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,
,,1
* Marriott Heart Disease Research Program Division of Cardiovascular Diseases, Department of Medicine,
Department of Molecular Pharmacology and Experimental Therapeutics,
Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; and
Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
1Correspondence: Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. E-mail: terzic.andre{at}mayo.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: ATP-sensitive K+ channel • Kir6.1 • metabolism • sepsis • septic shock • vasodilation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2
3)
. Central to this syndrome is a pronounced cytokine-induced cardiovascular state defined by a hypercontractile heart and altered vascular tone (4)
. Despite diverse infectious pathogens, the outcome in severe sepsis is governed by the nature and degree of the host response, with the cardiovascular status an ultimate determinant of survival (5
6
7)
. The Gram-negative bacterial cell wall endotoxin, LPS (lipopolysaccharide), evokes a surge in tumor necrosis factor-alpha (TNF
), precipitating an inflammatory mediated cascade of pathophysiologic events that imposes a high demand on the hyperdynamic septic heart (4
, 6)
. Although there is an understanding of the proinflammatory cytokine signaling that triggers hemodynamic changes in endotoxic and, more generally, septic shock (1
, 4)
, less is known of the molecular components that ensure metabolic stability while maintaining cardiac workload.
Particularly for organs that are highly active metabolically, such as the heart, imposition of the demands of stress necessitates augmentation of energetic supply. As heart muscle displays saturating levels of oxygen extraction under basal conditions, the cardiac capacity to meet increased demand is limited to the responsiveness of the coronary circulation to vasodilate and increase flow (8)
. Severe sepsis and septic shock are typified by potent systemic vasodilation (9
10
11)
, yet the cellular components that couple vasoreactivity with changes in metabolic demand are unsolved.
ATP-sensitive K+ (KATP) channels have emerged as protein complexes with the capability to decode signals of metabolic distress (12
13
14)
. By virtue of an intimate integration with intracellular energetic networks and a capacity for high-fidelity processing of incoming metabolic signals, KATP channels regulate cellular excitability-dependent functions (12
13
14
15
16)
. These channels are situated in high density within metabolically active tissues, where changes in the energetic state are conveyed through the ATP-binding cassette sulfonylurea receptor (SUR) regulatory subunit to the K+ channel pore, Kir6.x of the channel complex (12
13
14
15
16
17)
. It is the tissue-dependent channel pore that, requiring the regulatory SUR chaperone to function, adjusts membrane potential to match demand and maintain cellular well-being (12
13
14
15
16
17)
. In nonvascular tissue, including the myocardium, where the pore-forming isoform is Kir6.2, defects in KATP channel subunits jeopardize cellular stress tolerance and predispose to injury (13
14
15
16
17
18
19)
. In the vasculature, the pore-forming subunit of the KATP channel has been identified as the homologous but genetically distinct Kir6.1 protein encoded by the KCNJ8 gene, and Kir6.1-containing channels have been implicated in the regulation of arterial smooth muscle tone (20
21
22
23)
. The functional tissue specificity of Kir6.1 is underscored by knockout of the KCNJ8 gene that translates into loss of plasmalemmal KATP channel activity in the vasculature, in particular the coronary bed, but also maintenance of channel activity elsewhere, including the heart (23)
. Vascular Kir6.1 KATP channels may thereby harbor the potential to translate signals of demand, as occur under syndromes of systemic metabolic stress such as in severe sepsis, into optimal cardiovascular tolerance.
To test this hypothesis, we probed the outcome of genetic disruption of Kir6.1 in a model of severe sepsis with acute endotoxic shock. Knockout of the KCNJ8 gene interrupted a vital vasodilatory adaptive mechanism in LPS-induced endotoxemia, producing deficits in coronary flow, ischemic cardiac dysfunction, and premature death. Demonstrating the requirement of Kir6.1 in securing coronary vasoreactivity identifies a molecular link between metabolic demand and adequate cardiac performance in endotoxic shock.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Six- to 8-wk-old Kir6.1-KO mice were compared with age- and sex-matched WT littermate controls. All groups of mice were selected at the time of weaning and/or genotyping by tail polymerase chain reaction (PCR) (3–4 wk of age) and were observed for an average of 2 wk before experiments. Comparisons between groups were performed by ANOVA, Student’s t tests, nonparametric or log rank tests, using JMP software (SAS). Data are presented as mean ± SE; n refers to the sample size. P < 0.05 was predetermined. Chemicals were obtained from Sigma (St. Louis, MO, USA). The Mayo Clinic Institutional Animal Care and Use Committee approved all protocols.
Endotoxic shock
The shock state of severe sepsis was modeled by administration of E. coli LPS serotype 0111:B4 (4
, 6)
. Dose-response mortality curves were obtained over a range of LPS concentrations (0.1–1000 µg/g) administered i.p. in 100–200 µl sterile saline. Unless otherwise stated, for in vivo experiments the dose of LPS was 15 µg/g. To monitor survival, mice were observed without anesthesia hourly for 24 h, every 6 h for another 48 h, then daily for a total of 7 days. The effect of calcium channel blockade on LPS-induced mortality in the Kir6.1-KO was assessed by comparing survival in verapamil (5 µg/g s.c. every 5 h) vs. saline-treated mice. The effect of the KATP channel opener pinacidil (10 µg/g) on LPS-induced mortality (lipopolysaccharide 35 µg/g) in WT and Kir6.1-KO was evaluated and compared with vehicle-treated controls.
Telemetry and electrocardiography
To continuously monitor cardiac activity and core temperature in the conscious state, telemetry devices (Data Sciences International, St. Paul, MN, USA) were implanted in the peritoneum and leads were tunneled s.c. in a lead II configuration under isoflurane anesthesia in WT and Kir6.1-KO (13)
. After recovery from surgery (24 h), signals were acquired at 2 kHz before and after LPS administration. For continuous surface electrocardiographic (ECG) recordings following anesthesia with isoflurane (1%), WT and Kir6.1-KO mice had continuous ECG monitoring via limb lead electrodes. Tracings were recorded for 20 min before and up to 6 h after LPS administration.
Histopathology
Light microscopy was performed on paraffin-embedded myocardial sections stained with hematoxylin-eosin from 4% formalin-fixed left ventricles (LV) taken from WT and Kir6.1-KO mice 4–6 h after LPS or saline vehicle administration. Transmitted electron microscopy (EM) was performed on ultramicrotome-cut, lead citrate-stained LV sections with a JEOL 1200 EXII electron microscope (24)
.
In vivo hemodynamics
Echocardiography with heart rate measurements (c256 and 15L8, Acuson, Stockton, CA, USA) was performed in lightly sedated (1% isoflurane) WT and Kir6.1-KO before, 90, 180, and 360 min after LPS administration. Images were digitally acquired and stored for off-line blinded analysis. Echocardiographic measurements of LV dimensions were recorded at end-diastole (EDD) and end-systole (ESD) from three consecutive cardiac cycles using the leading edge method (24)
. LV fractional shortening (% fibrous sheath) was calculated as % fibrous sheath = [(EDD-ESD)/EDD] x 100. Ejection time (Et) was determined from the actual pulsed-wave Doppler tracings of LV outflow by measuring the interval from the beginning of the acceleration to the end of the deceleration. The myocardial velocity of LV circumferential shortening (Vcf expressed in circumferences per s) was calculated as Vcf = [(EDD-ESD)/EDD]Et. Blood pressure was measured under light sedation (1% isoflurane) by tail-cuff (Columbus Instruments, Columbus, OH, USA; ref. 25
) before and 90 min after LPS challenge.
Blood analysis
Blood oxygen concentration, pH, lactate (iSTAT Corporation, Abbott Park, IL, USA), and glucose (Glc) (Lifescan, Milpitas, CA, USA) were measured 6 h post-lipopolysaccharide or postsaline. Serum TNF levels were quantified at baseline, 90 and 180 min after LPS administration by ELISA (R&D Systems, Minneapolis, MN, USA).
Coronary flow
The aorta was cannulated in situ, heart excised, retrogradely perfused at 90 mm Hg with Krebs-Henseleit buffer (bubbled with 95% O2/5% CO2 at 37°C; pH 7.4), and paced at a rate of 600 beats/min (24)
. Coronary flow was continuously measured with a T106 small animal blood flow meter (Transonic Systems Inc., Ithaca, NY, USA). The effect of recombinant murine TNF was assessed at least 20 min after flow stabilization. In a subset of hearts, TNF was preceded by 10 min perfusion of 10 µM glyburide in the WT or followed by 1 µM verapamil in the Kir6.1-KO. Maximum vasodilation was defined as the peak increase in coronary flow observed in the WT in response to 10 µl of 1 mM adenosine after at least 10 min of return to baseline flow on TNF washout.
Aortic reactivity
Isolated aortic rings from WT and Kir6.1 knockout mice were studied in parallel. Rings were mounted in a thermostatic organ bath for isometric tension recordings and perfused continuously with a Krebs-Henseleit buffer (bubbled with 95% O2/5% CO2 at 37°C) as described (26)
. After an equilibration period of 30 min, the rings were progressively stretched to their optimal passive tension as assessed by the response to 0.1 M KCl. Vasomotor function of aortic rings from WT and Kir6.1 KO (n=6–8 each) were studied with concentration-dependent response curves generated in response to cumulative addition of HCl to alter pH or to the KATP channel opener pinacidil (10–9 to 10–4 M).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 2)
. The shock state of severe sepsis was simulated by i.p. administration of the endotoxin E. coli LPS in WT mice and in littermates lacking the pore-forming subunit of vascular KATP channels (Kir6.1-KO) through deletion of the KCNJ8 gene. In response to LPS, all mice displayed decreased activity, piloerection, periocular discharge, and diarrhea, typical early signs of endotoxemia. However, compared with the more tolerant WT (6 out of 22) or to vehicle-challenged Kir6.1-KO (0/10), in Kir6.1-KO mice an absence of vascular KATP channels predisposed to a prompt and massive mortality after 15 µg/g LPS administration (22/22, P<0.0001; Fig. 1
A). Kir6.1-KO mice began to die within the first 3 h, with 50% death observed at 7 h and mortality in the whole cohort confirmed within 24 h (Fig. 1A
). In WT, no fatality was observed in the initial 24 h, with the majority (73%) surviving long-term (Fig. 1A
). In the absence of Kir6.1, the high susceptibility to endotoxin-mediated stress was confirmed over a range of LPS concentrations (Fig. 1B
; P=0.009), with a readily demonstrable early death following LPS (Fig. 1C
) in the Kir6.1-KO (n=39) compared with the WT (n=61; P=0.0055). The LD50 to LPS at 12 h (Fig. 1C
) was 27-fold higher for Kir6.1-KO (6.7 µg/g) than the WT (185.4 µg/g; P<0.0001). These findings indicate a vital role for intact Kir6.1 in the host response to LPS challenge.
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Lack of Kir6.1 compromises cardiac adaptive performance in endotoxic shock
The development of cardiovascular impairment is a critical determinant of mortality in sepsis and septic shock (3
4
5
6)
. Death in the Kir6.1-KO following LPS was preceded by a progressive decline in cardiac activity captured on telemetry (n=4; Fig. 2
A, B). This was in contrast to the WT (n=3) in which cardiac activity was preserved above preLPS levels (Fig. 2A, B
). WT mice had normal electrocardiograms both before and after LPS challenge (Fig. 2C
). Electrocardiograms of the Kir6.1-KO at baseline showed intermittent transient abnormalities due to lack of coronary KATP channel activity (23)
and demonstrated, under LPS challenge, severe and persistent ST segment change, an electrophysiological marker of the development of global myocardial ischemic injury (Fig. 2C
). At autopsy, hearts from Kir6.1-KO mice displayed early features of myocyte coagulation necrosis with cytoplasmic hypereosinophilia within 4–6 h of LPS administration (n=8), pathological findings that were absent in endotoxic WT (n=8; Fig. 3
A) or saline-treated Kir6.1-KO hearts (n=6; not illustrated). Distinct from the normal architecture of WT hearts, the ultrastructure of cardiomyocytes in LPS-challenged Kir6.1-KO demonstrated disarray (Fig. 3B
) with swollen, amorphous deposit-laden mitochondria (Fig. 3B
, inset). Such pathological findings in Kir6.1-KO hearts, indicative of ischemic cardiomyocyte injury, translated into contractile dysfunction documented by serial echocardiography. While both the WT (n=10) and Kir6.1-KO (n=10) were normal before LPS, only the WT augmented cardiac performance early in response to LPS (% fractional shortening increased from 39±2 to 49±4; P<0.05) and maintained normal contractility through 3 and 6 h (Fig. 3C, E
). In contrast, Kir6.1-KO mice displayed no early positive inotropy (% fractional shortening of 40±2 vs. 42±4, P=0.64; Fig. 3C, D
), and progressed to left ventricular failure documented by deterioration of both left ventricular fractional shortening (Fig. 3D
) and circumferential shortening velocity (Fig. 3E
). Cardiac dysfunction in Kir6.1-KO was mediated by a marked elevation in end-systolic left ventricular diameter (54±13% increase from baseline, P<0.02), whereas no left ventricular dilation was noted in the WT (–3.3±5%, P=0.6; Fig. 3C
). Furthermore, Kir6.1-KO was deprived of tachycardia that accompanied the augmented cardiac performance in the endotoxic WT (Fig. 2A
). Three hours after LPS, WT increased heart rates by 16 ± 6% (P<0.05), a response not observed in Kir6.1-KO (–1±7%; P=0.92). In fact, in Kir6.1-KO at 6 h, heart rates had declined by 33 ± 6% (P<0.02) to 360 ± 19 beats per min while rates remained normal in WT at 476 ± 22 beats per min (P=0.62). Thus, in response to the demands imposed by LPS, Kir6.1-KO mice failed to augment cardiac performance, and developed marked ST segment elevation preceding and persisting with the progression to extreme bradycardia, extensive cardiomyocyte injury, and severe contractile dysfunction.
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Compared with the WT (n=4) that maintained a body temperature at 37.3 ± 0.2°C and 35.3 ± 1.0°C before and 6 h post-lipopolysaccharide (P=0.2), the cardiac-impaired endotoxic Kir6.1-KO (n=3) developed hypothermia, dropping from 36.5 ± 0.5°C to 29.3 ± 1.0°C (P<0.02). These systemic perturbations in the endotoxic Kir6.1-KO (n=5) were associated with a greater degree of metabolic acidosis characterized by lower serum pH (7.14±0.02 vs. 7.22±0.05; P<0.05) and higher serum lactate (4.0±1.6 mM vs. 1.8±0.2 mM; P<0.05) than seen in the WT (n=6). Noncardiovascular parameters, including hypoglycemia, were comparable between the WT (serum Glc from 166±15 to 52±14 mg/dl; P<0.001) and Kir6.1-KO (from 152±4 to 44±6 mg/dl; P<0.001), as was blood oxygen concentration (68.6±9 mm Hg in WT and 62.3±13 mm Hg in Kir6.1-KO; P=0.67). Thus, vascular Kir6.1-containing KATP channels contribute to attainment of the energetically demanding hyperdynamic cardiac state and maintenance of metabolic stability in endotoxic shock.
Loss of cytokine-induced vasodilation in Kir6.1-KO compromises coronary flow
The septic response is distinguished by a proinflammatory mediator cascade that activates cellular defense mechanisms required to combat infection (1)
. A critical early common denominator of this response to infectious organisms and their endotoxins is the cytokine TNF, which acts as an early mediator of the vasodilatory septic shock syndrome (27)
. Before LPS administration, both Kir6.1-KO and WT mice had undetectable serum TNF levels that rose to a similar extent after LPS injection, peaking at 90 min (Fig. 4
A). This suggests that the early cardiac dysfunction observed in the endotoxic Kir6.1-KO was independent from the LPS-induced serum TNF dynamics, implying a compromise in the host response to an otherwise equivalent cytokine surge.
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Execution of cardiac performance under stress necessitates adjustment in coronary flow to meet demand (8)
. The TNF-initiated hyperdynamic syndrome of severe sepsis characterized by increased cardiac output with vasodilation (4
, 5
, 27
, 28)
. While having similar rates of coronary flow at baseline (P=0.98), WT and Kir6.1-KO displayed a differential cytokine-induced vasodilatory response. Recombinant TNF, administered at a dose (4 µg/l) comparable to the peak serum level observed during LPS challenge (Fig. 4A
), induced coronary vasodilation only in WT hearts (Fig. 4B, C
). This local TNF-induced increase in flow was not observed in Kir6.1-KO (at 4 µg/l or even higher doses of 8 or 20 µg/l TNF) or in WT hearts pretreated with the KATP channel inhibitor, the sulfonylurea glyburide (Fig. 4B, C
). This indicates that unimpeded KATP channel activity is required to secure vascular smooth muscle tone regulation under a central early mediator of endotoxic shock. Furthermore, mirroring the lack of response at the coronary level, Kir6.1-KO did not systemically vasodilate (mean arterial pressure from 95±8 mm Hg before to 103±15 mm Hg after LPS, P=0.6), unlike the WT mice that manifested pronounced systemic vasodilation indicated by a 29 ± 4% fall in mean arterial pressure (85±6 mm Hg to 58±3 mm Hg, P<0.0001; Fig. 4D
). Thus, Kir6.1 is required for adaptive vasodilatory response to endotoxic shock.
Metabolic vasoreactivity lost in Kir6.1-KO
The downstream consequence of the cytokine-induced septic shock syndrome, the metabolic state of acidosis is itself a contributor to the vasodilatory state. Unlike the response in WT vessels, which relaxed to the modest reductions in pH observed in endotoxemia, in the Kir6.1-KO or glyburide-treated WT, acidosis did not induce vasorelaxation (Fig. 5
A). These differences persisted whether the endothelium was intact or not (not illustrated). Moreover, the potent endogenous vasodilator adenosine, which has been implicated in the maintenance of organ perfusion in sepsis (29
, 30)
and cardioprotection in the septic heart (31)
, induced robust coronary vasodilation in WT hearts (Fig. 5B
). Yet the coronary vascular bed of the Kir6.1-KO failed to vasodilate on adenosine administration (Fig. 5B
), displaying vasoconstriction analogous to the response to TNF (Fig. 4C
). These findings indicate a general deficit in vasodilation in the absence of Kir6.1, which is otherwise critical in the WT, where vital cytokine- or metabolic-mediated coronary vasoreactivity supports myocardial perfusion in response to demand.
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Potassium channel opener-induced survival benefit in endotoxic shock
Systemic administration of a KATP channel opener resulted in arterial (including coronary) vasodilation, an action notably absent in Kir6.1-KO animals (Fig. 6
A; ref. 23
). In the WT, at a dose of LPS that approximates the lethal dose50 (Fig. 1B
), provision of pinacidil, the prototypic and clinically available potassium channel opener, abrogated LPS-induced mortality (Fig. 6B, C
). Indeed, in the WT pinacidil reduced 24 h mortality from 60% to zero (Fig. 6B
) and provided enduring protection against endotoxic shock, increasing long-term survival by 72% (Fig. 6C
). Administration of pinacidil had no protective benefit in Kir6.1-KO mice (Fig. 6B, C
). Thus in the setting of life-threatening LPS challenge, whereas deletion of Kir6.1 shifts the survival curve toward an exaggerated mortality, use of a potassium channel opener imparts an increased survival, indicating the vital role of adequate vascular KATP channel function under endotoxemia.
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Rescue of adaptive vascular response offsets LPS-induced mortality in Kir6.1-KO
As the absence of KATP channel activity predisposes to calcium-dependent smooth muscle constriction (21
, 32
, 33)
, rescue of the vasodilatory response in Kir6.1-KO was achieved by bypassing the defective capacity of vessels to secure flow (Fig. 7
A). Application of the calcium channel antagonist, verapamil, to Kir6.1-KO hearts challenged with TNF reinstated coronary vasodilation (Fig. 7A
) to a level comparable to that of the flow response of the WT (Fig. 4B
). Furthermore, calcium channel inhibition negated the disproportionate LPS-induced mortality in the Kir6.1-KO (P<0.05, Fig. 7B
), resulting in a significant increase in median survival time from 7 to 24 h. Restoration of the vascular response to endotoxin-mediated stress after ablation of Kir6.1 is thus necessary to secure adequate organ perfusion, translating into prevention of premature and exaggerated mortality in endotoxic shock.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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35
36
37)
. The molecular determinants that secure an elevated state of adaptation to a spectrum of environmental challenges, and in particular septic threats imposed by endotoxins, remain poorly defined. Here we identify Kir6.1 as an essential molecular component in the response to lethal endotoxemia. Targeted disruption of the KCNJ8 gene that encodes the Kir6.1 pore and ablates vascular, but not nonvascular, KATP channel activity (23)
compromised coronary flow, precipitating cardiac damage and death after LPS challenge. Although with progression of the sepsis syndrome to severe sepsis and septic shock, excessive systemic vasodilation is deleterious and related to poor outcome (2
3
4
5)
, the present findings point to the significance of adequate, Kir6.1-supported coronary perfusion in maintaining cardiac function.
KATP channels have been implicated as endogenous mechanisms of cardiac stress tolerance, harnessing the capacity to translate signals of cellular distress, through metabolic sensing capabilities, into cardioprotective stress adaptation (38
39
40)
. While the stress-responsive requirement of KATP channels has been suggested for tissues with Kir6.2-containing channels such as the myocardium (13
, 41
42
43)
, the present findings implicate a comparable cardioprotective role for Kir6.1-containing KATP channels in the coronary vasculature contributing to a cardiac reserve necessary to respond to the metabolic stress imposed by endotoxic shock. The predisposition to precipitous mortality in endotoxemia in the KCNJ8 knockout correlated with a decline in electrical and mechanical cardiac activity, and marked electrophysiologic and histopathologic evidence of myocardial necrosis not observed in the more tolerant WT. While multiple factors may influence the Kir6.1-KO myocardial response, a major mechanism contributing to myocardial dysfunction and cell death in the Kir6.1-KO was mapped to a breakdown in the coupling of metabolic demand and vasoreactivity. The importance of Kir6.1, required for KATP channel-mediated coronary dilatation (23)
, was underscored by the aberrant coronary response to the cytokine TNF or metabolic challenges of acidosis or adenosine in the absence of the channel protein. Restoration of adequate coronary perfusion through L-type calcium channel inhibition with improved survival in the Kir6.1-KO, and the benefits of potassium channel opener application in the septic WT further suggested a vital role for adequate Kir6.1-mediated KATP channel function in the cardiovascular response to endotoxic challenge.
The findings of hypothermia and acidosis, under endotoxic challenge, in the Kir6.1-KO appear linked to a progressive impairment in cardiac output, although direct effects of Kir6.1 knockout on centers of homeostatic integration, such as in the hypothalamus, cannot be excluded. In fact, distribution of the Kir6.1-containing KATP channels throughout tissue beds may implicate broader consequences contributing to the Kir6.1 knockout phenotype under LPS challenge. Indeed, the absence of systemic hypotension early after LPS administration, at a time of preserved cardiac output, indicated a lack in the Kir6.1-KO of the drop in systemic vascular resistance-pathognomonic of the distributive shock state. This finding parallels the vasoconstriction and restoration of blood pressure seen with the sulfonylurea glyburide in established endotoxic hypotension (9
, 44)
. While it is recognized that excessive systemic vasodilation late in the syndrome of severe sepsis is associated with poor outcome, it is increasingly being identified that early in the hyperdynamic phase of the syndrome, coronary vasodilation may be a required support of myocardial function (45
46
47
48)
. Further analysis would determine the generalizability of the role of Kir6.1-containing KATP channels as necessary homeostatic molecules in endotoxemia to the wider syndrome of sepsis and other states of shock.
Through genetic ablation of channel subunits, vascular KATP channels have recently been linked to the maintenance of arterial tone with knockout mice prone to vascular spasm and arrhythmic death (23
, 33)
. The importance of intact Kir6.1-containing vascular channels in securing optimal myocardial stress response thereby establishes a framework for diagnostic and/or therapeutic intervention in critical illness. In this regard, defects in KATP channel proteins and/or modulators of channel function (23
, 33
, 49
50
51
52
53)
warrant investigation as determinants of hemodynamics in disease.
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ACKNOWLEDGMENTS |
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Received for publication April 24, 2006. Accepted for publication June 16, 2006.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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