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Biomedical subjects

Mark E Anderson

Publications and source records attributed to Mark E Anderson.

At least 37 records · Page 2Linked to original sources
PubMed2005

Sudden Infant Death Syndrome and prenatal maternal smoking: rising attributed risk in the Back to Sleep era.

BACKGROUND: Parental smoking and prone sleep positioning are recognized causal features of Sudden Infant Death. This study quantifies the relationship between prenatal smoking and infant death over the time period of the Back to Sleep campaign in the United States, which encouraged parents to use a supine sleeping position for infants. METHODS: This retrospective cohort study utilized the Colorado Birth Registry. All singleton, normal birth weight infants born from 1989 to 1998 were identified and linked to the Colorado Infant Death registry. Multivariable logistic regression was used to analyze the relationship between outcomes of interest and prenatal maternal cigarette use. Potential confounders analyzed included infant gender, gestational age, and birth year as well as maternal marital status, ethnicity, pregnancy interval, age, education, and alcohol use. RESULTS: We analyzed 488,918 birth records after excluding 5835 records with missing smoking status. Smokers were more likely to be single, non-Hispanic, less educated, and to report alcohol use while pregnant (p < 0.001). The study included 598 SIDS cases of which 172 occurred in smoke-exposed infants. Smoke exposed infants were 1.9 times (95% CI 1.6 to 2.3) more likely to die of SIDS. The attributed risk associating smoking and SIDS increased during the study period from approximately 50% to 80%. During the entire study period 59% (101/172) of SIDS deaths in smoke-exposed infants were attributed to maternal smoking. CONCLUSIONS: Due to a decreased overall rate of SIDS likely due to changing infant sleep position, the attributed risk associating maternal smoking and SIDS has increased following the Back to Sleep campaign. Mothers should be informed of the 2-fold increased rate of SIDS associated with maternal cigarette consumption.

Cohort Studies↗
PubMed2005

Calmodulin kinase II activity is required for normal atrioventricular nodal conduction.

BACKGROUND: Multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is abundant in myocardium. CaMKII activity is augmented by catecholamine stimulation, which enhances AV nodal conduction, suggesting the hypothesis that CaMKII also contributes to AV nodal conduction properties. OBJECTIVES: The purpose of this study was to test the potential role of CaMKII in regulating AV nodal conduction in heart. METHODS: We developed a novel mouse with genetic CaMKII inhibition by cardiac-specific expression of autocamtide 3 inhibitory peptide (AC3-I) mimicking a conserved sequence of the CaMKII regulatory domain. We also engineered a control transgenic mouse with cardiac expression of an inactive, scrambled version of AC3-I (autocamtide 3 control peptide [AC3-C]) and performed electrophysiologic measurements in vivo and in Langendorff-perfused isolated hearts. RESULTS: AC3-I and AC3-C were abundantly expressed in AV nodal cells. AC3-I mice with implanted ECG telemeters showed enhanced Wenckebach-type AV conduction block after isoproterenol (present in 9/9 mice) compared with AC3-C mice (present in 1/5 mice, P = .005). Intracardiac recordings showed significant PR and AH interval prolongation in AC3-I mice at baseline and after isoproterenol compared with AC3-C mice. HV durations were not different. Langendorff-perfused AC3-I hearts had significantly prolonged Wenckebach cycle lengths and AV nodal effective refractory periods compared with AC3-C hearts, whereas sinus node recovery time and left ventricular effective refractory times were similar between these genotypes. CONCLUSIONS: These studies define CaMKII as a critical determinant of normal and catecholamine-stimulated AV nodal conduction responses.

Analysis of Variance↗
PubMed2004

A microfluidic device to confine a single cardiac myocyte in a sub-nanoliter volume on planar microelectrodes for extracellular potential recordings.

A hybrid chip is described which combines a microfluidic network fabricated in a silicone elastomer (PDMS) with planar microelectrodes. It was used to measure extracellular potentials from single adult murine cardiac myocytes in a restricted extracellular space. The recorded variations in the extracellular potentials were caused by transmembrane currents associated with spontaneously initiated intracellular calcium waves. Single cells were trapped inside the 100 pl microchamber by pressure gradients and maintained for several hours by continuous perfusion. In addition, the localized delivery of drugs to a portion of the cell was demonstrated. The impedance of the electrodes was reduced by a factor of 10 to 20 after the electrodeposition of platinum black. Biopotentials recorded from single cells with platinum black electrodes showed a three-fold decrease in the noise, resulting in a maximum signal-to-noise ratio of 15:1. Characteristic variations in the frequency and shape of the extracellular potentials were observed among different cells which are most likely due to differences in the sarcoplasmic reticulum Ca(2+) load. Our device architecture permits the integration of electrochemical and optical sensors for multiparameter recordings.

Animals↗
PubMed2004

An EF-hand in the sodium channel couples intracellular calcium to cardiac excitability.

Sodium channels initiate the electrical cascade responsible for cardiac rhythm, and certain life-threatening arrhythmias arise from Na(+) channel dysfunction. We propose a novel mechanism for modulation of Na(+) channel function whereby calcium ions bind directly to the human cardiac Na(+) channel (hH1) via an EF-hand motif in the C-terminal domain. A functional role for Ca(2+) binding was identified electrophysiologically, by measuring Ca(2+)-induced modulation of hH1. A small hH1 fragment containing the EF-hand motif was shown to form a structured domain and to bind Ca(2+) with affinity characteristic of calcium sensor proteins. Mutations in this domain reduce Ca(2+) affinity in vitro and the inactivation gating effects of Ca(2+) in electrophysiology experiments. These studies reveal the molecular basis for certain forms of long QT syndrome and other arrhythmia-producing syndromes, and suggest a potential pharmacological target for antiarrhythmic drug design.

Amino Acid Sequence↗
PubMed2004

Calmodulin kinase is functionally targeted to the action potential plateau for regulation of L-type Ca2+ current in rabbit cardiomyocytes.

L-type Ca2+ current (ICa-L) triggers Ca2+ release from the sarcoplasmic reticulum (SR) and both SR and ICa-L are potential sources of intracellular Ca2+ (Ca2+i) for feedback regulation of ICa-L. Ca2+i bound to calmodulin (Ca2+-CaM) can inhibit ICa-L, while Ca2+-CaM can also activate Ca2+-CaM-dependent protein kinase II (CaMK) to increase ICa. However, it is not known whether ICa-L or the SR is the primary source of Ca2+ for ICa-L regulation. The L-type Ca2+ channel C terminus is implicated as a critical transduction element for ICa-L responses to Ca2+-CaM and CaMK, and the C terminus undergoes voltage-dependent steric changes, suggesting that Ca2+i control of ICa-L may also be regulated by cell membrane potential. We developed conditions to separately test the relationship of Ca2+-CaM and CaMK to ICa-L and SR Ca2+i release during voltage clamp conditions modelled upon time and voltage domains relevant to the cardiac action potential. Here we show that CaMK increases ICa-L after brief positive conditioning pulses, whereas Ca2+-CaM reduces ICa-L over a broad range of positive and negative conditioning potentials. SR Ca2+ release was required for both Ca2+-CaM and CaMK ICa-L responses after strongly positive conditioning pulses (+10 and +40 mV), while Ca2+i from ICa-L was sufficient for Ca2+-CaM during weaker depolarizations. These findings show that ICa-L responses to CaMK are voltage dependent and suggest a new model of L-type Ca2+ channel regulation where voltage-dependent changes control ICa-L responses to Ca2+-CaM and CaMK signalling.

Action Potentials↗
PubMed2004

Calmodulin kinase and L-type calcium channels; a recipe for arrhythmias?

L-type Ca2+ channels (LTCCs) are the main portal for Ca2+ entry into cardiac myocytes. These ion channel proteins open in response to cell membrane depolarizations elicited by action potentials, and LTCC current (I(Ca)) flows during the action potential plateau, to increase cellular Ca2+ (Ca2+(i)) and trigger myocardial contraction. I(Ca) is also implicated in the genesis of cardiac arrhythmias under conditions such as heart failure and cardiac hypertrophy, in which the action potential plateau and QT interval are prolonged. This article reviews recent findings about the molecular regulation of LTCCs by the Ca2+-dependent signaling molecule, calmodulin kinase II (CaMKII), and compares this form of regulation with regulation by calmodulin-binding domains and beta-adrenergic receptor agonists. LTCC dysregulation is discussed in the context of new results showing that CaMKII can be a proarrhythmic signal in disease conditions in which Ca2+(i) is disordered and cardiac repolarization is excessively prolonged.

Arrhythmias, Cardiac↗
PubMed2004

Successful school-based intervention for inner-city children with persistent asthma.

OBJECTIVE: Because children attend school daily, school-based interventions for children with persistent asthma could provide effective disease management for inner-city asthmatic children. The Kunsberg School in Denver, Colorado, enrolls children with chronic diseases, including asthma, into a daily program of school-based disease management. This study sought to determine the impact of the Kunsberg program on asthma utilization. METHODS: Children attending Kunsberg (n=18) who received primary care at Denver Health were compared with a group of matched control children who also received primary care at Denver Health, but did not attend Kunsberg (n=36). Asthma-related utilization for an average of 2.9 years before and after Kunsberg enrollment was assessed. RESULTS: The 18 Kunsberg and 36 control subjects were mostly minority children in low-income families, without significant demographic differences between groups. Compared with controls, the Kunsberg cohort experienced fewer hospitalizations (0.5 vs. 0.9 hospitalizations/subject/ year, p=0.05), fewer emergency department (ED) visits (1.4 vs. 2.8 ED visits/ subject/year, p=0.04), and fewer follow-up visits for asthma (3.7 vs. 5.0 visits/subject/ year, p=0.01) in the time period (mean 2.9 years; range 1-6 years) following the intervention. Hospital- and clinic-based asthma utilization costs decreased 80% following enrollment in the school (8122 dollars/year to 1588 dollars/year per child), compared to a 19% decrease in the control group. Among the Kunsberg children with hospitalizations prior to school enrollment (n=8), hospital days decreased from 3.5 days to 0.1 days annually (p<0.01), ED visits decreased from 2.1 to 0.6 visits annually (p=0.02), and follow-up visits decreased from 6.8 to 2.1 visits annually (p=0.02). As part of their school program, 89% of Kunsberg enrollees received inhaled corticosteroids daily on a monitored basis while at school. CONCLUSIONS: The Kunsberg school program improved asthma control and reduced disease severity for at-risk inner-city asthmatic children, leading to cost reduction for asthma management. Directly observed controller therapy at school can be an important component of a school-based program for children with chronic conditions.

Adolescent↗
PubMed2003

Frequency of late recurrence of intra-atrial reentry tachycardia after radiofrequency catheter ablation in patients with congenital heart disease.

Forty-seven catheter ablation procedures for intra-atrial reentry tachycardia were performed in 40 patients with palliated congenital heart disease. The acute success rate was 87% and the recurrence rate was 34% during an average follow-up of 36 months. Of those patients who had recurrence, 88% did so within 1 year of ablation. Of the 23 patients who were free of recurrence 1 year after ablation, 21 (91%) remain free from recurrence at an average of 45 months (median 39; range 15 to 88) after ablation.

Adolescent↗
PubMed2003

C terminus L-type Ca2+ channel calmodulin-binding domains are 'auto-agonist' ligands in rabbit ventricular myocytes.

L-type Ca2+ channel C terminus calmodulin (CaM)-binding domains are molecular determinants for Ca(2+)-CaM-dependent increases in L-type Ca2+ current (ICa), and a CaM-binding IQ domain mimetic peptide (IQmp) increases L-type Ca2+ channel current by promoting a gating mode with prolonged openings (mode 2), suggesting the intriguing possibility that CaM-binding domains are 'auto-agonist' signalling molecules. In order to test the breadth of this concept, we studied the effect of a second C terminus CaM-binding domain (CB) mp (CBmp), in conjunction with IQmp, on single L-type Ca2+ channel currents in excised cell membrane patches from rabbit ventricular myocytes. Here we show that both CBmp and IQmp are agonist ligands that non-additively increase L-type Ca2+ channel opening probability (Po) by inducing mode 2 gating. CBmp and IQmp agonist effects were lost under conditions favouring calcification of CaM (Ca(2+)-CaM, 150 nM free Ca2+ and 10-20 microM CaM), but persisted in the presence of CaM (0-20 microM) under conditions adverse to Ca(2+)-CaM (20 mM BAPTA), indicating that CaM-binding domains increase L-type Ca2+ channel Po by a low Ca(2+)-CaM activity mechanism. Increasing Ca(2+)-CaM in the bath (cytosol) reduced the efficacy of CBmp and IQmp signals with Ba2+ as charge carrier, suggesting that CaM binding motifs target a site outside of the pore region. We measured the combined effects of CBmp and Ca(2+)-CaM-dependent protein kinase II (CaMKII) on L-type Ca2+ channels by using an engineered Ca(2+)-CaM-independent form of CaMKII that remains active under low Ca(2+)-CaM conditions, permissive for CBmp signalling. CBmp and CaMKII increased L-type Ca2+ channel Po in a non-additive manner, suggesting that low and high Ca(2+)-CaM-dependent L-type Ca2+ channel facilitation pathways converge upon a common signalling mechanism.

Amino Acid Sequence↗
PubMed2003

Temporal changes in ventricular function assessed echocardiographically in conscious and anesthetized mice.

The mouse is an important model system for cardiovascular biology, with echocardiography a critical tool for noninvasive measurement of cardiac morphology and function. The feasibility and short-term temporal consistency of repeated echocardiographic measurements in conscious mice has not been previously evaluated. We performed serial 2-dimensional guided M-mode transthoracic echocardiographic measurements at 5- to 10-minute intervals over 60 minutes in conscious mice and in mice treated with 1 of 3 anesthetic regimens: ketamine and acepromazine (n = 14); pentobarbital (n = 14); and ketamine and xylazine (n = 13). Unanesthetized mice received intraperitoneal saline (n = 6) or no injection (n = 7). In sequentially repeated measurements over 1 hour in conscious mice, none of the measured or derived echocardiographic parameters differed from baseline, whereas all 3 anesthetic regimens produced significant, prolonged, and temporally variable decreases in heart rate and fractional shortening. The relationship between heart rate and fractional shortening was not altered by anesthetic choice. Serial echocardiographic assessments of cardiac function, dimension, and mass can be performed with high reproducibility in conscious mice.

Acepromazine↗
PubMed2002

Cytoskeletal disrupting agents prevent calmodulin kinase, IQ domain and voltage-dependent facilitation of L-type Ca2+ channels.

A calmodulin (CaM) binding 'IQ' domain on the L-type Ca(2+) channel (LTCC) C terminus and calmodulin kinase II (CaMK) both signal increases in LTCC opening probability (P(o)) by shifting LTCCs into a gating mode (mode 2) with long openings through a process called facilitation. However, the mechanism whereby CaMK and the IQ domain are targeted to LTCCs is unknown. Endogenous CaMK is targeted to LTCCs in excised cell membrane patches because LTCC P(o) increased significantly in CaM-enriched (20 microM) bath solution and this effect was prevented by a specific CaMK inhibitory peptide, but not by an inactive control peptide. Pre-exposure of myocytes to the cytoskeletal disrupting agents nocodazole (microtubule specific) or cytochalasin D (microfilament specific) prevented the effects of CaM-dependent increases in P(o) of LTCCs in excised membrane patches. Neither cytochalasin D nor nocodazole altered the distribution of LTCC gating modes under basal conditions in on-cell mode or excised cell membrane patches, but each of these agents occluded the response of LTCCs to exogenous, constitutively active CaMK and to an IQ-mimetic peptide (IQmp). Cytochalasin D and nocodazole pretreatment also prevented LTCC facilitation that followed a cell membrane depolarizing prepulse. In contrast, cytochalasin D and nocodazole did not affect the increase in LTCC P(o) or prevent the shift to mode 2 gating in response to protein kinase A, indicating that cytoskeletal disruption specifically prevents prepulse, CaMK and IQ-dependent LTCC facilitation.

Animals↗
PubMed2002

Calmodulin kinase II and arrhythmias in a mouse model of cardiac hypertrophy.

BACKGROUND: Calmodulin kinase (CaMK) II is linked to arrhythmia mechanisms in cellular models where repolarization is prolonged. CaMKII upregulation and prolonged repolarization are general features of cardiomyopathy, but the role of CaMKII in arrhythmias in cardiomyopathy is unknown. METHODS AND RESULTS: We studied a mouse model of cardiac hypertrophy attributable to transgenic (TG) overexpression of a constitutively active form of CaMKIV that also has increased endogenous CaMKII activity. ECG-telemetered TG mice had significantly more arrhythmias than wild-type (WT) littermate controls at baseline, and arrhythmias were additionally increased by isoproterenol. Arrhythmias were significantly suppressed by an inhibitory agent targeting endogenous CaMKII. TG mice had longer QT intervals and action potential durations than WT mice, and TG cardiomyocytes had frequent early afterdepolarizations (EADs), a hypothesized mechanism for triggering arrhythmias. EADs were absent in WT cells before and after isoproterenol, whereas EAD frequency was unaffected by isoproterenol in TG mice. L-type Ca2+ channels (LTTCs) can activate EADs, and LTCC opening probability (Po) was significantly higher in TG than WT cardiomyocytes before and after isoproterenol. A CaMKII inhibitory peptide equalized TG and WT LTCC Po and eliminated EADs, whereas a peptide antagonist of the Na+/Ca2+ exchanger current, also hypothesized to support EADs, was ineffective. CONCLUSIONS: These findings support the hypothesis that CaMKII is a proarrhythmic signaling molecule in cardiac hypertrophy in vivo. Cellular studies point to EADs as a triggering mechanism for arrhythmias but suggest that the increase in arrhythmias after beta-adrenergic stimulation is independent of enhanced EAD frequency.

Action Potentials↗
PubMed2002

Reduced repolarization reserve in ventricular myocytes from female mice.

OBJECTIVE: Cardiac repolarization is prolonged and repolarization reserve (RR) is diminished in female rabbits and humans, compared to males. Reduced RR is evidenced by the relatively greater increase in ventricular action potential duration (APD) in myocytes from females in response to drugs that block repolarizing K(+) currents. Mice are an increasingly important experimental model animal for cardiovascular research, but gender-dependent differences have not been reported for repolarization in murine ventricular myocytes. METHODS: APD and repolarizing K(+) currents were measured in isolated ventricular myocytes from adult littermate male and female mice. Repolarizing K(+) currents were dissected into transient (I(to)) and sustained (I(sus)) components and the selective I(sus) antagonist FK506 was used to probe for differences in RR. RESULTS: Under control conditions APD at 50% (APD(50)) and at 90% (APD(90)) repolarization was significantly longer in females (APD(50)=15 +/- 3 ms, n=6 and APD(90)=63 +/- 6 ms, n=6) compared to males (APD(50)=8 +/- 2 ms, n=7 and APD(90)=42 +/- 9 ms, n=7) at 1.0 Hz. At 0.3 Hz stimulation frequency APD(90), but not APD(50), was significantly longer in females (APD(50)=12 +/- 2 ms and APD(90)=54 +/- 5 ms, n=10) compared to males (APD(50)=11 =/- 2 ms and APD(90)=47 +/- 7 ms, n=10). FK506 treatment (25 microM) selectively and equally inhibited I(sus) in all cells, and significantly increased APD(50) and APD(90) in males and females at 0.3 and 1.0 Hz. However, increases in APD(50) and APD(90) (0.3 and 1.0 Hz) in response to FK506 were significantly greater in myocytes from females compared to males. Voltage clamp measurement of I(to) and I(sus) revealed that males had a relatively more prominent I(to) while females exhibited a more prominent I(sus). CONCLUSIONS: Ventricular action potential repolarization is prolonged in myocytes from female compared to male mice. Female mice have reduced RR that is unmasked by FK506. These findings suggest that gender is an important variable for cardiovascular studies using mice.

Action Potentials↗
PubMed2002

Calmodulin inhibitor W-7 unmasks a novel electrocardiographic parameter that predicts initiation of torsade de pointes.

BACKGROUND: We have shown that the calmodulin inhibitor W-7 suppresses torsade de pointes (TdP) without shortening the QT interval, which is consistent with other findings that QT prolongation, per se, is insufficient to generate TdP. ECGs were analyzed from a well-characterized animal model of TdP to identify more reliable predictors of this life-threatening ventricular arrhythmia. METHODS AND RESULTS: TdP was induced using methoxamine and clofilium in 12 of 14 rabbits pretreated with vehicle control, whereas pretreatment with W-7 (50 micromol/kg), an inhibitor of the intracellular Ca2+-binding protein calmodulin, significantly suppressed TdP induction (1 of 11 rabbits with TdP, P<0.001). W-7 did not affect heart rate, increases in QT intervals, or dispersion compared with measurements in vehicle-treated control animals. However, a progressive and significant increase in the ratio of U-wave to T-wave amplitude (UTA) occurred before TdP onset in control animals, and this was prevented by W-7. CONCLUSIONS: Selective suppression of TdP inducibility by W-7, without shortening the duration of cardiac repolarization, allowed identification of the UTA ratio as a new electrocardiographic index for predicting TdP onset. These findings are consistent with the idea that prolonged repolarization is not the proximate cause of arrhythmia initiation, and they suggest that an increased UTA ratio reflects activation of intracellular Ca2+/calmodulin-dependent processes that are required for triggering TdP in this model.

Animals↗
PubMed2002

A calcium sensor in the sodium channel modulates cardiac excitability.

Sodium channels are principal molecular determinants responsible for myocardial conduction and maintenance of the cardiac rhythm. Calcium ions (Ca2+) have a fundamental role in the coupling of cardiac myocyte excitation and contraction, yet mechanisms whereby intracellular Ca2+ may directly modulate Na channel function have yet to be identified. Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted CaM binding and eliminated Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM were restored by intracellular application of a peptide modelled after the IQ domain. A naturally occurring mutation (A1924T) in the IQ domain altered hH1 function in a manner characteristic of the Brugada arrhythmia syndrome, but at the same time inhibited slow inactivation induced by Ca2+/CaM, yielding a clinically benign (arrhythmia free) phenotype.

Amino Acid Sequence↗
PubMed2002

Calmodulin and the philosopher's stone: Changing Ca2+ into arrhythmias.

Calmodulin and the Philosopher's Stone. It has been recognized for some time that intracellular Ca2+ ([Ca2+]i) can contribute to the genesis of cardiac arrhythmias, but understanding of the molecular signaling machinery that links disordered [Ca2+]i to arrhythmias has been lacking. Exciting recent work has focused on the ubiquitous intracellular Ca2+-binding protein calmodulin. Calmodulin is a molecular sensor that can translate increases in [Ca2+]i into modulatory signals for ion channels and activate other Ca2+-dependent signaling molecules. This article will examine the implications of these recent findings for arrhythmogenesis and the development of new antiarrhythmic therapies.

Arrhythmias, Cardiac↗