Myocardial Calcium Research Articles

Heart failure – are there gender aspects?

Gender differences in the syndrome of heart failure (HF) occur in etiology and pathophysiology, in the clinical presentation and course of the syndrome. In addition, gender specific treatment responses and gender associated differences in the behavior of treating physicians are found. Hypertension and diabetes play a major role as causes of HF in women and both interact in their pathophysiology with the renin angiotensin system (RAS). Modulation of the RAS by estrogens explains specific differences between pre- and postmenopausal women and men. Myocardial growth processes and myocardial calcium handling are differentially regulated in female and male myocytes. Myocardial remodeling with age and as a consequence of mechanical load differs in women and men. For yet unknown reasons, HF with preserved systolic function seems to be more frequent in women than in men and the clinical course of systolic failure is different in both genders.

ANESTHETIC PRECONDITIONING CONFERS ACUTE CARDIOPROTECTION VIA UP-REGULATION OF MANGANESE SUPEROXIDE DISMUTASE AND PRESERVATION OF MITOCHONDRIAL RESPIRATORY ENZYME ACTIVITY

The cellular and molecular mechanisms that underlie cardioprotection against I/R by anesthetic-induced preconditioning (APC) require further elucidation. Using isoflurane as a representative anesthetic, we evaluated the hypothesis that APC induces myocardial protection against I/R by attenuation of excessive reactive oxygen species and restoration of mitochondrial bioenergetics through postischemic up-regulation of manganese superoxide dismutase (MnSOD) expression and preservation of respiratory enzyme activity. Pentobarbital anesthetized open-chest Sprague-Dawley rats were subject to 30-min left coronary artery occlusion, followed by 120-min reperfusion. Before ischemia, rats were randomly assigned to receive 0.9% saline, two cycles of brief coronary artery occlusion and reperfusion, or a 30-min exposure to 1.0 minimum alveolar concentration isoflurane in the absence or presence of a specific mitochondrial adenosine triphosphate-sensitive potassium (KATP) channel blocker, 5-hydroxydecanoate; a membrane-permeable superoxide scavenger, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl; or a NOS inhibitor, N(G)-nitro-L-arginine methyl ester. Isoflurane exposure induced an initial increase in myocardial superoxide (O2-), but not NO level. It also significantly decreased infarct size and restored mitochondrial respiratory enzyme activity or ATP production in I/R rat hearts, along with suppression of the O2- surge at reperfusion and increase in MnSOD expression or enzyme activity. These protective effects were abrogated by 5-hydroxydecanoate or 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl, but not by N(G)-nitro-L-arginine methyl ester pretreatment. These results suggest that opening of mitochondrial KATP channel, followed by O2- signaling, induces postischemic augmentation of MnSOD and preservation of mitochondrial respiratory enzyme activities, leading to attenuated cardiac O2- surge and restored ATP production during reperfusion, and underlie APC-induced cardioprotection.

Molecular Events in the Cardiomyopathy of Sepsis

Septic cardiomyopathy is a well-described complication of severe sepsis and septic shock. However, the interplay of its underlying mechanisms remains enigmatic. Consequently, we constantly add to our pathophysiological understanding of septic cardiomyopathy. Various cardiosuppressive mediators have been discovered, as have multiple molecular mechanisms (alterations of myocardial calcium homeostasis, mitochondrial dysfunction, and myocardial apoptosis) that may be involved in myocardial dysfunction during sepsis. Finally, the detrimental roles of nitric oxide and peroxynitrite have been unraveled. Here, we describe our present understanding of systemic, supracellular, and cellular molecular mechanisms involved in sepsis-induced myocardial suppression.

Treatment of experimental verapamil poisoning with levosimendan utilizing a rodent model of drug toxicity

Background. Levosimendan is an inotropic agent used in the treatment of heart failure. It is a myocardial calcium sensitizer, binding to cardiac troponin-C, and a vascular K+ATP-channel agonist producing peripheral vasodilatation. Aims. To assess the effect of levosimendan on cardiac output (CO), blood pressure (BP), and heart rate (HR) in a rodent model of severe verapamil poisoning. Methods. Male Wistar rats were anesthetized, ventilated, and canulated with jugular and femoral venous catheters and a femoral arterial catheter. CO, systolic BP, MAP, and HR were recorded. Verapamil was infused at 6 mg/kg/h until MAP dropped to 50% of baseline (time-0) and then reduced to 4 mg/kg/h. There were five treatment groups (n = 7 per group): 1) normal saline infusion (control); 2) CaCl2 loading dose and infusion (CaCl2); 3) levosimendan 24 microgram/kg loading dose and 0.6 microgram/kg/min infusion (Levo-24); 4) levosimendan 6 microgram/kg loading dose and 0.4 microgram/kg/min infusion (Levo-6); and 5) levosimendan 0.4 microgram/kg/min infusion with concurrent CaCl2 loading dose and infusion (Levo + CaCl2). Hemodynamic parameters were recorded for 70 minutes. Primary outcome measures were changes observed in CO, BP, and HR with treatments compared to control. Secondary outcome measure was survival. Results were analyzed using one-way ANOVA with Dunnet's post-test comparison with the control group. Results. All groups had similar BP, HR, and CO at base line and peak toxicity. The control group's HR, BP, and CO progressively fell during the verapamil infusion. Levo-24, Levo + CaCl2, and CaCl2 maintained CO compared with control from t = 20 min and Levo6 from t = 30min (p < 0.05). CaCl2 (from t = 10 min) and Levo + CaCl2 (from t = 20 min) produced significant improvements in BP compared to control. However, BP did not return to pre-toxicity levels. Levo-6 and Levo-24 groups did not recover from the hypotension seen at pre-treatment maximal toxicity. HR was maintained in all treatment groups compared to control animals. Twenty-nine percent (2/7) of control, 86% (6/7) levosimendan, 100% (7/7) CaCl2, and Levo + CaCl2 animals survived to the end of the protocol. Conclusions. Levosimendan increased CO in this model of verapamil poisoning to a similar degree as CaCl2 alone, but it did not improve BP from time of maximal toxicity. The addition of CaCl2 to Levosimendan did not appear to result in any further improvement in CO and BP compared to CaCl2 alone. The failure of levosimendan to improve BP may result from vasodilation induced by levosimendan peripheral vascular K+ATP-channel agonism. This may compound the vasodilatory effects of verapamil and offset any hemodynamic improvements produced by increased cardiac output.

Preconditioning With Na+/H+ Exchange Inhibitor HOE642 Reduces Calcium Overload and Exhibits Marked Protection on Immature Rabbit Hearts

Inhibition of Na/H exchanger isoform-1 (NHE1) has shown significant protection in adult myocardium during ischemia/reperfusion injury; however, the effect is unclear in immature myocardium. We evaluated the effects of HOE642 (a potent, highly selective NHE1 inhibitor) preconditioning on immature rabbit hearts. Twenty immature (2-3 weeks old) New Zealand white rabbits were randomly divided into the control group (n = 10) and the HOE642 preconditioning group (n = 10). The immature isolated hearts were subjected to 45 minutes of normothermic global ischemia plus 60 minutes of reperfusion after being established on the Langendorff apparatus. During reperfusion, the recovery rates of cardiac function (LVDP, +dp/dtmax, -dp/dtmax, and coronary flow) were about 90% in the HOE642 treated group and about 50% in the control group (p < 0.05). HOE642 preconditioning can significantly decrease the release of cardiac specific enzymes CK, CK-MB and LDH (p < 0.05) and the myocardial water content (p < 0.05). Meanwhile, HOE642 markedly attenuated intracellular calcium overload (265.8 +/- 41.1 vs. 500.7 +/- 60.8 mg/kg dry wt) (p < 0.01). The blinded ultrastructural assessment under transmission electron microscopy illustrated that preconditioning with HOE642 produced evident myocyte salvage. This study demonstrates that preconditioning with HOE642 provides a significant protection during ischemia/reperfusion injury in immature myocardium, mostly by reducing myocardial calcium overload.

Myocardial mechanical dysfunction and calcium overload following rewarming from experimental hypothermia in vivo

Rewarming patients from accidental hypothermia are regularly complicated with cardiovascular instability ranging from minor depression of cardiac output to fatal circulatory collapse also termed “rewarming shock”. Since altered Ca 2+ handling may play a role in hypothermia-induced heart failure, we studied changes in Ca 2+ homeostasis in in situ hearts following hypothermia and rewarming. A rat model designed for studies of the intact heart in a non-arrested state during hypothermia and rewarming was used. Rats were core cooled to 15 °C, maintained at 15 °C for 4 h and thereafter rewarmed. As time-matched controls, one group of animals was kept at 37 °C for 5 h. Total intracellular myocardial Ca 2+ content ([Ca 2+] i) was measured using 45Ca 2+. Following rewarming we found a significant reduction of stroke volume and cardiac output compared to prehypothermic control values as well as to time-matched controls. Likewise, we found that hypothermia and rewarming resulted in a more than six-fold increase in [Ca 2+] i to 3.01 ± 0.43 μmol/g dry weight compared to 0.44 ± 0.05 μmol/g dry weight in normothemia control. These findings indicate that hypothermia-induced alterations in the Ca 2+-handling result in Ca 2+ overload during hypothermia, which may contribute to myocardial failure during and after rewarming.

Ranolazine in patients with coronary artery disease

Traditional anti-anginal agents such as β-blockers and nitrates improve symptoms of cardiac ischemia by affecting either blood pressure or heart rates. Despite aggressive therapy, many patients suffer persistent angina, and optimal therapy is limited by intolerance to traditional agents. Ranolazine, a novel anti-anginal agent that is approved for use in the US, is felt to improve ischemic symptoms by reducing myocardial cellular sodium and calcium overload via inhibition of the late sodium current (INa) of the cardiac action potential. Several Phase-III trials in patients with chronic angina have demonstrated that ranolazine improves exercise tolerance and reduces ischemic symptoms as compared with placebo. In the largest evaluation of ranolazine, the MERLIN-TIMI 36 trial (Metabolic Efficiency with Ranolazine for Less Ischemia in non ST elevation acute coronary syndrome), ranolazine did not reduce the risk of death or recurrent myocardial infarction in patients with non-ST-elevation acute coronary syndromes, but it did improve ischemic symptoms over the subsequent year of therapy. Thus, ranolazine offers clinicians a new therapy in the long-term treatment of patients with chronic angina.

Hemodynamic Effects of Intralipid after Verapamil Intoxication May Be Due to a Direct Effect of Fatty Acids on Myocardial Calcium Channels

Hemodynamic Effects of Intralipid after Verapamil Intoxication May Be Due to a Direct Effect of Fatty Acids on Myocardial Calcium Channels

Hemodynamic Effects of Intralipid after Verapamil Intoxication May Be Due to a Direct Effect of Fatty Acids on Myocardial Calcium Channels

Academic Emergency MedicineVolume 14, Issue 8 p. 761-761 Free Access Hemodynamic Effects of Intralipid after Verapamil Intoxication May Be Due to a Direct Effect of Fatty Acids on Myocardial Calcium Channels Gildas Gueret MD, Gildas Gueret MD Department of Anesthesiology and Critical Care, University Hospital Brest, Brest, FranceSearch for more papers by this authorJean Pierre Pennec PhD, Jean Pierre Pennec PhD Department of Anesthesiology and Critical Care, University Hospital Brest, Brest, FranceSearch for more papers by this authorCharles C. Arvieux MD, PhD, Corresponding Author Charles C. Arvieux MD, PhD Department of Anesthesiology and Critical Care, University Hospital Brest, Brest, France (Email: [email protected]).Search for more papers by this author Gildas Gueret MD, Gildas Gueret MD Department of Anesthesiology and Critical Care, University Hospital Brest, Brest, FranceSearch for more papers by this authorJean Pierre Pennec PhD, Jean Pierre Pennec PhD Department of Anesthesiology and Critical Care, University Hospital Brest, Brest, FranceSearch for more papers by this authorCharles C. Arvieux MD, PhD, Corresponding Author Charles C. Arvieux MD, PhD Department of Anesthesiology and Critical Care, University Hospital Brest, Brest, France (Email: [email protected]).Search for more papers by this author First published: 28 June 2008 https://doi.org/10.1197/j.aem.2007.04.006Citations: 18AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References Tebbutt S, Harvey M, Nicholson T Cave G. Intralipid prolongs survival in a rat model of verapamil toxicity Acad Emerg Med 2006; 13: 134– 139. Bania TC, Chu J, Perez E, Su M, Hahn IH. Hemodynamic effects of intravenous fat emulsion in an animal model of severe verapamil toxicity resuscitated with atropine, calcium, and saline Acad Emerg Med 2007; 14: 105– 111. Weinberg GL, Ripper R, Murphy P, et al. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart Reg Anesth Pain Med 2006; 31: 296– 303. Huang JM, Xian H, Bacaner M. Long-chain fatty acids activate calcium channels in ventricular myocytes Proc Natl Acad Sci U S A 1992; 89: 6452– 6456. Citing Literature Volume14, Issue8August 2007Pages 761-761 ReferencesRelatedInformation

Ranolazine in patients with angina and coronary artery disease

The optimal management of coronary artery disease is based on achieving two parallel objectives: 1) prevention of major cardiovascular events, and 2) resolution of symptoms. Traditional antianginal agents improve ischemic symptoms by reducing myocardial oxygen demand through modulation of heart rate, preload, and/or afterload. Ranolazine is a novel antianginal agent believed to relieve ischemia by reducing myocardial cellular sodium and calcium overload via inhibition of the late sodium current of the cardiac action potential. In three randomized double-blind trials in selected patients with chronic angina, ranolazine prolonged exercise duration and reduced symptoms when compared with placebo when given as either monotherapy or in combination with traditional antianginal pharmacotherapy. When evaluated in patients with non-ST-elevation acute coronary syndromes, ranolazine reduced recurrent ischemia but did not significantly reduce the risk of death or myocardial infarction at 1 year. Ranolazine complements traditional antianginal agents and offers clinicians a new option in the long-term treatment of patients with angina.

Myocardial Depression Associated with Pneumococcal Septic Shock Reversed by Levosimendan

Levosimendan is a myocardial calcium sensitiser and potassium-ATP channel opener Levosimendan has been used in critically ill patients in various conditions to support myocardial function as an inotrope, lusitrope and vasodilator. We report the use of levosimendan in a patient with invasive streptococcal septic shock.

Determination of the Absolute Configuration of a Chiral Oxadiazol-3-one Calcium Channel Blocker, Resolved Using Chiral Chromatography, via Concerted Density Functional Theory Calculations of Its Vibrational Circular Dichroism, Electronic Circular Dichroism, and Optical Rotation

The chiral oxadiazol-3-one 2 has recently been shown to exhibit myocardial calcium entry channel blocking activity, substantially higher than that of diltiazem. To determine the enantioselectivity of this activity, the enantiomers of 2 have been resolved using chiral chromatography. The absolute configuration (AC) of 2 has been determined by comparison of density functional theory (DFT) calculations of its vibrational circular dichroism (VCD) spectrum, electronic circular dichroism (ECD) spectrum, and optical rotation (OR) to experimental VCD, ECD, and OR data. All three chiroptical properties yield identical ACs; the AC of 2 is unambiguously determined to be S(+)/R(-).

Reduced myocardial calcium responsiveness after coronary microembolization

We have recently reported that the myocardial dysfunction observed several hours after coronary microembolization (ME) is related to an oxidative modification of tropomyosin (Canton et al., Eur Heart J 27:875–881, 2006). We have now investigated the impact of ME on calcium responsiveness at a time when myocardial function is reduced, i.e. 6 h after ME. In 10 anesthetized pigs the LAD was cannulated and perfused by an extracorporeal perfusion system. Regional myocardial function was assessed by sonomicrometry. Five pigs received saline as placebo and served as controls. In 5 pigs, ME was induced by injection of microspheres (Ø42 μ; 3000/ml/min coronary inflow) through the perfusion system. Calcium responsiveness was determined by measuring the increase in myocardial work (pressure vs. wall excursion) in response to a graded intracoronary infusion of CaCl2 at baseline and at 6 h after ME or placebo, respectively. Graded CaCl2 increased myocardial work at baseline stepwise. At any CaCl2 myocardial work was attenuated 6 h after ME, whereas it was not different from baseline after 6 h in controls. The absolute concentration of Ca in coronary blood to achieve the half maximal increase in myocardial work remained unchanged in controls (baseline: 189±18 μg/ml, mean±SEM; 6 h: 212±22 μg/ml) and after ME (baseline: 179±8 μg/ml; 6 h: 175±17 μg/ml).

Direct Myocardial Effects of Levosimendan in Humans With Left Ventricular Dysfunction

Enthusiasm for the development of Ca2+ sensitizers as inotropic agents for heart failure has been tempered by reports of impaired relaxation. Levosimendan, which increases myofilament Ca2+ sensitivity via Ca2+-dependent binding to troponin C, exerts positive inotropic and lusitropic effects in failing human myocardium in vitro. We sought to determine the direct effects of levosimendan on failing human myocardium in vivo, and in particular whether levosimendan exerts heart rate-dependent effects on systolic or diastolic function. Ten patients with left ventricular dysfunction caused by nonischemic dilated cardiomyopathy (mean left ventricular ejection fraction, 27+/-2%) were instrumented with an infusion catheter in the left main coronary artery, a high-fidelity micromanometer-tipped catheter in the left ventricle, and a bipolar pacing wire in the right atrium. Inotropic (peak +dP/dt) and lusitropic (Tau) responses were assessed during continuous intracoronary drug infusion in sinus rhythm followed by atrial pacing at 20, 40, and 60 beats per minute above the sinus rate. Under control conditions (intracoronary 5% dextrose in water), atrial-pacing tachycardia decreased Tau by 13% (P<0.05), but did not increase +dP/dt. Intracoronary levosimendan (3.75 and 12.5 microg/min for 15 minutes each) increased +dP/dt dose-dependently and decreased Tau over a range of heart rates, but did not alter the slope of the force-frequency or relaxation-frequency relationship. Myocardial calcium sensitization with levosimendan exerts mild inotropic and lusitropic effects in humans with left ventricular dysfunction, but does not alter the force-frequency or relaxation-frequency relationship.

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WITHDRAWN: Reduced myocardial calcium responsiveness after coronary microembolization

WITHDRAWN: Reduced myocardial calcium responsiveness after coronary microembolization

Myocardial KATP channels are critical to Ca2+ homeostasis in the metabolically stressed heart in vivo

myocardial atp-sensitive potassium (KATP) channels appear to play central roles in the adaptation of the heart to both physiological and pathological metabolic stress ([1][1], [3][2], [5][3], [7][4], [8][5], [14][6], [16][7], [21][8]). In the heart, KATP channels are thought to act as metabolic

Studies on oxyradical, lipid peroxidation, cytochrome C and mitochondrial calcium in myocardium from diabetic rats

The present study was undertaken to observe the difference of nitrogen monoxidum (NO), malondialdehyde (MDA), cytochrome C (Cyt-C), nitric oxide synthase (NOS), mitochondrial calcium and superoxide dismutase (SOD) in myocardium between noninsulin dependent diabetes mellitus (NIDDM) rats and normal rats. Methods: Twenty NIDDM rats were made, and 20 normal rats were used as control. The levels of NO, MDA, Cyt-C, NOS, mitochondrial calcium and SOD in myocardial cells from all rats were measured, and histological changes were observed. Results: Compared with control, the levels of NO (2.28±0.40∗ vs 1.81±0.33 μmol/g protein), NOS (0.49±0.09∗ vs 0.39±0.07 U/mg protein), MDA (7.87±0.31∗ vs 7.36±0.53 nmol/mg protein), cytoplasma Cyt-C (3.68±0.17∗ vs 3.25±0.34 g/L) and mitochondrial calcium (2.90±0.35∗ vs 2.47±0.23 μg/L) were higher (NIDDM rats vs control, ∗P<0.05) in the NIDDM rats. But, the levels of mitochondrial Cyt-C (0.19±0.05∗ vs 0.28±0.06 mmol/L) and mitochondrial SOD (0.81±0.21∗ vs 1.18±0.39 U/mg protein) were lower (NIDDM rats vs control, ∗P<0.05) in the NIDDM rats compared with control. Under microscope, myocardium deliquescenced and mitochondria swelled, and inflammatory cell infiltrated in mesenchyma. Conclusions: Oxyradical, lipid peroxidation, Cyt-C and mitochondrial calcium are involved in the damage of myocardium in NIDDM rats.

Superior Logistic Model for Decay of Ca2+ Transient and Isometric Relaxation Force Curve in Rabbit and Mouse Papillary Muscles

A decrease in myocardial intracellular calcium concentration ([Ca(2+)](i)) precedes relaxation, and a monoexponential function is typically used for fitting the decay of the Ca(2+) transient. However, a logistic function has been shown to be a better fit for the relaxation force curve, compared to the conventional monoexponential function. In the present study, we compared the logistic and monoexponential functions for fitting the [Ca(2+)](i) declines, which were measured using the aequorin method, and isometric relaxation force curves at 4 different onsets: the minimum time-derivative of [Ca(2+)](i) (d[Ca(2+)](i)/dt (min)) and force (dF/dt(min)), and the 10%, 20% and 30% lower [Ca(2+)](i) levels and forces over the data-sampling period in 7 isolated rabbit right ventricular and 15 isolated mouse left ventricular papillary muscles. Logistic functions were significantly superior for fitting the [Ca(2+)] (i) declines and relaxation force curves, compared to monoexponential functions. Changes in the normalized logistic [Ca(2+)] (i) decline and relaxation force time constants at the delayed onsets relative to their 100% values at d[Ca(2+)] (i)/dt(min) and dF/dt(min) were significantly smaller than the changes in the normalized monoexponential time constants. The ratio of the logistic relaxation force time constant relative to the logistic [Ca(2+)](i) decline time constant was significantly smaller in mouse than in rabbit. We conclude that the logistic function more reliably characterizes the [Ca(2+)](i) decline and relaxation force curve at any onset, irrespective of animal species. Simultaneous analyses using the logistic model for decay of the Ca(2+) transient and myocardial lusitropism might be a useful strategy for analysis of species-specific myocardial calcium handling.

Impaired myocardial contractility and calcium handling in hereditary dilated cardiomyopathy

Impaired myocardial contractility and calcium handling in hereditary dilated cardiomyopathy