Changes in vascular properties, not ventricular properties, predominantly contribute to baroreflex regulation of arterial pressure.

Baroreflex modulates both the ventricular and vascular properties and stabilizes arterial pressure (AP). However, how changes in those mechanical properties quantitatively impact the dynamic AP regulation remains unknown. We developed a framework of circulatory equilibrium, in which both venous return and cardiac output are expressed as functions of left ventricular (LV) end-systolic elastance (Ees), heart rate (HR), systemic vascular resistance (R), and stressed blood volume (V). We investigated the contribution of each mechanical property using the framework of circulatory equilibrium. In six anesthetized dogs, we vascularly isolated carotid sinuses and randomly changed carotid sinus pressure (CSP), while measuring the LV Ees, aortic flow, right and left atrial pressure, and AP for at least 60 min. We estimated transfer functions from CSP to Ees, HR, R, and V in each dog. We then predicted these parameters in response to changes in CSP from the transfer functions using a data set not used for identifying transfer functions and predicted changes in AP using the equilibrium framework. Predicted APs matched reasonably well with those measured (r2=0.85-0.96, P<0.001). Sensitivity analyses indicated that Ees and HR (ventricular properties) accounted for 14±4 and 4±2%, respectively, whereas R and V (vascular properties) accounted for 32±4 and 39±4%, respectively, of baroreflex-induced AP regulation. We concluded that baroreflex-induced dynamic AP changes can be accurately predicted by the transfer functions from CSP to mechanical properties using our framework of circulatory equilibrium. Changes in the vascular properties, not the ventricular properties, predominantly determine baroreflex-induced AP regulation.

Ventricular premature complexes successfully ablated from the non-coronary cusp: a case report.

Background: Ventricular premature complexes (VPCs) occasionally originate from the aortic sinus of Valsalva. Because the anterior part of the left coronary cusp (LCC) and right coronary cusp (RCC) are connected through the ventricular musculature at their bases, VPCs are more common in the LCC and the RCC than in the non-coronary cusp (NCC). We herein report a case in which VPCs were successfully ablated from the NCC, which is considered rare. Case summary: A 30-year-old woman was admitted to our hospital for the ablation of VPCs, which comprised 43% of the total heart beats. The clinical VPCs had an inferior axis and left bundle branch block morphology with a precordial transition between V4 and V5. Three-dimensional mapping of the target VPCs indicated that the earliest activation site was RCC. After radiofrequency (RF) energy application at the RCC, VPCs were temporally suppressed but recurred after 24 min. Remapping of the recurrent VPCs revealed that the earliest activation site shifted from the RCC to the His region. To avoid the risk of atrioventricular block, RF energy was applied from the NCC, which resulted in successful elimination of the VPCs without any complications. Discussion: The present case suggests that RF energy application from the NCC may be a safe and effective option for the ablation of VPCs with the earliest activation at the RCC and His region.

Japanese multicenter registry evaluating the antegrade dissection reentry with cardiac computerized tomography for chronic coronary total occlusion.

Recently, antegrade dissection re-entry (ADR) with re-entry device for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has evolved to become one of the pillar techniques of the hybrid algorithm. Although the success rate of the device is high, it could be improved. We sought to evaluate the current trends and issues associated with ADR in Japan and evaluate the potential of cardiac computed tomography angiography (CCTA) for ADR procedure. A total 48 patients with CTO suitable for ADR evaluated by baseline conventional angiography and CCTA were enrolled. Procedural success and technical success were evaluated as the primary and secondary observations. Furthermore, all puncture points were analyzed by CCTA. CT score at each punctured site depended on the location of plaque deposition (none; + 0, at isolated myocardial site; + 1, at epicardial site; + 2) and the presence of calcification (none; + 0, presence; + 1) was analyzed and calculated (score 0-3). Overall procedure success rate was 95.8%. Thirty-two cases were attempted with the ADR procedure and 25 cases of them were successful. The technical success rate was 78.1% and myocardial infarction or other major complications were not observed in any cases. CT score at 60 puncture sites in 32 cases were analyzed and the score at technical success points was significantly smaller compared to that at technical failure points (0.68 ± 1.09 vs 1.77 ± 1.09, p < 0.0001). CTO-PCI with Stingray device in Japan could achieve a high procedure success and technical success rate. Pre procedure cardiac CT evaluation might support ADR procedure for appropriate patient selection or puncture site selection.

Paroxysmal atrioventricular block induced during paroxysmal intra-atrial reentrant tachycardia.

Paroxysmal atrio-ventricular (AV) block is a relatively rare form of bradyarrhythmia that may be caused by vagal reflex, intrinsic His-Prukinje system (HPS) disorder, or idiopathic mechanisms. We report a case with paroxysmal AV block and syncopal episodes that appeared only during intra-atrial reentrant tachycardia (IART) after an ablation procedure. Syncope did not occur under sinus rhythm with stable 1:1 AV conduction. An HPS disorder was proven in an electrophysiological study. It was suggested that paroxysmal AV block was induced via a tachycardia-dependent mechanism with an exacerbation of latent HPS disorder. The occurrence of the IART was only transient, and there was no recurrent syncope during one-year follow-up. Pacemaker implantation could be avoided. .

Prevalence and clinical implication of metabolic syndrome in chronic heart failure.

BACKGROUND: Metabolic syndrome (MetS) is a pathological condition with a clustering of metabolic components and is a well-known risk and prognostic factor for ischemic heart disease (IHD). However, the prevalence and clinical significance of MetS remain to be fully elucidated in chronic heart failure (CHF), an important clinical syndrome caused by various cardiac abnormalities. METHODS AND RESULTS: The present nationwide, large-scale clinical study enrolled 3,603 patients with stage C/D CHF from 6 institutes in Japan. First, the prevalence of MetS in CHF patients was demonstrated to be 45% in males and 19% in females, which is more than double compared with the general population in Japan. The CHF patients with MetS were characterized by younger age, higher prevalence of current smoking and drinking, IHD, and hypertensive heart disease, whereas the prevalence of HF with preserved ejection fraction and MetS was higher in elderly female patients. Next, the contribution of the metabolic components (waist circumference, hypertension, glucose intolerance/diabetes mellitus and dyslipidemia) was found to be comparable between the ischemic and the non-ischemic CHF patients. CONCLUSIONS: The prevalence of MetS in CHF patients is more than double compared with the general population in Japan and suggest that the metabolic components may have a substantial effect on the development of both ischemic and non-ischemic CHF.

Modulation of the myocardial redox state by vagal nerve stimulation after experimental myocardial infarction.

AIMS: Redox alteration plays a major role in the pathogenesis of heart failure (HF). Since vagal nerve stimulation (VNS) is known to improve survival and attenuate cardiac remodelling, we hypothesized that VNS may modulate the myocardial redox state. METHODS AND RESULTS: Using a chronic HF mouse model, we applied VNS for 15 min and measured myocardial redox status using in vivo electron spin resonance spectroscopy. Signal decay rate of the nitroxyl probe, an index of redox status, was enhanced in HF compared with sham (0.16 +/- 0.01 vs. 0.13 +/- 0.01 min(-1), P < 0.05; n = 6), and VNS normalized this enhancement (0.13 +/- 0.01 min(-1), P < 0.05). Atropine sulphate abolished the VNS effects, indicating that the VNS modulates myocardial redox state via muscarinic receptors. N(omega)-Nitro-L-arginine methyl ester treatment and fixed-rate atrial pacing showed a trend to suppress the VNS effects, suggesting the involvement of nitric oxide-based signalling and myocardial oxygen consumption. Moreover, VNS decreased the myocardial norepinephrine (NE) level (0.25 +/- 0.07 vs. 0.60 +/- 0.12 ng/mL, P < 0.05; n = 6). Reactive oxygen species production from cultured cardiomyocytes was enhanced by beta-adrenergic activation, which was partially antagonized by 10 micromol/L acetylcholine (ACh) (relative value compared with control: NE 3.7 +/- 0.5, NE + ACh 2.5 +/- 0.3, P < 0.05; n = 12). CONCLUSION: The present study suggests that VNS modulates the cardiac redox status and adrenergic drive, and thereby suppresses free radical generation in the failing heart.

Soluble TNF receptors prevent apoptosis in infiltrating cells and promote ventricular rupture and remodeling after myocardial infarction.

OBJECTIVE: Tumor necrosis factor (TNF)-alpha induced in damaged myocardium has been considered to be cardiotoxic. However, the negative results of RENEWAL and ATTACH prompt us to reconsider the role of TNF-alpha in cardiovascular diseases. The present study aimed to evaluate the effects of soluble TNF receptor treatment on myocardial infarction (MI). METHODS: An adenovirus encoding a 55-kDa TNF receptor-IgG fusion protein (AdTNFR1) was used to neutralize TNF-alpha, and an adenovirus encoding LacZ (AdLacZ) served as control. In the pre-MI treatment protocol, mice were given an intravenous injection of AdTNFR1 or AdLacZ 1 week before left coronary artery ligation to induce MI. In the post-MI treatment protocol, mice were treated with AdTNFR1 or AdLacZ 1 week after left coronary ligation. RESULTS: Treatment with AdTNFR1 neutralized bioactivity of TNF-alpha that was activated after MI and prevented apoptosis of infiltrating cells in infarct myocardium. However, pre-MI treatment with AdTNFR1 promoted ventricular rupture by reducing fibrosis with further activation of matrix metalloproteinase (MMP)-9. Post-MI treatment with AdTNFR1 exacerbated ventricular dysfunction and remodeling, with enhanced fibrosis of non-infarct myocardium with further MMP-2 activation. CONCLUSIONS: Both pre- and post-MI treatments with AdTNFR1 were deleterious in a mouse MI model. Thus, TNF-alpha may play not only toxic but also protective roles in MI.

How to quantitatively synthesize dynamic changes in arterial pressure from baroreflexly modulated ventricular and arterial properties.

Baroreflex regulates arterial pressure by modulating ventricular and vascular properties. We investigated if the framework of circulatory equilibrium that we developed previously (Am J Physiol 2004, 2005) by extending the classic Guyton's framework is capable of predicting baroreflex induced changes in arterial pressure. In animal experiments, we estimated open loop transfer functions of baroreflexly modulated ventricular and vascular properties, synthesized baroreflex induced dynamic changes in arterial pressure using the estimated transfer functions and compared the predicted responses with measured responses. We demonstrated that the predicted baroreflex induced changes in arterial pressure matched reasonable well with those measured. We conclude that the framework of circulatory equilibrium is generalizable under the condition where baroreflex dynamically changes arterial pressure.

Up-regulation of type 2 iodothyronine deiodinase in dilated cardiomyopathy.

AIMS: Thyroid hormone (TH) has prominent effects on the heart, and hyperthyroidism is occasionally found to be a cause of dilated cardiomyopathy (DCM). We aim to explore the potential role of TH in the pathogenesis of DCM. METHODS AND RESULTS: The pathophysiological role of TH in the heart was investigated using a knock-in mouse model of inherited DCM with a deletion mutation DeltaK210 in the cardiac troponin T gene. Serum tri-iodothyronine (T(3)) levels showed no significant difference between wild-type (WT) and DCM mice, whereas cardiac T(3) levels in DCM mice were significantly higher than those in WT mice. Type 2 iodothyronine deiodinase (Dio2), which produces T(3) from thyroxin, was up-regulated in the DCM mice hearts. The cAMP levels were increased in DCM mice hearts, suggesting that transcriptional up-regulation of Dio2 gene is mediated through the evolutionarily conserved cAMP-response element site in its promoter. Propylthiouracil (PTU), an anti-thyroid drug, prevented the hypertrophic remodelling of the heart in DCM mice and improved their cardiac function and life expectancy. Akt and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation increased in the DCM mice hearts and PTU treatment significantly reduced the phosphorylation levels, strongly suggesting that Dio2 up-regulation is involved in cardiac remodelling in DCM through activating the TH-signalling pathways involving Akt and p38 MAPK. Dio2 gene expression was also markedly up-regulated in the mice hearts developing similar eccentric hypertrophy after myocardial infarction. CONCLUSION: Local hyperthyroidism via transcriptional up-regulation of the Dio2 gene may be an important underlying mechanism for the hypertrophic cardiac remodelling in DCM.

Time-dependent changes of myocardial and systemic oxidative stress are dissociated after myocardial infarction.

Reactive oxygen species (ROS) is increased in myocardium after myocardial infarction (MI), which may play a causal role in cardiac remodelling. However, there is scant direct and longitudinal evidence that systemic oxidative stress is enhanced accompanying an increase of ROS in myocardium. The authors conducted a comprehensive investigation of ROS markers by simultaneously sampling urine, blood and myocardium and in vivo ESR for the heart at different stages of post-MI cardiac remodelling in mouse with permanent occlusion of left coronary artery. Systemic oxidative markers increased at early days after MI and were normalized later. In contrast, TBARS and 4-hexanoyl-Lys staining were increased in non-infarct myocardium at day 28. The enhancement of ESR signal decay of methoxycarbonyl-PROXYL measured at the chest was associated with the progression of left ventricle dilatation and dysfunction. This study provided the direct evidence that redox alteration and production of ROS occurred in myocardium during the progression of cardiac remodelling and failure; however, ROS marker levels in blood and urine do not reflect the production of ROS from failing myocardium.

Effect of anaesthesia-induced alterations in haemodynamics on in vivo kinetics of nitroxyl probes in electron spin resonance spectroscopy.

Although the advent of in vivo electron spin resonance (ESR) spectroscopy has allowed analysis of the redox status of living animals, whether the haemodynamic condition affects the signal decay rate remains unknown. Three kinds of haemodynamic conditions were generated by changing the anaesthetic dosage in mice. Haemodynamics was analysed (n=6 each) and in vivo ESR was performed to measure the signal decay rates of three nitroxyl spin probes (carbamoyl-, carboxy- and methoxycarbonyl-PROXYL) at the chest and head regions (n=6 for each condition and probe). Haemodynamic analysis revealed negative inotropic and chronotropic effects on the cardiovascular system depending on the depth of anaesthesia. Although signal decay rates differed among three probes, they were not affected by heart rate alteration. In this study we report the haemodynamics-independent signal decay rate of nitoxyl probes.

Tumor necrosis factor-alpha is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction.

Tumor necrosis factor (TNF)-alpha induced in damaged myocardium has been considered to be cardiotoxic. TNF-alpha initiates its biological effects by binding two distinct receptors: R1 (p55) and R2 (p75). Although TNF-alpha has been shown to be cardiotoxic via R1-mediated pathways, little is known about the roles of R2-mediated pathways in myocardial infarction (MI). We created MI in R1 knockout (R1KO), R2KO, and wild-type (WT) mice by ligating the left coronary artery. Functional, histological, and biochemical analyses were performed 4 wk after ligation. Although infarct size was not different among WT, R1KO, and R2KO mice, post-MI survival was significantly improved in R1KO but not R2KO mice. R1KO significantly ameliorated contractile dysfunction after MI, whereas R2KO significantly exaggerated ventricular dilatation and dysfunction. Myocyte hypertrophy and interstitial fibrosis in noninfarct myocardium was exacerbated in R2KO but not in R1KO mice. Expression of R1, which was not affected by MI and was nullified in R1KO mice, was significantly upregulated in R2KO mice. In contrast, expression of R2, which was significantly upregulated by MI and was nullified in R2KO mice, was unaffected in R1KO mice. Meanwhile, TNF-alpha expression, which was significantly upregulated in noninfarct myocardium after MI, was not affected by R1KO or R2KO. However, transcript levels of IL-6, IL-1beta, transforming growth factor-beta, and monocyte chemotactic protein-1, which were significantly upregulated after MI, were significantly downregulated in R1KO mice. In contrast, transcript levels of IL-6 and IL-1beta were significantly further upregulated in R2KO mice. TNF-alpha is toxic via R1 and protective via R2 in a murine model of MI. Selective blockade of R1 may be a candidate therapeutic intervention for MI.

Efferent vagal nerve stimulation induces tissue inhibitor of metalloproteinase-1 in myocardial ischemia-reperfusion injury in rabbit.

Vagal nerve stimulation has been suggested to ameliorate left ventricular (LV) remodeling in heart failure. However, it is not known whether and to what degree vagal nerve stimulation affects matrix metalloproteinase (MMP) and tissue inhibitor of MMP (TIMP) in myocardium, which are known to play crucial roles in LV remodeling. We therefore investigated the effects of electrical stimulation of efferent vagal nerve on myocardial expression and activation of MMPs and TIMPs in a rabbit model of myocardial ischemia-reperfusion (I/R) injury. Anesthetized rabbits were subjected to 60 min of left coronary artery occlusion and 180 min of reperfusion with (I/R-VS, n = 8) or without vagal nerve stimulation (I/R, n = 7). Rabbits not subjected to coronary occlusion with (VS, n = 7) or without vagal stimulation (sham, n = 7) were used as controls. Total MMP-9 protein increased significantly after left coronary artery occlusion in I/R-VS and I/R to a similar degree compared with VS and sham values. Endogenous active MMP-9 protein level was significantly lower in I/R-VS compared with I/R. TIMP-1 mRNA expression was significantly increased in I/R-VS compared with the I/R, VS, and sham groups. TIMP-1 protein was significantly increased in I/R-VS and VS compared with the I/R and sham groups. Cardiac microdialysis technique demonstrated that topical perfusion of acetylcholine increased dialysate TIMP-1 protein level, which was suppressed by coperfusion of atropine. Immunohistochemistry demonstrated a strong expression of TIMP-1 protein in cardiomyocytes around the dialysis probe used to perfuse acetylcholine. In conclusion, in a rabbit model of myocardial I/R injury, vagal nerve stimulation induced TIMP-1 expression in cardiomyocytes and reduced active MMP-9.

Blockade of NF-kappaB improves cardiac function and survival after myocardial infarction.

NF-kappaB is a key transcription factor that regulates inflammatory processes. In the present study, we tested the hypothesis that blockade of NF-kappaB ameliorates cardiac remodeling and failure after myocardial infarction (MI). Knockout mice with targeted disruption of the p50 subunit of NF-kappaB (KO) were used to block the activation of NF-kappaB. MI was induced by ligation of the left coronary artery in male KO and age-matched wild-type (WT) mice. NF-kappaB was activated in noninfarct as well as infarct myocardium in WT+MI mice, while the activity was completely abolished in KO mice. Blockade of NF-kappaB significantly reduced early ventricular rupture after MI and improved survival by ameliorating congestive heart failure. Echocardiographic and pressure measurements revealed that left ventricular fractional shortening and maximum rate of rise of left ventricular pressure were significantly increased and end-diastolic pressure was significantly decreased in KO+MI mice compared with WT+MI mice. Histological analysis demonstrated significant suppression of myocyte hypertrophy as well as interstitial fibrosis in the noninfarct myocardium of KO+MI mice. Blockade of NF-kappaB did not ameliorate expression of proinflammatory cytokines in infarct or noninfarct myocardium. In contrast, phosphorylation of c-Jun NH2-terminal kinase was almost completely abolished in KO+MI mice. The present study demonstrates that targeted disruption of the p50 subunit of NF-kappaB reduces ventricular rupture as well as improves cardiac function and survival after MI. Blockade of NF-kappaB might be a new therapeutic strategy to attenuate cardiac remodeling and failure after MI.