Mechanisms of intrinsic beating variability in cardiac cell cultures and model pacemaker networks

Heart rate variability (HRV) exhibits fluctuations characterized by a power law behavior of its power spectrum. The interpretation of this nonlinear HRV behavior, resulting from interactions between extracardiac regulatory mechanisms, could be clinically useful. However, the involvement of intrinsic variations of pacemaker rate in HRV has scarcely been investigated. We examined beating variability in spontaneously active incubating cultures of neonatal rat ventricular myocytes using microelectrode arrays. In networks of mathematical model pacemaker cells, we evaluated the variability induced by the stochastic gating of transmembrane currents and of calcium release channels and by the dynamic turnover of ion channels. In the cultures, spontaneous activity originated from a mobile focus. Both the beat-to-beat movement of the focus and beat rate variability exhibited a power law behavior. In the model networks, stochastic fluctuations in transmembrane currents and stochastic gating of calcium release channels did not reproduce the spatiotemporal patterns observed in vitro. In contrast, long-term correlations produced by the turnover of ion channels induced variability patterns with a power law behavior similar to those observed experimentally. Therefore, phenomena leading to long-term correlated variations in pacemaker cellular function may, in conjunction with extracardiac regulatory mechanisms, contribute to the nonlinear characteristics of HRV.

Dynamic changes of cardiac conduction during rapid pacing

Slow conduction and unidirectional conduction block (UCB) are key mechanisms of reentry. Following abrupt changes in heart rate, dynamic changes of conduction velocity (CV) and structurally determined UCB may critically influence arrhythmogenesis. Using patterned cultures of neonatal rat ventricular myocytes grown on microelectrode arrays, we investigated the dynamics of CV in linear strands and the behavior of UCB in tissue expansions following an abrupt decrease in pacing cycle length (CL). Ionic mechanisms underlying rate-dependent conduction changes were investigated using the Pandit-Clark-Giles-Demir model. In linear strands, CV gradually decreased upon a reduction of CL from 500 ms to 230-300 ms. In contrast, at very short CLs (110-220 ms), CV first decreased before increasing again. The simulations suggested that the initial conduction slowing resulted from gradually increasing action potential duration (APD), decreasing diastolic intervals, and increasing postrepolarization refractoriness, which impaired Na(+) current (I(Na)) recovery. Only at very short CLs did APD subsequently shorten again due to increasing Na(+)/K(+) pump current secondary to intracellular Na(+) accumulation, which caused recovery of CV. Across tissue expansions, the degree of UCB gradually increased at CLs of 250-390 ms, whereas at CLs of 180-240 ms, it first increased and subsequently decreased. In the simulations, reduction of inward currents caused by increasing intracellular Na(+) and Ca(2+) concentrations contributed to UCB progression, which was reversed by increasing Na(+)/K(+) pump activity. In conclusion, CV and UCB follow intricate dynamics upon an abrupt decrease in CL that are determined by the interplay among I(Na) recovery, postrepolarization refractoriness, APD changes, ion accumulation, and Na(+)/K(+) pump function.

Myofibroblasts induce ectopic activity in cardiac tissue

Focal ectopic activity in cardiac tissue is a key factor in the initiation and perpetuation of tachyarrhythmias. Because myofibroblasts as present in fibrotic remodeled myocardia and infarct scars depolarize cardiomyocytes by heterocellular electrotonic interactions via gap junctions in vitro, we investigated using strands of cultured ventricular cardiomyocytes coated with myofibroblasts, whether this interaction might give rise to depolarization-induced abnormal automaticity. Whereas uncoated cardiomyocyte strands were invariably quiescent, myofibroblasts induced synchronized spontaneous activity in a density dependent manner. Activations appeared at spatial myofibroblast densities >15.7% and involved more than 80% of the preparations at myofibroblast densities of 50%. Spontaneous activity was based on depolarization-induced automaticity as evidenced by: (1) suppression of activity by the sarcolemmal K(ATP) channel opener P-1075; (2) induction of activity in current-clamped single cardiomyocytes undergoing depolarization to potentials similar to those induced by myofibroblasts in cardiomyocyte strands; and (3) induction of spontaneous activity in cardiomyocyte strands coated with connexin 43 transfected Hela cells but not with communication deficient HeLa wild-type cells. Apart from unveiling the mechanism underlying the hallmark of monolayer cultures of cardiomyocytes, ie, spontaneous electromechanical activity, these findings open the perspective that myofibroblasts present in structurally remodeled myocardia following pressure overload and infarction might contribute to arrhythmogenesis by induction of ectopic activity.

Gap junction channels and cardiac impulse propagation

The role of gap junction channels on cardiac impulse propagation is complex. This review focuses on the differential expression of connexins in the heart and the biophysical properties of gap junction channels under normal and disease conditions. Structural determinants of impulse propagation have been gained from biochemical and immunocytochemical studies performed on tissue extracts and intact cardiac tissue. These have defined the distinctive connexin coexpression patterns and relative levels in different cardiac tissues. Functional determinants of impulse propagation have emerged from electrophysiological experiments carried out on cell pairs. The static properties (channel number and conductance) limit the current flow between adjacent cardiomyocytes and thus set the basic conduction velocity. The dynamic properties (voltage-sensitive gating and kinetics of channels) are responsible for a modulation of the conduction velocity during propagated action potentials. The effect is moderate and depends on the type of Cx and channel. For homomeric-homotypic channels, the influence is small to medium; for homomeric-heterotypic channels, it is medium to strong. Since no data are currently available on heteromeric channels, their influence on impulse propagation is speculative. The modulation by gap junction channels is most prominent in tissues at the boundaries between cardiac tissues such as sinoatrial node-atrial muscle, atrioventricular node-His bundle, His bundle-bundle branch and Purkinje fibers-ventricular muscle. The data predict facilitation of orthodromic propagation.

Heart failure in two West Highland white terriers caused by congenital angiomatous cardiac anomaly

The paper describes the clinical and pathological characteristics of an unusual cystic congenital cardiac anomaly that caused clinical signs of congestive heart failure, respiratory distress and cardiac arrhythmias in two West Highland white terrier puppies. In both dogs a definitive diagnosis was made postmortem.

Cardiac image fusion from stand-alone SPECT and CT: clinical experience

Myocardial perfusion imaging with SPECT (SPECT-MPI) and 64-slice CT angiography (CTA) are both established techniques for the noninvasive evaluation of coronary artery disease (CAD). Three-dimensional (3D) SPECT/CT image fusion may offer an incremental diagnostic value by integrating both sets of information. We report our first clinical experiences with fused 3D SPECT/CT in CAD patients. METHODS: Thirty-eight consecutive patients with at least 1 perfusion defect on SPECT-MPI (1-d adenosine stress/rest SPECT with (99m)Tc-tetrofosmin) and 64-slice CTA were included. 3D volume-rendered fused SPECT/CT images were generated and compared with the findings from the side-by-side analysis with regard to coronary lesion interpretation by assigning the perfusion defects to their corresponding coronary lesion. RESULTS: The fused SPECT/CT images added information on pathophysiologic lesion severity in 27 coronary stenoses (22%) of 12 patients (29%) (P<0.001). Among 40 equivocal lesions on side-by-side analysis, the fused interpretation confirmed hemodynamic significance in 14 lesions and excluded functional relevance in 10 lesions. In 3 lesions, assignment of perfusion defect and coronary lesion appeared to be reliable on side-by-side analysis but proved to be inaccurate on fused interpretation. Added diagnostic information by SPECT/CT was more commonly found in patients with stenoses of small vessels (P=0.004) and involvement of diagonal branches (P=0.01). CONCLUSION: In addition to being intuitively convincing, 3D SPECT/CT fusion images in CAD may provide added diagnostic information on the functional relevance of coronary artery lesions.

Benefits of cardiac surgery in octogenarians--a postoperative quality of life assessment

OBJECTIVE: Assessment of postoperative quality of life in patients over 80 years after cardiac surgery including coronary artery bypass grafting (CABG), aortic valve replacement (AVR) and combined procedures. METHODS: Quality of life of n=136 patients over 80 years at operation (82.3+/-2.1 years), undergoing isolated CABG in 61 patients (45%), isolated AVR in 34 patients (25%) and a combination of CABG and AVR in 41 patients (30%) between January 1999 and December 2003 was reviewed. Preoperatively 66.2% presented in NYHA-class III/IV or CCS-class III/IV. Mean ejection fraction (EF) was 59.5%+/-14.0 (range 25-90%). Quality of life assessment was performed via a Seattle Angina Questionnaire. Follow-up was 100% complete for a total of 890 days (69-1853 days). RESULTS: Five-year survival was 70% for the CABG group, 75% for the AVR group and 65% for the CABG/AVR group. Quality of life was remarkable in all of the three groups after surgery. Overall 97 patients (81%) were not or little disabled in their daily activity. One hundred and twelve patients (93%) were free or considerably less symptomatic. Seventy-eight patients or 65% reported to be very satisfied with their current quality of life and 112 patients (93%) felt very reassured to have continuous full access to medical treatment despite of their advanced age. CONCLUSIONS: A remarkable quality of life and important improvement in the functional status after cardiac surgery in patients over 80 paired with a satisfactory medium-term survival justify early intervention for heart disease in this age group. Therefore, referral practice for patients over 80 years for heart surgery should be handled liberally.

ECG-triggered muscular counterpulsation for treatment of low cardiac output

BACKGROUND: Skeletal muscular counterpulsation (MCP) has been used as a new noninvasive technique for treatment of low cardiac output. The MCP method is based on ECG-triggered skeletal muscle stimulation. The purpose of the present study was to evaluate acute hemodynamic changes induced by MCP in the experimental animal. METHODS: Eight anaesthetized pigs (43+/-4 kg) were studied at rest and after IV â-blockade (10 mg propranolol) before and after MCP. Muscular counterpulsation was performed on both thighs using trains (75 ms duration) of multiple biphasic electrical impulses with a width of 1 ms and a frequency of 200 Hz at low (10 V) and high (30 V) amplitude. ECG-triggering was used to synchronize stimulation to a given time point. LV pressure-volume relations were determined using the conductance catheter. After baseline measurements, MCP was carried out for 10 minutes at low and high stimulation amplitude. The optimal time point for MCP was determined from LV pressure-volume loops using different stimulation time points during systole and diastole. Best results were observed during end-systole and, therefore, this time point was used for stimulation. RESULTS: Under control conditions, MCP was associated with a significant decrease in pulmonary vascular resistance (-18%), a decrease in systemic vascular resistance (-11%) and stroke work index (-4%), whereas cardiac index (+2%) and ejection fraction (+6%) increased slightly. Pressure-volume loops showed a leftward shift with a decrease in end-systolic volume. After â-blockade, cardiac function decreased (HR, MAP, EF, dP/dt max), but it improved with skeletal muscle stimulation (HR +10% and CI +17%, EF +5%). There was a significant decrease in pulmonary (-19%) and systemic vascular resistance (-29%). CONCLUSIONS: In the animal model, ECG-triggered skeletal muscular counterpulsation is associated with a significant improvement in cardiac function at baseline and after IV â-blockade. Thus, MCP represents a new, non-invasive technique which improves cardiac function by diastolic compression of the peripheral arteries and veins, with a decrease in systemic vascular resistance and increase in cardiac output.

Mechanism of Ca(v)1.2 channel modulation by the amino terminus of cardiac beta2-subunits

L-type calcium channels are composed of a pore, alpha1c (Ca(V)1.2), and accessory beta- and alpha2delta-subunits. The beta-subunit core structure was recently resolved at high resolution, providing important information on many functional aspects of channel modulation. In this study we reveal differential novel effects of five beta2-subunits isoforms expressed in human heart (beta(2a-e)) on the single L-type calcium channel current. These splice variants differ only by amino-terminal length and amino acid composition. Single-channel modulation by beta2-subunit isoforms was investigated in HEK293 cells expressing the recombinant L-type ion conducting pore. All beta2-subunits increased open probability, availability, and peak current with a highly consistent rank order (beta2a approximately = beta2b > beta2e approximately = beta2c > beta2d). We show graded modulation of some transition rates within and between deep-closed and inactivated states. The extent of modulation correlates strongly with the length of amino-terminal domains. Two mutant beta2-subunits that imitate the natural span related to length confirm this conclusion. The data show that the length of amino termini is a relevant physiological mechanism for channel closure and inactivation, and that natural alternative splicing exploits this principle for modulation of the gating properties of calcium channels.

Effects of non-ionic iodinated contrast media on patient heart rate and pressures during intra-cardiac or intra-arterial injection

PURPOSE: To compare the effects on heart rate (HR), on left ventricular (LV) or arterial pressures, and the general safety of a non-ionic low-osmolar contrast medium (CM) and a non-ionic iso-osmolar CM in patients undergoing cardiac angiography (CA) or peripheral intra-arterial digital subtraction angiography (IA-DSA). MATERIALS AND METHODS: Two double-blind, randomized studies were conducted in 216 patients who underwent CA (n=120) or peripheral IA-DSA (n=96). Patients referred for CA received a low-osmolar monomeric CM (iomeprol-350, n=60) or an iso-osmolar dimeric CM (iodixanol-320; n=60). HR and LV peak systolic and end-diastolic pressures were determined before and after the first injection during left and right coronary arteriography and left ventriculography. Monitoring for all types of adverse event (AE) was performed for 24 h following the procedure. t-tests were performed to compare CM for effects on HR. Patients referred for IA-DSA received iomeprol-300 (n=49) or iodixanol-320 (n=47). HR and arterial blood pressure (BP) were evaluated before and after the first 4 injections. Monitoring for AE was performed for 4 h following the procedure. Repeated-measures ANOVA was used to compare mean HR changes across the first 4 injections, whereas changes after the first injection were compared using t-tests. RESULTS: No significant differences were noted between iomeprol and iodixanol in terms of mean changes in HR during left coronary arteriography (p=0.8), right coronary arteriography (p=0.9), and left ventriculography (p=0.8). In patients undergoing IA-DSA, no differences between CM were noted for effects on mean HR after the first injection (p=0.6) or across the first 4 injections (p=0.2). No significant differences (p>0.05) were noted in terms of effects on arterial BP in either study or on LV pressures in patients undergoing CA. Non-serious AE considered possibly CM-related (primarily headache and events affecting the cardiovascular and digestive systems) were reported more frequently by patients undergoing CA and more frequently after iodixanol (14/60 [23.3%] and 2/47 [4.3%]; CA and IA-DSA, respectively) than iomeprol (10/60 [16.7%] and 1/49 [2%], respectively). CONCLUSIONS: Iomeprol and iodixanol are safe and have equally negligible effects on HR and LV pressures or arterial BP during and after selective intra-cardiac injection and peripheral IA-DSA. CLINICAL APPLICATION: Iomeprol and iodixanol are safe and equally well tolerated with regard to cardiac rhythm and clinical preference should be based on diagnostic image quality alone.

Arginine vasopressin in advanced cardiovascular failure during the post-resuscitation phase after cardiac arrest

Arginine vasopressin (AVP) has been employed successfully during cardiopulmonary resuscitation, but there exist only few data about the effects of AVP infusion for cardiovascular failure during the post-cardiac arrest period. Cardiovascular failure is one of the main causes of death after successful resuscitation from cardiac arrest. Although the "post-resuscitation syndrome" has been described as a "sepsis-like" syndrome, there is little information about the haemodynamic response to AVP in advanced cardiovascular failure after cardiac arrest. In this retrospective study, haemodynamic and laboratory variables in 23 patients with cardiovascular failure unresponsive to standard haemodynamic therapy during the post-cardiac arrest period were obtained before, and 30 min, 1, 4, 12, 24, 48, and 72 h after initiation of a supplementary AVP infusion (4 IU/h). During the observation period, AVP significantly increased mean arterial blood pressure (58+/-14 to 75+/-19 mmHg, p < 0.001), and decreased noradrenaline (norepinephrine) (1.31+/-2.14 to 0.23+/-0.3 microg/kg/min, p = 0.03), adrenaline (epinephrine) (0.58+/-0.23 to 0.04+/-0.03 microg/kg/min, p = 0.001), and milrinone requirements (0.46+/-0.15 to 0.33+/-0.22 microg/kg/min, p < 0.001). Pulmonary capillary wedge pressure changed significantly (p < 0.001); an initial increase being followed by a decrease below baseline values. While arterial lactate concentrations (95+/-64 to 21+/-18 mg/dL, p < 0.001) and pH (7.27+/-0.14 to 7.4+/-0.14, p < 0.001) improved significantly, total bilirubin concentrations (1.12+/-0.95 to 3.04+/-3.79 mg/dL, p = 0.001) increased after AVP. There were no differences in the haemodynamic or laboratory response to AVP between survivors and non-survivors. In this study, advanced cardiovascular failure that was unresponsive to standard therapy could be reversed successfully with supplementary AVP infusion in >90% of patients surviving cardiac arrest.

Electroencephalographic changes after pediatric cardiac surgery with cardiopulmonary bypass: is slow wave activity unfavorable?

Pediatric cardiac surgery with cardiopulmonary bypass (CPB) is frequently associated with neurologic deficits. We describe the postoperative EEG changes, assess their possible causes, and evaluate their relevance to neurologic outcome. Thirty-one children and five neonates with congenital heart disease were included. EEG recording started after intubation and continued until 22-96 h after CPB. In addition to conventional analysis, spectral analysis was performed for occipital and frontal electrodes, and differences between pre- and postoperative delta power (delta-deltaP) were calculated. Maximum values of occipital delta-deltaP that occurred within 48 h after CPB were correlated with clinical variables and with perioperative markers of oxidative stress and inflammation. Occipital delta-deltaP correlated with frontal delta-deltaP, and maximum delta-deltaP correlated with conventional rating. Distinct rise of deltaP was detected in 18 of 21 children without any acute or long-term neurologic deficits but only in five of 10 children with temporary or permanent neurologic deficits. Furthermore, maximally registered delta-deltaP was inversely associated with duration of CPB and postoperative ventilation. Maximal delta-deltaP was also inversely associated with the loss of plasma ascorbate (as an index of oxidative stress) and plasma levels of IL-6 and IL-8. Slow wave activity frequently occurs within 48 h after CPB. However, our data do not support the notion that EEG slowing is associated with adverse neurologic outcome. This is supported by the fact that EEG slowing was associated with less oxido-inflammatory stress.