling. Given that CoQ(10) supplementation has been suggested to have positive outcomes in heart failure patients, chronic CoQ(10) supplementation may be an attractive adjunct therapy for diabetic heart failure.

Real-time assessment of myocardial viability in the catheterization laboratory using the intracoronary electrograms recorded by the PTCA guidewire in patients with left ventricular dysfunction: comparison with delayed-enhancement magnetic resonance imaging.

OBJECTIVES: This study aimed to determine whether the intracoronary electrograms (IC-EGMs) recorded using a standard percutaneous coronary intervention guidewire could provide myocardial viability information. BACKGROUND: The revascularization of dysfunctional but viable myocardium may confer prognostic benefits compared with medical therapy in patients with post-ischemic heart failure. However, knowledge of myocardial viability is often unavailable at the time of the procedure. METHODS: The peak-to-peak voltage of 317 IC-EGMs recordings from 25 patients with a previous myocardial infarction and systolic dysfunction were matched with corresponding delayed-enhancement magnetic resonance imaging sites using a 17-segment model of the left ventricle. RESULTS: Sixty-seven recordings were obtained from segments classified as complete scar on delayed-enhancement magnetic resonance imaging (group A), 162 from partially viable segments (group B), and 88 from fully viable segments (group C). Three high-pass (HP) filters (0.5, 30, and 100 Hz) were applied to the signals to modulate their spatial resolution. For all filters, the peak-to-peak voltage significantly decreased from group C to group B to group A (p < 0.001 for all comparisons). When receiver-operating characteristic analysis was used to compare nonviable (group A) with viable (group B + C) segments, the optimal discriminating voltages were 4.6, 2.2, and 0.78 mV for, respectively, HP-0.5, HP-30, and HP-100 filters, with a sensitivity of 92%, 94%, and 99% and a specificity of 70%, 79%, and 69%. CONCLUSIONS: The amplitude of the IC-EGMs discriminates viable from nonviable left ventricular segments. Because this technique is simple and inexpensive and provides real-time results, it is potentially useful to aid decision making in the catheterization laboratory.

In vivo diffusion tensor MRI of the human heart: reproducibility of breath-hold and navigator-based approaches.

The aim of this study was to implement a quantitative in vivo cardiac diffusion tensor imaging (DTI) technique that was robust, reproducible, and feasible to perform in patients with cardiovascular disease. A stimulated-echo single-shot echo-planar imaging (EPI) sequence with zonal excitation and parallel imaging was implemented, together with a novel modification of the prospective navigator (NAV) technique combined with a biofeedback mechanism. Ten volunteers were scanned on two different days, each time with both multiple breath-hold (MBH) and NAV multislice protocols. Fractional anisotropy (FA), mean diffusivity (MD), and helix angle (HA) fiber maps were created. Comparison of initial and repeat scans showed good reproducibility for both MBH and NAV techniques for FA (P > 0.22), MD (P > 0.15), and HA (P > 0.28). Comparison of MBH and NAV FA (FAMBHday1 = 0.60 ± 0.04, FANAVday1 = 0.60 ± 0.03, P = 0.57) and MD (MDMBHday1 = 0.8 ± 0.2 × 10(-3) mm(2) /s, MDNAVday1 = 0.9 ± 0.2 × 10(-3) mm(2) /s, P = 0.07) values showed no significant differences, while HA values (HAMBHday1Endo = 22 ± 10°, HAMBHday1Mid-Endo = 20 ± 6°, HAMBHday1Mid-Epi = -1 ± 6°, HAMBHday1Epi = -17 ± 6°, HANAVday1Endo = 7 ± 7°, HANAVday1Mid-Endo = 13 ± 8°, HANAVday1Mid-Epi = -2 ± 7°, HANAVday1Epi = -14 ± 6°) were significantly different. The scan duration was 20% longer with the NAV approach. Currently, the MBH approach is the more robust in normal volunteers. While the NAV technique still requires resolution of some bulk motion sensitivity issues, these preliminary experiments show its potential for in vivo clinical cardiac diffusion tensor imaging and for delivering high-resolution in vivo 3D DTI tractography of the heart.

Tocotrienols reverse cardiovascular, metabolic and liver changes in high carbohydrate, high fat diet-fed rats.

Tocotrienols have been reported to improve lipid profiles, reduce atherosclerotic lesions, decrease blood glucose and glycated haemoglobin concentrations, normalise blood pressure in vivo and inhibit adipogenesis in vitro, yet their role in the metabolic syndrome has not been investigated. In this study, we investigated the effects of palm tocotrienol-rich fraction (TRF) on high carbohydrate, high fat diet-induced metabolic, cardiovascular and liver dysfunction in rats. Rats fed a high carbohydrate, high fat diet for 16 weeks developed abdominal obesity, hypertension, impaired glucose and insulin tolerance with increased ventricular stiffness, lower systolic function and reduced liver function. TRF treatment improved ventricular function, attenuated cardiac stiffness and hypertension, and improved glucose and insulin tolerance, with reduced left ventricular collagen deposition and inflammatory cell infiltration. TRF improved liver structure and function with reduced plasma liver enzymes, inflammatory cell infiltration, fat vacuoles and balloon hepatocytes. TRF reduced plasma free fatty acid and triglyceride concentrations but only omental fat deposition was decreased in the abdomen. These results suggest that tocotrienols protect the heart and liver, and improve plasma glucose and lipid profiles with minimal changes in abdominal obesity in this model of human metabolic syndrome.

Isothiocyanates ameliorate the symptom of heart dysfunction and mortality in a murine AIDS model by inhibiting apoptosis in the left ventricle.

Cardiac involvement has been reported in as many as 45-55% of patients with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), and significant cardiac morbidity is reported in 6-7% of HIV patients. We investigated the inhibitory effects of isothiocyanates (ITCs) on heart dysfunction and mortality by regulating apoptosis in the left ventricle of the heart in a murine AIDS model. Mice were divided into six groups: an uninfected group, an untreated LP-BM5 retrovirus-infected group, and four LP-BM5 retrovirus-infected groups treated with one of four ITCs (sulforaphane [SUL], indolo[3,2-b]carbazole, benzyl isothiocyanate [BITC], or phenethyl isothiocyanate [PEITC]). After 16 weeks, the median survival time of the LP-BM5 retrovirus-infected mice was 87 days, whereas that of the uninfected control group and all ITC treatment groups was over 112 days. SUL, PEITC, and BITC significantly inhibited apoptosis in the left ventricle by increasing the Bcl-2/Bax ratio compared with LP-BM5-infected mice. In addition, SUL and PEITC suppressed inducible nitric oxide synthase (iNOS) expression at both the mRNA and protein levels in the left ventricle of heart tissue infected with the LP-BM5 retrovirus by inactivating cytoplasmic nuclear factor κB (NF-κB). In conclusion, LP-BM5 retrovirus infection was related to survival of murine AIDS mice, and NF-κB-mediated iNOS expression may be an important mediator of left ventricle dysfunction of the heart. Furthermore, certain ITCs may have the potential to improve AIDS-related heart dysfunction due to their inhibition of apoptosis by decreasing iNOS and Bax expression through suppression of NF-κB.

Ginseng reverses established cardiomyocyte hypertrophy and postmyocardial infarction-induced hypertrophy and heart failure.

BACKGROUND: A major challenge in the treatment of heart failure is the ability to reverse already-established myocardial remodeling and ventricular dysfunction, with few available pharmacological agents prescribed for the management of heart failure having demonstrated successful reversal of the remodeling and hypertrophic processes. North American ginseng (Panax quinquefolius) has previously been shown to effectively prevent cardiomyocyte hypertrophy and heart failure. Here, we determined whether North American ginseng can reverse established cardiomyocyte hypertrophy in cultured myocytes as well as hypertrophy and left ventricular dysfunction in experimental heart failure secondary to coronary artery occlusion. METHODS AND RESULTS: Ginseng was administered in drinking water (0.9 g/L) ad libitum to rats after 4 weeks of sustained coronary artery ligation when heart failure was established or to angiotensin II- (100 nmol/L), endothelin-1- (10 nmol/L), or phenylephrine- (10 µmol/L) induced hypertrophic cultured neonatal ventricular cardiomyocytes. Echocardiographic and catheter-based measurements of hemodynamic parameters 4 weeks after starting ginseng treatment (8 weeks postinfarction) revealed nearly complete reversibility of systolic and diastolic abnormalities. Similarly, ginseng administration to hypertrophic cardiomyocytes resulted in a complete reversal to a normal phenotype after 24 hours as determined by cell surface area and expression of molecular markers. The effects of ginseng both in vivo and in cultured cardiomyocytes were associated with reversal of calcineurin activation and reduced nuclear translocation of the transcription factor NFAT3 (nuclear factor of activated T cells 3) in cultured myocytes. Moreover, the beneficial effect of ginseng was associated with normalization in the gene expression of profibrotic markers, including collagen (I and III) and fibronectin. CONCLUSIONS: This study demonstrates a marked ability of ginseng to reverse cardiac hypertrophy, myocardial remodeling, and heart failure, which was associated with and likely mediated by reversal of calcineurin activation. Ginseng may offer a potentially effective approach to reverse the myocardial remodeling and heart failure processes, particularly in combination with other treatment modalities.

LV dyssynchrony as assessed by phase analysis of gated SPECT myocardial perfusion imaging in patients with Wolff-Parkinson-White syndrome.

PURPOSE: The purpose of this study was to evaluate left ventricular (LV) mechanical dyssynchrony in patients with Wolff-Parkinson-White (WPW) syndrome pre- and post-radiofrequency catheter ablation (RFA) using phase analysis of gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). METHODS: Forty-five WPW patients were enrolled and had gated SPECT MPI pre- and 2-3 days post-RFA. Electrophysiological study (EPS) was used to locate accessory pathways (APs) and categorize the patients according to the AP locations (septal, left and right free wall). Electrocardiography (ECG) was performed pre- and post-RFA to confirm successful elimination of the APs. Phase analysis of gated SPECT MPI was used to assess LV dyssynchrony pre- and post-RFA. RESULTS: Among the 45 patients, 3 had gating errors, and thus 42 had SPECT phase analysis. Twenty-two patients (52.4%) had baseline LV dyssynchrony. Baseline LV dyssynchrony was more prominent in the patients with septal APs than in the patients with left or right APs (p < 0.05). RFA improved LV synchrony in the entire cohort and in the patients with septal APs (p < 0.01). CONCLUSION: Phase analysis of gated SPECT MPI demonstrated that LV mechanical dyssynchrony can be present in patients with WPW syndrome. Septal APs result in the greatest degree of LV mechanical dyssynchrony and afford the most benefit after RFA. This study supports further investigation in the relationship between electrical and mechanical activation using EPS and phase analysis of gated SPECT MPI.

Iron chelation therapy in the management of transfusion-related cardiac iron overload.

Iron overload is one of the major causes of morbidity and death in patients undergoing chronic transfusion therapy. Furthermore, excessive iron accumulation in the heart may result in impaired left ventricular dysfunction. With accurate monitoring techniques and treatment regimens, progression of heart complications can be followed, and their natural history changed. Iron chelation therapy is the mainstay of prevention and reversal of myocardial iron overload. Despite recent appraisals of general chelating strategies, the management of iron chelation in chronically transfused patients with a focus on the heart has not been extensively assessed. New studies published in the past couple of years have provided important new data in this topic and therefore this review summarizes the major studies that examined the removal of iron from the heart with the iron chelators: deferoxamine, deferiprone, and deferasirox. Since chronically transfused patients and their cardiac clinical presentations vary widely, this review tries to identify--with each drug--the precise scenarios evaluated, linking patients' baseline characteristics, clinical setting, and drug intake and dosing. Ultimately, by stratifying patients according to their cardiac iron overload status and ventricular function, this review identifies possible approaches for the initial treatment and follow-up of transfusion-related cardiac iron overload.

Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial.

AIMS: Coronary artery disease (CAD) is associated with endothelial dysfunction and mitochondrial dysfunction (MD). The aim of this study was to investigate whether co-enzyme Q10 (CoQ) supplementation, which is an obligatory coenzyme in the mitochondrial respiratory transport chain, can reverse MD and improve endothelial function in patients with ischaemic left ventricular systolic dysfunction (LVSD). METHODS AND RESULTS: We performed a randomized, double-blind, placebo-controlled trial to determine the effects of CoQ supplement (300 mg/day, n=28) vs. placebo (controls, n=28) for 8 weeks on brachial flow-mediated dilation (FMD) in patients with ischaemic LVSD(left ventricular ejection fraction <45%). Mitochondrial function was determined by plasma lactate/pyruvate ratio (LP ratio). After 8 weeks, CoQ-treated patients had significant increases in plasma CoQ concentration (treatment effect 2.20 µg/mL, P<0.001) and FMD (treatment effect 1.51%, P=0.03); and decrease in LP ratio (treatment effect -2.46, P=0.03) compared with controls. However, CoQ treatment did not alter nitroglycerin-mediated dilation, blood pressure, blood levels of fasting glucose, haemoglobin A1c, lipid profile, high-sensitivity C-reactive protein and oxidative stress as determined by serum superoxide dismutase and 8-isoprostane (all P>0.05). Furthermore, the reduction in LP ratio significantly correlated with improvement in FMD (r=-0.29, P=0.047). CONCLUSION: In patients with ischaemic LVSD, 8 weeks supplement of CoQ improved mitochondrial function and FMD; and the improvement of FMD correlated with the change in mitochondrial function, suggesting that CoQ improved endothelial function via reversal of mitochondrial dysfunction in patients with ischaemic LVSD.