Myocardial Catecholamine Research Articles

Evaluation of Autonomic Nervous System Through Spectral Analysis in Patients with Ischemic Heart Failure: A Systematic Review

Abstract Heart failure is one of the most complex pathologies and most prevalent diseases, with around 64 million people affected globally (2% of the total adult population). In the initial phase of heart failure, studies have shown that the autonomic nervous system is in a state of imbalance, with an increase in the influence of the sympathetic nervous system on the heart. Persistence of long-term activation of the autonomic nervous system produces a decrease in the levels of myocardial catecholamines and also promotes down-regulation of beta-1 receptors. This article is a systematic review of papers from four well-known and important scientific databases on the subject of power spectral analysis of ECG Holter monitoring in patients with heart failure. The PRISMA technique was used to identify the most relevant articles on this subject, and their results were presented based on importance of their use for the diagnosis of heart failure, for risk stratification of sudden death or arrhythmias, for the evaluation of certain treatments used, or for other possible pathophysiological mechanisms involved in the evolution of the disease.

Behavior of Hypertrophied Right Ventricle during the Development of Left Ventricular Failure Due to Myocardial Infarction.

In order to determine the behavior of the right ventricle, we have reviewed the existing literature in the area of cardiac remodeling, signal transduction pathways, subcellular mechanisms, β-adrenoreceptor-adenylyl cyclase system and myocardial catecholamine content during the development of left ventricular failure due to myocardial infarction. The right ventricle exhibited adaptive cardiac hypertrophy due to increases in different signal transduction pathways involving the activation of protein kinase C, phospholipase C and protein kinase A systems by elevated levels of vasoactive hormones such as catecholamines and angiotensin II in the circulation at early and moderate stages of heart failure. An increase in the sarcoplasmic reticulum Ca2+ transport without any changes in myofibrillar Ca2+-stimulated ATPase was observed in the right ventricle at early and moderate stages of heart failure. On the other hand, the right ventricle showed maladaptive cardiac hypertrophy at the severe stages of heart failure due to myocardial infarction. The upregulation and downregulation of β-adrenoreceptor-mediated signal transduction pathways were observed in the right ventricle at moderate and late stages of heart failure, respectively. The catalytic activity of adenylate cyclase, as well as the regulation of this enzyme by Gs proteins, were seen to be augmented in the hypertrophied right ventricle at early, moderate and severe stages of heart failure. Furthermore, catecholamine stores and catecholamine uptake in the right ventricle were also affected as a consequence of changes in the sympathetic nervous system at different stages of heart failure. It is suggested that the hypertrophied right ventricle may serve as a compensatory mechanism to the left ventricle during the development of early and moderate stages of heart failure.

Elevated MAOA impairs intracellular β 1 ‐adrenegic signaling and myocardial contractility in heart failure

Rationale: We recently identified a pool of β1ARs at the sarcoplasmic reticulum (SR) senses cytosolic catecholamines and promotes cardiac contractility. Monoamine oxidase A (MAOA), the major enzyme metabolizing myocardial catecholamines is upregulated in heart failure (HF) together with blunted β1AR signaling. However, the regulation of intracellular β1ARs signaling in HF remains unknown. Objective To uncover the role of MAOA in the spatiotemporal regulation of intracellular β1AR signaling and cardiac contractility. Methods and Results Echocardiogram analysis showed that cardiac-specific deletion (cKO) or pharmacological inhibition of MAOA did not affect the baseline cardiac output but significantly amplified the inotropy of catecholamine (epinephrine) in vivo. Enzyme immunoassay revealed elevated catecholamine concentrations and cAMP/PKA activities in MAOA-cKO mice hearts compared with their flox/flox (FF) littermates. We measured the subcellular-localized β1AR in living cardiomyocytes using PKA biosensors targeted at SR or plasma membrane (PM). Compared with FF cardiomyocytes, MAOA-cKO exhibited an increased PKA activity at SR, but not PM upon epinephrine stimulation. Consistently, phosphorylation of phospholamban (PLB), a major target of SR-localized β1AR signals, was enhanced by MAOA-cKO. More importantly, deleting MAOA increased the response of calcium transients and contractility to epinephrine. Blocking the entry of catecholamines by organic cation transporter 3 (OCT3) inhibitor abolished the differential effects in MAOA-cKO vs FF. Similarly, the effect of MAOA-cKO on intracellular β1AR/PKA/PLB signaling and cardiac excitation-contraction coupling (EC-coupling) was recapitulated by pharmacological inhibition of MAOA. In contrast, overexpression of MAOA in cardiomyocytes suppressed epinephrine-induced PKA activation at the SR, PLB phosphorylation and contractility. Furthermore, the increased expression of MAOA in failing cardiomyocytes suppressed activation of intracellular β1AR and attenuated PKA phosphorylation of PLB and inotropic responses. Inhibition of MAOA restored intracellular β1AR signaling and EC coupling in failing cardiomyocytes, and rescued the inotropy response in HF mice. Conclusion MAOA modulates catecholamine-promoted EC coupling via tuning the intracellular β1AR signaling and PKA phosphorylation of PLB. Inhibition of MAOA restores β1AR/PKA signaling at the SR and cardiac contractility in HF.

Compromised right ventricular contractility in an ovine model of heart transplantation following 24 h donor brain stem death

BackgroundHeart failure is an inexorably progressive disease with a high mortality, for which heart transplantation (HTx) remains the gold standard treatment. Currently, donor hearts are primarily derived from patients following brain stem death (BSD). BSD causes activation of the sympathetic nervous system, increases endothelin levels, and triggers significant inflammation that together with potential myocardial injury associated with the transplant procedure, may affect contractility of the donor heart. We examined peri-transplant myocardial catecholamine sensitivity and cardiac contractility post-BSD and transplantation in a clinically relevant ovine model. MethodsDonor sheep underwent BSD (BSD, n = 5) or sham (no BSD) procedures (SHAM, n = 4) and were monitored for 24h prior to heart procurement. Orthotopic HTx was performed on a separate group of donor animals following 24h of BSD (BSD-Tx, n = 6) or SHAM injury (SH-Tx, n = 5). The healthy recipient heart was used as a control (HC, n = 11). A cumulative concentration-effect curve to (-)-noradrenaline (NA) was established using left (LV) and right ventricular (RV) trabeculae to determine β1-adrenoceptor mediated potency (-logEC50 [(-)-noradrenaline] M) and maximal contractility (Emax). ResultsOur data showed reduced basal and maximal (-)-noradrenaline induced contractility of the RV (but not LV) following BSD as well as HTx, regardless of whether the donor heart was exposed to BSD or SHAM. The potency of (-)-noradrenaline was lower in left and right ventricles for BSD-Tx and SH-Tx compared to HC. ConclusionThese studies show that the combination of BSD and transplantation are likely to impair contractility of the donor heart, particularly for the RV. For the donor heart, this contractile dysfunction appears to be independent of changes to β1-adrenoceptor sensitivity. However, altered β1-adrenoceptor signalling is likely to be involved in post-HTx contractile dysfunction.

Effects of sympathectomy on myocardium remodeling and function

OBJECTIVES:To evaluate the effects of sympathectomy on the myocardium in an experimental model.METHODS:The study evaluated three groups of male Wistar rats: control (CT; n=15), left unilateral sympathectomy (UNI; n=15), and bilateral sympathectomy (BIL; n=31). Sympathectomy was performed by injection of absolute alcohol into the space of the spinous process of the C7 vertebra. After 6 weeks, we assessed the chronotropic properties at rest and stress, cardiovascular autonomic modulation, myocardial and peripheral catecholamines, and beta-adrenergic receptors in the myocardium. The treadmill test consisted of an escalated protocol with a velocity increment until the maximal velocity tolerated by the animal was reached.RESULTS:The bilateral group had higher levels of peripheral catecholamines, and consequently, a higher heart rate (HR) and blood pressure levels. This suggests that the activation of a compensatory pathway in this group may have deleterious effects. The BIL group had basal tachycardia immediately before the exercise test and increased tachycardia at peak exercise (p<0.01); the blood pressure had the same pattern (p=0.0365). The variables related to autonomic modulation were not significantly different between groups, with the exception of the high frequency (HF) variable, which showed significant differences in CT vs UNI. There was no significant difference in beta receptor expression between groups. There was a higher concentration of peripheral norepinephrine in the BIL group (p=0.0001), and no significant difference in myocardial norepinephrine (p=0.09).CONCLUSION:These findings suggest that an extra cardiac compensatory pathway increases the sympathetic tonus and maintains a higher HR and higher levels of peripheral catecholamines in the procedure groups. The increase in HF activity can be interpreted as an attempt to increase the parasympathetic tonus to balance the greater sympathetic activity.

Chromogranin-A serum levels in patients with takotsubo syndrome and ST elevation acute myocardial infarction

BackgroundSympathergic hyperactivity is considered one of the main trigger precipitating takotsubo syndrome (TTS). Chromogranin-A (CgA), a prognostic biomarker of sympatho-adrenal activation, is markedly high in acute coronary syndrome (ACS) and heart failure (HF), but its role in TTS is unknown. MethodsCgA serum levels from patients with TTS and symptoms onset <24 hours were consecutively evaluated and compared with anterior ST-elevation myocardial infarction (STEMI) patients from November 2016 to December 2019. Short and long-term follow-up data were recorded. ResultsEleven women with TTS and 10 subjects with anterior STEMI were analyzed and compared; differences were not significant in terms of age, gender and cardiovascular risk factors. NT-pro-BNP levels were similar (9,887 ± 12,170 vs 8,969 ± 15,053 pg/ml, p = .88), while troponin-I levels were higher in patients with STEMI (4 ± 3.2 vs 13.3 ± 10 ng/dl, p = .03). CgA admission levels were significantly lower in TTS patients (2.2 ± 1.5 vs 7.3 ± 6.2 nMol/l, p = .017), even after multivariable correction for principal bias. CgA levels correlated with NTproBNP levels (p = .02) and were higher in subjects with in-hospital events (3.7 ± 1.1 vs 1.6 ± 1.2 nMol/l, p = .03), even after multivariable forward stepwise analysis (p < .01). CgA levels <3.25 nMol/l (AUC 0.754, 95% C.I. 0.54–0.968) were able to discriminate TTS from anterior STEMI (negative predictive power of 99%). ConclusionsSystemic CgA levels in the acute phase of TTS are lower than in anterior STEMI, possibly indicating a greater myocardial catecholamine release rather than adrenal.

What causes sudden death in patients with chronic heart failure and a reduced ejection fraction?

Sudden death characterizes the mode of demise in 30–50% of patients with chronic heart failure and a reduced ejection fraction. Occasionally, these events have an identifiable pathophysiological trigger, e.g. myocardial infarction, catecholamine surges, or electrolyte imbalances, but in most circumstances, there is no acute precipitating mechanism. Instead, adverse left ventricular remodelling and fibrosis creates an exceptionally fragile and highly vulnerable substrate, which can be characterized using the model developed in theoretical physics of ‘self-organizing criticality’. This framework has been applied to describe the genesis of avalanches, nodes of traffic congestion unrelated to an accident, the abrupt system-wide failure of electrical grids, and the initiation of cancer and neurodegenerative diseases. Self-organizing criticality within the ventricular myocardium relies on complex adaptations to progressive stress and stretch, which evolve inevitably to an abrupt end (termed ‘cascading failure’), even though the rate of deterioration of the underlying disease process has not changed. The result is acute circulatory collapse (i.e. sudden death) in the absence of an identifiable triggering event. Cascading failure in a severely remodelled or fibrotic heart can become manifest electrically as a first-time ventricular tachyarrhythmia that is responsive to the shock delivered by an implantable cardioverter-defibrillator (ICD). Alternatively, it may present as an acute mechanical failure, which is manifest as (i) asystole, bradyarrhythmia, or electromechanical dissociation; or (ii) incessant ventricular fibrillation that persists despite repetitive ICD discharges; in both instances, the sudden deaths cannot be prevented by an ICD. This conceptual framework explains why anti-remodelling and antifibrotic interventions (i.e. neurohormonal antagonists and cardiac resynchronization) reduce the risk of sudden death in patients with heart failure in the absence of an ICD and provide incremental benefits in those with an ICD. The adoption of anti-remodelling and antifibrotic treatments may explain why the incidence of sudden death in clinical trials of heart failure has declined dramatically over the past 10–15 years, independent of the use of ICDs.

The effects of endogenous and exogenous catecholamines on hypoxic cardiac performance in red-bellied piranhas.

Catecholamines protect the fish heart during hypoxia. However, the humoral adrenergic stress response may only be invoked in extremis. We investigated the hypothesis that endogenous (e.g., neuronal) myocardial catecholamines may also impact cardiac performance during hypoxia in a hypoxia-tolerant tropical fish, the red-bellied piranha (Pygocentrus nattereri). First, we measured endogenous tissue catecholamines and in vitro catecholamine release from piranha myocardium using ultraperformance liquid chromatography. Ventricle homogenates contained detectable levels of both adrenaline (7.27 ng/g) and noradrenaline (14.48 ng/g), but only noradrenaline was released from ventricular tissue incubated in Ringer's solution. Noradrenaline released in this assay was not affected by hypoxia but was promoted by the catecholamine releasing agent tyramine. Our second series of experiments explored cardiac contractile performance in vitro using tyramine, exogenous noradrenaline or adrenaline, and propranolol (a β-adrenoceptor antagonist). In ventricular strip preparations, β-adrenergic blockade with propranolol had no effects on twitch force or contraction kinetics in either normoxia or hypoxia, confirming that spontaneous endogenous catecholamine release did not impact cardiac performance. However, in the absence of propranolol, tyramine mimicked the positive inotropic effect of noradrenaline (10 µM) during hypoxia, although adrenaline was capable of generating larger effects. Our results suggest that, although it is not spontaneously released, inducible endogenous noradrenaline release may have a significant β-adrenoceptor-dependent impact on hypoxic performance in the fish heart.

The influence of sildenafil on myocardial catecholamine level in a swine model of ventricular fibrillation

Objective To reveal the changes of catecholamine and lactate levels in myocardial interstitial fluid during cardiopulmonary resuscitation in order to prove the protective effects of sildenafil pretreatment on post-resuscitation myocardial function in swine model of ventricular fibrillation(VF). Methods Twenty-four swine were randomly(random number) divided into three groups: saline group, sildenafil group and shame operation group. Sildenafil in dose of 0.5 mg/kg dissolved in 40 mL of saline was given to swine once intraperitoneally 40 min prior to VF in sildenafil group.The equivalent volume of saline (0.9% NaCl) alone was administered instead in saline groups. There was no treatment in shame operation group. After ventricular fibrillation untreated for 8 min, open-chest cardiopulmonary resuscitation was initiated. The hemodynamic variables were recorded at baseline, 4 min, 1 h and 6 h after restoration of spontaneous circulation(ROSC). The interstitial fluid from the left ventricle wall was collected by using the microdialysis tubes at given intervals, in which the levels of dopamine, norepinephrine, epinephrine, and lactate were measured. The samples for pathological examination were taken at 24 hours after ROSC. Results The levels of catecholamine and lactate in the sildenafil group were lower than those in saline group at all different intervals(P<0.05 or P<0.01). The cumulative defibrillation energy was lower in the sildenafil group than that in the saline group(P<0.05). The hemodynamic changes and myocardial histological damage in sildenafil group were milder than those in saline group(P<0.05). The pathologic changes of myocardium and mitochondria in saline group were more severe than those in sildenafil group. Conclusions Sildenafil pretreatment prior to VF can effectively reduce endogenous catecholamine secretion and lactate levels in myocardial tissue, protecting the myocardium and improving post-resuscitation myocardial function. Key words: Sildenafil; Cardiopulmonary resuscitation; Microdialysis; Catecholamine; Lactate; Hemodynamics

Effect of Shen-Fu Injection Pretreatment to Myocardial Metabolism During Untreated Ventricular Fibrillation in a Porcine Model.

Background:Shen-Fu injection (SFI) can attenuate ischemia-reperfusion injury, protect cardiac function, and improve microcirculation during cardiopulmonary resuscitation. We hypothesized that SFI may also have an influence on myocardial metabolism during ventricular fibrillation (VF). In this study, we used SFI pretreatment prior to VF to discuss the changes of myocardial metabolism and catecholamine (CA) levels during untreated VF, trying to provide new evidence to the protection of SFI to myocardium.Methods:Twenty-four pigs were divided into three groups: Saline group (SA group), SFI group, and SHAM operation group (SHAM group). Thirty minutes prior to the induction of VF, the SFI group received 0.24 mg/ml SFI through an intravenous injection; the SA group received an equal amount of sodium chloride solution. The interstitial fluid from the left ventricle (LV) wall was collected through the microdialysis tubes during VF. Adenosine diphosphate (ADP), adenosine triphosphate (ATP), and Na+ -K+ -ATPase and Ca2+ -ATPase enzyme activities were measured after untreated VF. Peak-to-trough VF amplitude and median frequency were analyzed for each of these 5-s intervals.Results:The levels of glucose and glutamate were lower after VF in both the SA and SFI groups, compared with baseline, and the levels in the SFI group were higher than those in the SA group. Compared with baseline, the levels of lactate and the lactate/pyruvate ratio increased after VF in both SA and SFI groups, and the levels in the SFI group were lower than those in the SA group. In both the SA and SFI groups, the levels of dopamine, norepinephrine, and epinephrine increased significantly. There were no statistical differences between the two groups. The content of ATP, ADP, and phosphocreatine in the SFI group was higher than those in the SA group. The activity of LV Na+ -K+ -ATPase was significantly higher in the SFI group than in the SA group. Amplitude mean spectrum area (AMSA) was significantly lower in the SA and SFI groups at 8- and 12-min compared with 4-min. The AMSA in the SFI group was higher than that in the SA group at each time point during untreated VF.Conclusions:SFI pretreatment can improve myocardial metabolism and reduce energy exhaustion during VF, and it does not aggravate the excessive secretion of endogenous CAs.

Molecular imaging biomarkers for dementia with Lewy bodies: an update.

Dementia with Lewy body (DLB) is considered to be the second most common form of neurodegenerative disorders after Alzheimer's disease (AD), affecting as many as 100,000 people in the UK and up to 1.3 million in the USA. However, nearly half of patients with DLB remain undiagnosed thus depriving many of them from an early and adequate treatment of their distressing symptoms. Accurate and early diagnosis of DLB is important for both patients and their caregivers, since the neuropsychiatric symptoms require specific management. In the current study, we review the most recent developments in the field of molecular nuclear imaging to diagnose DLB. The review addresses, the neurotransmitter based (dopaminergic, cholinergic, and glutamatergic) nuclear imaging techniques, role of the autonomic dysfunction and its visualization in DLB with myocardial sympathetic imaging and vesicular catecholamine uptake, as well as the use of amyloid polypeptides and glial markers as molecular imaging probes in the clinical diagnosis of DLB. Most of the above nuclear imaging methods are restricted to highly specialized clinical centers, and thus not applicable to a large number of patients requiring dementia (e.g. DLB) diagnosis in routine clinical setting. Validating them against more readily accessible peripheral biomarkers, e.g. CSF and blood biomarkers linked to the DLB process, may facilitate their use in wider clinical settings.

Acute Coronary Syndrome and Pheochromocytoma Management: About Two Cases

Acute Coronary Syndrome and Pheochromocytoma Management: About Two Cases Two cases of acute coronary syndrome, the first revealing a pheochromocytoma and the second complicating its preoperative preparation for surgery are described. In both cases, a normal coronary angiography eliminated myocardial infarction. In the first case, an acute left ventricular dysfunction due to myocardial catecholamine toxicity was noted. The second patient had chest pain and syncope before and after a preoperative management using continuous IV administration of urapidil. Laparoscopic surgical resection of pheochromocytoma was uneventful in both cases.

Abstract 201: Beta-Adrenergic Stimulation Promotes Early Electrical Failure During Simulated VF-Induced Cardiac Arrest And Delays Electrical Recovery Upon Reperfusion

During cardiac arrest adrenergic stimulation is enhanced due to both endogenous increase in myocardial tissue catecholamine levels and exogenous epinephrine administration during resuscitation. Whereas alpha-adrenergic stimulation may be beneficial for hemodynamic recovery, there is growing evidence that beta-adrenergic stimulation is detrimental. Clinically, there is controversy as to whether epinephrine administration improves overall survival in cardiac arrest. Here we investigated the effects of beta-adrenergic stimulation on electrical activity during simulated ventricular fibrillation (VF) [[Unable to Display Character: –]] induced cardiac arrest and subsequent reperfusion. We performed optical mapping of the voltage-sensitive dye RH237 in the anterior right and left ventricles (RV and LV) of Langendorff-perfused rabbit hearts subjected to normothermic global no-flow ischemia and rapid pacing (cycle length 200 ms) in the presence or in the absence of isoproterenol (ISO, 30 nM). 2,3-butanedione monoxime (20 mM) was used to reduce motion artifact. Excitable area was measured in optical maps based on the criterion of the minimum time-derivative of the upstroke of the optical action potential. ISO markedly accelerated electrical depression in both LV and RV (more in LV) compared to control hearts (see Figure, * indicate comparisons with significant difference between groups at p&lt;0.05). In addition, ISO delayed recovery of electrical activity upon reperfusion (62±14% recovery in ISO vs.98±2% recovery in control at 5 min of reperfusion, p&lt;0.01). Furthermore, ISO tended to increase the incidence of post-reperfusion arrhythmias compared to control (83% vs. 25%, respectively; p=NS). We conclude that beta-adrenergic stimulation aggravates electrical dysfunction under conditions typically present during cardiac arrest/resuscitation, which might contribute to the overall detrimental outcomes of natural or induced catecholamine increase in this setting.

Cardiac sympathetic imaging withmIBG in cirrhosis and portal hypertension: relation to autonomic and cardiac function

Autonomic and cardiac dysfunction is frequent in cirrhosis and includes increased sympathetic nervous activity, impaired heart rate variability (HRV), and baroreflex sensitivity (BRS). Quantified (123)I-metaiodobenzylguanidine (mIBG) scintigraphy reflects cardiac noradrenaline uptake, and in patients with cardiac failure it predicts outcome. In this study, we aimed to investigate cardiac sympathetic neuronal function in cirrhosis by mIBG scintigraphy in relation to cardiovascular function. Ten patients with alcoholic cirrhosis and 10 age- and sex-matched healthy controls participated in the study. Heart/mediastinum (H/M) ratios of mIBG uptake were calculated 15 and 230 min after intravenous injection of mIBG. Furthermore, washout rate (WOR) of mIBG was calculated. The patients underwent a liver vein catheterization with determination of splanchnic and systemic hemodynamics and measurement of HRV and BRS. mIBG-scintigraphy revealed significantly increased WOR in patients with cirrhosis compared with controls (P < 0.005), whereas H/M uptakes were equal in the groups. Forty percent of the patients had reduced uptake of mIBG in the infero-lateral segment of the left ventricle. WOR correlated significantly with central circulation time, an estimate of central hypovolemia (r = -0.64, P < 0.05) and frequency-corrected QT(F) interval (r = 0.71, P = 0.01). Patients with cirrhosis had significantly decreased HRV and BRS correlating with indicators of abnormal cathecholamine uptake by mIBG although the catecholamine level was normal in the patients. In conclusion, in alcoholic cirrhosis, mIBG scintigraphy reveals autonomic dysfunction and impaired myocardial distribution of sympathetic nervous activity. It is associated to indicators of central hypovolemia, QT interval, and decreased HRV and BRS. Measurement of myocardial catecholamine uptake by mIBG may add important information on autonomic and cardiac dysfunction in cirrhosis.

Influence of Mild Metabolic Acidosis on Cardiac Contractility and Isoprenaline Response in Isolated Ovine Myocardium

The postoperative course after major surgical procedures such as cardiothoracic operations is often accompanied by acute metabolic abnormalities due to large volume and temperature shifts. In general, those intervention-induced trauma might cause the use of catecholamines to stabilize hemodynamics. Within the cardiac community, there are still controversial discussions about standardized medical therapy to treat postoperative acidosis, for example, buffering versus nonbuffering for improving catecholaminergic response of myocardial contractility. The aim of this study was to investigate the influence of mild (and thus clinically relevant) acidosis on myocardial contractility and catecholamine response in explanted trabeculae of ovine hearts. Intact trabeculae (n = 24) were isolated from the right ventricle of healthy sheep hearts. Two different groups (group 1: pH = 7.40, n = 9 and group 2: pH = 7.20, n = 13) were investigated, and force amplitudes were measured at frequencies between 30 and 180 beats per minute and increasing catecholamine concentrations (isoprenaline 0-3 × 10(-6) mM). Force-frequency relation experiments in the presence of a physiological and/or mild acidotic pH solution showed no significant differences. Mean force amplitudes normalized to the lowest frequency showing no significant differences in force development between 0.5 and 3 Hz (n = 9 vs. 13, P = n.s.) (0.5 Hz absolute values 3.1 ± 2.6 for pH = 7.40 vs. 3.8 ± 2.6 mN/mm(2) for pH = 7.20, P = n.s.). Moreover, there was no significant difference in relaxation kinetics between the two groups. Furthermore, the experiments showed similar catecholamine responses in both groups. Force amplitudes normalized to baseline and maximum force showed no significant differences in force development between baseline and maximum isoprenaline concentrations (n = 6 vs. 9, P = n.s.) (baseline absolute values 4.3 ± 4.0 for pH = 7.40 vs. 3.9 ± 1.2 mN/mm(2) for pH = 7.20, P = n.s.). Additionally, relaxation kinetics did not show differences after catecholamine stimulation. The presented experiments revealed no significant negative inotropic effects on isometrically contracting ovine trabeculae with mild metabolic acidosis (pH = 7.2) compared with physiological pH (7.4). Additionally, similar catecholamine responses were seen in both groups. Further investigations (e.g., in vivo and/or in failing hearts with reduced compensatory reserves) will be necessary to examine optimal medical treatment for metabolic abnormalities after cardiac surgery.

Initial salivary α-amylase activity predicts malignant ventricular arrhythmias and short-term prognosis after ST-segment elevation myocardial infarction

BackgroundVentricular arrhythmias (VA), including ventricular tachycardia and ventricular fibrillation, are the most common remediable cause of death in patients with acute myocardial infarction. Augmented sympathetic neural activity to the heart...

Stress-induced cardiomyopathy

Stress-induced cardiomyopathy is a relatively uncommon syndrome with difficult definition. Cases with transient and reversible left ventricular dysfunction, precipitated by emotional stress and without coronary artery disease, are called takotsubo syndrome, left ventricular apical ballooning, and broken heart syndrome. Many names used to refer to this syndrome are related to the shape of the left ventricle and/or the precipitating factors, but there is not yet a consensus about the proper name. Situations related to physical stress, such as intracranial bleeding, have similar patterns, including the absence of previous cardiac involvement. The increased blood levels of endogenous catecholamine, and increase of myocardial catecholamine in areas with high density of sympathetic innervations, seem to be the mechanisms for myocardial cell necrosis with eosinophilic transverse bands. The localized spasm of the epicardial coronaries, or diffuse microcirculatory dysfunction, is also one of the proposed mechanisms. There are still some areas of controversy that have no definite answer.

Mechanisms of Enhanced β-Adrenergic Reserve From Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT) is the first clinical heart failure treatment that improves chamber systolic function in both the short-term and long-term yet also reduces mortality. The mechanical impact of CRT is immediate and well documented, yet its long-term influences on myocyte function and adrenergic modulation that may contribute to its sustained benefits are largely unknown. We used a canine model of dyssynchronous heart failure (DHF; left bundle ablation, atrial tachypacing for 6 weeks) and CRT (DHF for 3 weeks, biventricular tachypacing for subsequent 3 weeks), contrasting both to nonfailing controls. CRT restored contractile synchrony and improved systolic function compared with DHF. Myocyte sarcomere shortening and calcium transients were markedly depressed at rest and after isoproterenol stimulation in DHF (both anterior and lateral walls), and CRT substantially improved both. In addition, beta(1) and beta(2) stimulation was enhanced, coupled to increased beta(1) receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (Galpha(i)) suppression of beta-adrenergic stimulation was greater in DHF and reversed by CRT. Galpha(i) expression itself was unaltered; however, expression of negative regulators of Galpha(i) signaling (particularly RGS3) rose uniquely with CRT over DHF and controls. CRT blunted elevated myocardial catecholamines in DHF, restoring levels toward control. CRT improves rest and beta-adrenergic-stimulated myocyte function and calcium handling, upregulating beta(1) receptors and adenylate cyclase activity and suppressing G(i)-coupled signaling associated with novel RGS upregulation. The result is greater rest and sympathetic reserve despite reduced myocardial neurostimulation as components underlying its net benefit.

Abnormal Sympathetic Innervation of Viable Myocardium and the Substrate of Ventricular Tachycardia After Myocardial Infarction

The aim of this study was to characterize the relationship between impaired sympathetic innervation and arrhythmia with noninvasive biologic imaging in an animal model of post-infarct ventricular tachycardia (VT). Innervation might be abnormal in the normally perfused borderzone of myocardial infarction, contributing to myocardial catecholamine overexposure and arrhythmogenic risk. Myocardial infarction was induced by mid-left anterior descending coronary artery balloon occlusion in 11 pigs. Positron emission tomography (PET) of tissue perfusion and catecholamine uptake and storage was performed with [13N]-ammonia and [11C]-epinephrine 4 to 12 weeks later. Magnetic resonance imaging and invasive electrophysiology (electroanatomic mapping, basket catheter, VT inducibility) were performed within 1 week of PET. When compared with a normal database of 9 healthy animals, reduced perfusion was observed in 37 +/- 7% of the left ventricle (LV). Epinephrine retention was reduced in 44 +/- 7% of LV, resulting in a perfusion/innervation mismatch of 7 +/- 4% LV. Sustained monomorphic VT was inducible in 7 of 11 animals. These animals showed a larger perfusion/innervation mismatch (10 +/- 4% vs. 4 +/- 2% LV for animals without VT; p = 0.02). Regionally, the degree of perfusion/innervation mismatch did not correlate with wall thickness or thickening but showed a significant correlation with reduced myocardial voltage (r = 0.93; p = 0.001) and with the site of earliest VT activation (chi-square 13.1; p < 0.001). Noninvasive mapping of cardiac sympathetic nerve terminals reveals regionally impaired catecholamine uptake and storage in the normally perfused borderzone after experimental myocardial infarction. These areas might be useful to characterize the individual risk for ventricular arrhythmia.

In Vivo Effects of Myocardial Creatine Depletion on Left Ventricular Function, Morphology, and Energy Metabolism—Consequences in Acute Myocardial Infarction

The failing heart is characterized by disturbed myocardial energy metabolism and creatine (Cr) depletion. The aims of this study were to in vivo evaluate the effects of Cr depletion on: a) left ventricular (LV) function and morphology during rest and stress, b) LV energy metabolism, c) catecholamine in LV and plasma content, and d) incidence of malignant ventricular arrhythmias (MVA) during acute myocardial infarction (MI). Male rats weighing approximately 200 g were used. Two groups were studied: the rats treated with Cr analogue beta-guanidinopropionic acid (BGP) (n = 25) and controls (n = 23). BGP (1 M) was administered by subcutaneously implanted osmotic minipumps over 4 weeks. The rats (BGP n = 9, control n = 12) were than examined with transthoracic echocardiography at basal and at stress conditions induced by transesophageal pacing. In vivo (31)P magnetic resonance spectroscopy (MRS) was used for evaluation of myocardial energy status (BGP n = 7, control n = 12). (31)P MRS, echocardiography and high-performance liquid chromatography analysis of myocardial Cr, total adenine nucleotides and catecholamines in myocardium and plasma were performed on noninfarcted hearts. Myocardial infarction was induced in a subgroup of animals (BGP n = 15, control n = 15) by ligation of the left coronary artery resulting in a large ( approximately 50%) anterolateral MI and acute HF. A computerized electrocardiogram tracing was obtained continuously before induction of MI and up to 60 minutes postinfarction. Qualitative and quantitative variables of ventricular arrhythmias were analyzed using arrhythmia score. Body weight (BW) was lower (P < .01), whereas LV/BW was higher (P < .01) in the BGP group. Total myocardial Cr pool was decreased for at least 50% (P < .01) compared with the controls. There was no difference in total nucleotide pool. Phosphocreatine/adenosine-3-phosphate ratio was lower in the BGP group (P < .01). LV systolic function was disturbed during rest and stress (P < .05). Similarly, LV dimensions were increased in the BGP group (P < .05). Induction of acute MI resulted in markedly increased incidence of MVA and higher mortality in the BGP group (P < .01). Myocardial Cr depletion results in functional and structural LV alterations associated with lower myocardial energy reserve. Intact myocardial Cr metabolism is important for normal LV function during basal and stress conditions. Acute MI in the setting of myocardial Cr depletion leads to excessive mortality from ventricular arrhythmias and progressive heart failure.