Mechanisms mediating muscle metaboreflex control of cardiac output during exercise: Impaired regulation in heart failure.

The ability to increase cardiac output during dynamic exercise is paramount for the ability to maintain workload performance. Reflex control of the cardiovascular system during exercise is complex and multifaceted involving multiple feedforward and feedback systems. One major reflex thought to mediate the autonomic adjustments to exercise is termed the muscle metaboreflex and is activated via afferent neurons within active skeletal muscle which respond to the accumulation of interstitial metabolites during exercise when blood flow and O2 delivery are insufficient to meet metabolic demands. This is one of the most powerful cardiovascular reflexes capable of eliciting profound increases in sympathetic nerve activity, arterial blood pressure, central blood volume mobilization, heart rate and cardiac output. This review summarizes the mechanisms meditating muscle metaboreflex-induced increases in cardiac output. Although much has been learned from studies using anaesthetized and/or decerebrate animals, we focus on studies in conscious animals and humans performing volitional exercise. We discuss the separate and interrelated roles of heart rate, ventricular contractility, ventricular preload and ventricular-vascular coupling as well as the interaction with other cardiovascular reflexes which modify muscle metaboreflex control of cardiac output. We discuss how these mechanisms may be altered in subjects with heart failure with reduced ejection fraction and offer suggestions for future studies.

Influence of heart rate on right ventricular function assessed by right heart catheterization and echocardiography in healthy anesthetized dogs.

BACKGROUND: Right ventricular (RV) functional assessment has received considerable attention in veterinary medicine since various diseases, such as cardiovascular, respiratory, endocrine, and neoplastic disease, may affect RV function. Heart rate (HR) is an important factor that can influence RV function through changes in loading condition and contractility. However, no study has yet evaluated the association between HR and RV function in the same individuals. This study aimed to evaluate the influence of elevated HR on RV function using right heart catheterization and echocardiography, and investigate the association between right heart catheterization and echocardiographic indices. RESULTS: Right atrial pacing was performed in eight dogs at 120, 140, 160, and 180 bpm. With an increase in HR, the RV systolic volume, RV diastolic volume, and stroke volume significantly decreased; however, the cardiac output, end-systolic elastance (Ees), and effective arterial elastance (Ea) significantly increased. Significant changes were not observed in RV pressure and Ees/Ea. The RV area normalized by body weight, RV fractional area change normalized by body weight (RV FACn), and tricuspid annular plane systolic excursion normalized by body weight (TAPSEn) significantly decreased with increased HR. Peak systolic myocardial velocity of the lateral tricuspid annulus (RV s'), RV strain, and RV strain rate of only the RV free wall analysis (RV-SrL3seg) showed no significant changes with the increase in HR; however, there was an increase in the RV strain rate of the RV global analysis (RV-SrL6seg). Multiple regression analysis revealed that HR, RV FACn, and RV- SrL6seg had significant associations with the Ees, and the TAPSEn and RV-SrL3seg with Ees/Ea. CONCLUSIONS: Decreased venous return and shortened relaxation time decreased the RV FAC, TAPSE, RV s', and RV strain, and might underestimate the RV function. Ees increased with the increase in HR, reflecting the myocardial force-frequency relation; as a result, RV-SrL6seg could be a useful tool for Ees estimation. Additionally, the RV-SrL3seg could detect RV performance, reflecting the balance between RV contractility and RV afterload.

Characteristics and physiological basis of falls in ventricular outputs after immediate cord clamping at delivery in preterm fetal lambs.

KEY POINTS: Controversy exists about the physiological mechanism(s) underlying decreases in cardiac output after immediate clamping of the umbilical cord at birth. To define these mechanisms, the four major determinants of ventricular output (afterload, preload, heart rate and contractility) were measured concurrently in fetal lambs at 15 s intervals over a 2 min period after cord clamping and before ventilation following delivery. After cord clamping, right (but not left) ventricular output fell by 20% in the initial 30 s, due to increased afterload associated with higher arterial blood pressures, but both outputs then halved over 45 s, due to a falling heart rate and deteriorating ventricular contractility accompanying rapid declines in arterial oxygenation to asphyxial levels. Ventricular outputs subsequently plateaued from 75 to 120 s, associated with rebound rises in ventricular contractility accompanying asphyxia-induced surges in circulating catecholamines. These findings provide a physiological basis for the clinical recommendation that effective ventilation should occur within 60 s after immediate cord clamping. ABSTRACT: Controversy exists about the physiological mechanism(s) underlying large decreases in cardiac output after immediate clamping of the umbilical cord at birth. To define these mechanisms, anaesthetized preterm fetal lambs (127(1)d, n = 12) were instrumented with flow probes and catheters in major central arteries, and a left ventricular (LV) micromanometer-conductance catheter. Following immediate cord clamping at delivery, haemodynamics, LV and right ventricular (RV) outputs, and LV contractility were measured at 15 s intervals during a 2 min non-ventilatory period, with aortic blood gases and circulating catecholamine (noradrenaline and adrenaline) concentrations measured at 30 s intervals. After cord clamping, (1) RV (but not LV) output fell by 20% in the initial 30 s, due to a reduced stroke volume associated with increased arterial blood pressures, (2) both outputs then halved over the next 45 s, associated with falls in heart rate, arterial blood pressures and ventricular contractility accompanying a rapid decline in arterial oxygenation to asphyxial levels, (3) reduced outputs subsequently plateaued from 75 to 120 s, associated with rebound rises in blood pressures and ventricular contractility accompanying exponential surges in circulating catecholamines. These findings are consistent with a time-dependent decline of ventricular outputs after immediate cord clamping, which comprised (1) an initial, minor fall in RV output related to altered loading conditions, (2) ensuing large decreases in both LV and RV outputs related to the combination of bradycardia and ventricular dysfunction during emergence of an asphyxial state, and (3) subsequent stabilization of reduced LV and RV outputs during ongoing asphyxia, supported by cardiovascular stimulatory effects of marked sympathoadrenal activation.

Relationship between fiducial points on the peripheral and central blood pressure waveforms: rate of rise of the central waveform is a determinant of peripheral systolic blood pressure.

Central systolic blood pressure (cSBP, the peak of the central waveform) is usually regarded as the determinant of peripheral systolic blood pressure with amplification of peripheral systolic blood pressure (pSBP) measured with reference to cSBP. However, the earlier portion of the central waveform up to the first systolic shoulder (P1) may be the major determinant of pSBP. We performed in silico simulation studies and examined previously acquired experimental data (n = 131) in which peripheral and central blood pressure waveforms had been acquired both invasively and noninvasively to examine the determinants of pSBP. Measurements were made at baseline and during perturbation of hemodynamics by inotropic and vasoactive drugs. In silico simulations using a central-to-peripheral transfer function demonstrated that pSBP is dependent on P1 and the rate of change (dP/dt) of central pressure up to the time of P1 but not cSBP. In computational simulations, peripheral reflection in the radial artery was closely related to dP/dt, and 97% of the variability in amplification as measured with reference to P1 was explained by dP/dt. In vivo, amplification of pSBP over P1 was correlated with dP/dt (R > 0.75, P < 0.0001 for all data sets), and P1 and dP/dt were independently correlated with pSBP, explaining 90% of the variability in pSBP. We conclude that P1 and dP/dt are major determinants of pSBP and that pSBP and cSBP are, in part, determined by different cardiac, central, and peripheral vascular properties.NEW & NOTEWORTHY Peripheral systolic BP is determined mainly by the first shoulder and the rate of rise of the central systolic blood pressure waveform rather than the peak of this waveform (central systolic BP). Peripheral and central systolic blood pressure are determined by different cardiac and vascular properties.

In vivo application and validation of a novel noninvasive method to estimate the end-systolic elastance.

Accurate assessment of the left ventricular (LV) systolic function is indispensable in the clinic. However, estimation of a precise index of cardiac contractility, i.e., the end-systolic elastance (Ees), is invasive and cannot be established as clinical routine. The aim of this work was to present and validate a methodology that allows for the estimation of Ees from simple and readily available noninvasive measurements. The method is based on a validated model of the cardiovascular system and noninvasive data from arm-cuff pressure and routine echocardiography to render the model patient-specific. Briefly, the algorithm first uses the measured aortic flow as model input and optimizes the properties of the arterial system model to achieve correct prediction of the patient's peripheral pressure. In a second step, the personalized arterial system is coupled with the cardiac model (time-varying elastance model) and the LV systolic properties, including Ees, are tuned to predict accurately the aortic flow waveform. The algorithm was validated against invasive measurements of Ees (multiple pressure-volume loop analysis) taken from n = 10 patients with heart failure with preserved ejection fraction and n = 9 patients without heart failure. Invasive measurements of Ees (median = 2.4 mmHg/mL, range = [1.0, 5.0] mmHg/mL) agreed well with method predictions (normalized root mean square error = 9%, ρ = 0.89, bias = -0.1 mmHg/mL, and limits of agreement = [-0.9, 0.6] mmHg/mL). This is a promising first step toward the development of a valuable tool that can be used by clinicians to assess systolic performance of the LV in the critically ill.NEW & NOTEWORTHY In this study, we present a novel model-based method to estimate the left ventricular (LV) end-systolic elastance (Ees) according to measurement of the patient's arm-cuff pressure and a routine echocardiography examination. The proposed method was validated in vivo against invasive multiple-loop measurements of Ees, achieving high correlation and low bias. This tool could be most valuable for clinicians to assess the cardiovascular health of critically ill patients.

Noninvasive cardiac psychophysiology as a tool for translational science with marmosets.

The importance of marmosets for comparative and translational science has grown in recent years because of their relatively rapid development, birth cohorts of twins, family social structure, and genetic tractability. Despite this, they remain understudied in investigations of affective processes. In this methodological note, we establish the validity of using noninvasive commercially available equipment to record cardiac physiology and compute indices of autonomic nervous system activity-a major component of affective processes. Specifically, we recorded electrocardiogram and impedance cardiogram, from which we derived heart rate, respiration rate, measures of high-frequency heart rate variability (indices of parasympathetic autonomic nervous system activity), and ventricular contractility (an index of sympathetic autonomic nervous system activity). Our methods produced physiologically plausible data, and further, animals with increased heart rates during testing were also more reactive to isolation from their social partner and presentation of novel objects, though no relationship was observed between reactivity and specific indices of parasympathetic or sympathetic nervous system activity.

The new clinical standard of integrated quadruple stress echocardiography with ABCD protocol.

BACKGROUND: The detection of regional wall motion abnormalities is the cornerstone of stress echocardiography. Today, stress echo shows increasing trends of utilization due to growing concerns for radiation risk, higher cost and stronger environmental impact of competing techniques. However, it has also limitations: underused ability to identify factors of clinical vulnerability outside coronary artery stenosis; operator-dependence; low positivity rate in contemporary populations; intermediate risk associated with a negative test; limited value of wall motion beyond coronary artery disease. Nevertheless, stress echo has potential to adapt to a changing environment and overcome its current limitations. INTEGRATED-QUADRUPLE STRESS-ECHO: Four parameters now converge conceptually, logistically, and methodologically in the Integrated Quadruple (IQ)-stress echo. They are: 1- regional wall motion abnormalities; 2-B-lines measured by lung ultrasound; 3-left ventricular contractile reserve assessed as the stress/rest ratio of force (systolic arterial pressure by cuff sphygmomanometer/end-systolic volume from 2D); 4- coronary flow velocity reserve on left anterior descending coronary artery (with color-Doppler guided pulsed wave Doppler). IQ-Stress echo allows a synoptic functional assessment of epicardial coronary artery stenosis (wall motion), lung water (B-lines), myocardial function (left ventricular contractile reserve) and coronary small vessels (coronary flow velocity reserve in mid or distal left anterior descending artery). In "ABCD" protocol, A stands for Asynergy (ischemic vs non-ischemic heart); B for B-lines (wet vs dry lung); C for Contractile reserve (weak vs strong heart); D for Doppler flowmetry (warm vs cold heart, since the hyperemic blood flow increases the local temperature of the myocardium). From the technical (acquisition/analysis) viewpoint and required training, B-lines are the kindergarten, left ventricular contractile reserve the primary (for acquisition) and secondary (for analysis) school, wall motion the university, and coronary flow velocity reserve the PhD program of stress echo. CONCLUSION: Stress echo is changing. As an old landline telephone with only one function, yesterday stress echo used one sign (regional wall motion abnormalities) for one patient with coronary artery disease. As a versatile smart-phone with multiple applications, stress echo today uses many signs for different pathophysiological and clinical targets. Large scale effectiveness studies are now in progress in the Stress Echo2020 project with the omnivorous "ABCD" protocol.

[Quantitative Assessment of Alterations of Reginal Contractility of the Left Ventricle in Patients With Ischemic Heart Disease].

BACKGROUND: An important aspect of ischemic heart disease (IHD) diagnosis is the assessment of alterations of regional contractility (ARC) of the left ventricle. Speckle tracking imaging is a relatively new diagnostic method used for this purpose. Aim of this study was to identify optimal parameters of left ventricular (LV) deformation by speckle-tracking echocardiography which can differentiate quantitatively degrees of ARC of all left ventricular segments in patients with acute and chronic forms of IHD. MATERIALS AND METHODS: We compared parameters of LV longitudinal, radial, and circular deformation in 216 patients with IHD in dependence on the presence of ARC. RESULTS: The most sensitive and specific indicator of ARC of LV anterior septal wall was found to be the value of longitudinal systolic deformation of the middle and apical segments (diagnostic thresholds -13.5 % and 14.7 %, respectively). Such indicator for LV inferior wall was value of circular systolic strain (diagnostic threshold for the basal segment -12.9 %, for the middle segment -10.7%).

Improvement of Right Ventricular Hemodynamics with Left Ventricular Endocardial Pacing during Cardiac Resynchronization Therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) with biventricular epicardial (BV-CS) or endocardial left ventricular (LV) stimulation (BV-EN) improves LV hemodynamics. The effect of CRT on right ventricular function is less clear, particularly for BV-EN. Our objective was to compare the simultaneous acute hemodynamic response (AHR) of the right and left ventricles (RV and LV) with BV-CS and BV-EN in order to determine the optimal mode of CRT delivery. METHODS: Nine patients with previously implanted CRT devices successfully underwent a temporary pacing study. Pressure wires measured the simultaneous AHR in both ventricles during different pacing protocols. Conventional epicardial CRT was delivered in LV-only (LV-CS) and BV-CS configurations and compared with BV-EN pacing in multiple locations using a roving decapolar catheter. RESULTS: Best BV-EN (optimal AHR of all LV endocardial pacing sites) produced a significantly greater RV AHR compared with LV-CS and BV-CS pacing (P < 0.05). RV AHR had a significantly increased standard deviation compared to LV AHR (P < 0.05) with a weak correlation between RV and LV AHR (Spearman rs = -0.06). Compromised biventricular optimization, whereby RV AHR was increased at the expense of a smaller decrease in LV AHR, was achieved in 56% of cases, all with BV-EN pacing. CONCLUSIONS: BV-EN pacing produces significant increases in both LV and RV AHR, above that achievable with conventional epicardial pacing. RV AHR cannot be used as a surrogate for optimizing LV AHR; however, compromised biventricular optimization is possible. The beneficial effect of endocardial LV pacing on RV function may have important clinical benefits beyond conventional CRT.

Stimulation of the cardiopulmonary baroreflex enhances ventricular contractility in awake dogs: a mathematical analysis study.

The cardiopulmonary baroreflex responds to an increase in central venous pressure (CVP) by decreasing total peripheral resistance and increasing heart rate (HR) in dogs. However, the direction of ventricular contractility change is not well understood. The aim was to elucidate the cardiopulmonary baroreflex control of ventricular contractility during normal physiological conditions via a mathematical analysis. Spontaneous beat-to-beat fluctuations in maximal ventricular elastance (Emax), which is perhaps the best available index of ventricular contractility, CVP, arterial blood pressure (ABP), and HR were measured from awake dogs at rest before and after ß-adrenergic receptor blockade. An autoregressive exogenous input model was employed to jointly identify the three causal transfer functions relating beat-to-beat fluctuations in CVP to Emax (CVP → Emax), which characterizes the cardiopulmonary baroreflex control of ventricular contractility, ABP to Emax, which characterizes the arterial baroreflex control of ventricular contractility, and HR to Emax, which characterizes the force-frequency relation. The CVP → Emax transfer function showed a static gain of 0.037 ± 0.010 ml(-1) (different from zero; P < 0.05) and an overall time constant of 3.2 ± 1.2 s. Hence, Emax would increase and reach steady state in ∼16 s in response to a step increase in CVP, without any change to ABP or HR, due to the cardiopulmonary baroreflex. Following ß-adrenergic receptor blockade, the CVP → Emax transfer function showed a static gain of 0.0007 ± 0.0113 ml(-1) (different from control; P < 0.10). Hence, Emax would change little in steady state in response to a step increase in CVP. Stimulation of the cardiopulmonary baroreflex increases ventricular contractility through ß-adrenergic receptor system mediation.

Physical exercise is essential for increasing ventricular contractility in hypertensive rats treated with losartan.

The treatment of hypertensive patients with losartan is very common. Despite the reduction in blood pressure, its effects on cardiac contractility and sympathetic autonomic drive are still controversial. In turn, aerobic physical training (APT) also presents an important therapeutic option, providing significant improvements in cardiovascular autonomic control, however little is known about its effects on cardiac contractility, especially when associated with losartan. Therefore, we investigated in spontaneously hypertensive rats (SHR) the effects of losartan and APT on cardiac hemodynamics and functionality, with emphasis on autonomic tonic balance and cardiac contractility. Sixty-four SHR (18 weeks old) were divided into four groups (N = 16): vehicle; vehicle submitted to APT through swimming for 12 weeks; treated with losartan (5 mg·kg-1·d-1) for 12 weeks; and treated with losartan associated with APT. The groups were submitted to cardiac morphological and functional analysis by echocardiography; double blockade of cardiac autonomic receptors with atropine and propranolol; and coronary bed reactivity and left ventricular contractility analyses by the Langendorff technique. APT improved functional parameters and autonomic balance by reducing sympathetic drive and/or increasing vagal drive. In contrast, it promoted a concentric remodeling of the left ventricle (LV). Treatment with losartan reduced sympathetic autonomic drive and cardiac morphological parameters, but there were no significant gains in cardiac functionality and contractility. When combined, the concentric remodeling of the LV to APT was abolished and gains in cardiac functionality and contractility were observed. Our findings suggest that the effects of losartan and APT are complementary and should be applied together in the treatment of hypertension. In spontaneously hypertensive rats, the combination of aerobic physical training with losartan treatment was crucial to greater blood pressure reductions and an increase in left ventricular contractility. Furthermore, losartan treatment prevented the concentric left ventricular remodeling caused by aerobic physical training.

Is perfusion index a surrogate indicator of left ventricular contractility in neonates? A prospective study.

Introduction: Noninvasive blood pressure monitoring may not accurately reflect cardiac contractility in neonates due to low vascular tone. The perfusion index (PI) is a noninvasive method of assessing the strength of peripheral pulses. It is shown to have a significant correlation with the left ventricular output. This prospective study estimates the correlation between PI and cardiac contractility in neonates. Methods and Results: All hemodynamically stable neonates who were on substantial enteral feeds and not on any respiratory or inotropic support underwent measurement of PI and echocardiography examination. Various indices of left ventricular contractility were estimated, and the correlation coefficient between them and PI was determined. Fifty-six neonates were studied. The median (interquartile range [IQR]) PI was 1.5 (1.25-1.75). The median (IQR) PI in preterm neonates was 1.5 (1.2-1.8) and that in term neonates was 1.8 (1.25-2.7) (P = 0.064). PI had a correlation of 0.205 with fractional shortening (P = 0.129) and 0.13 with left ventricular ejection fraction (P = 0.821). The Spearman's correlation coefficient between PI and velocity of circumference fiber shortening was 0.009 (P = 0.945). The Spearman's correlation coefficient between PI and cardiac output was -0.115 (P = 0.400). Conclusion: The PI does not correlate with left ventricular contractility parameters in neonates.

Mechanism-Driven Modeling to Aid Non-invasive Monitoring of Cardiac Function via Ballistocardiography.

Left ventricular (LV) catheterization provides LV pressure-volume (P-V) loops and it represents the gold standard for cardiac function monitoring. This technique, however, is invasive and this limits its applicability in clinical and in-home settings. Ballistocardiography (BCG) is a good candidate for non-invasive cardiac monitoring, as it is based on capturing non-invasively the body motion that results from the blood flowing through the cardiovascular system. This work aims at building a mechanistic connection between changes in the BCG signal, changes in the P-V loops and changes in cardiac function. A mechanism-driven model based on cardiovascular physiology has been used as a virtual laboratory to predict how changes in cardiac function will manifest in the BCG waveform. Specifically, model simulations indicate that a decline in LV contractility results in an increase of the relative timing between the ECG and BCG signal and a decrease in BCG amplitude. The predicted changes have subsequently been observed in measurements on three swine serving as pre-clinical models for pre- and post-myocardial infarction conditions. The reproducibility of BCG measurements has been assessed on repeated, consecutive sessions of data acquisitions on three additional swine. Overall, this study provides experimental evidence supporting the utilization of mechanism-driven mathematical modeling as a guide to interpret changes in the BCG signal on the basis of cardiovascular physiology, thereby advancing the BCG technique as an effective method for non-invasive monitoring of cardiac function.

Acute Hemodynamic Effects of Cardiac Resynchronization Therapy Versus Alternative Pacing Strategies in Patients With Left Ventricular Assist Devices.

Background The hemodynamic effects of cardiac resynchronization therapy in patients with left ventricular assist devices (LVADs) are uncharacterized. We aimed to quantify the hemodynamic effects of different ventricular pacing configurations in patients with LVADs, focusing on short-term changes in load-independent right ventricular (RV) contractility. Methods and Results Patients with LVADs underwent right heart catheterization during spontaneous respiration without sedation and with pressures recorded at end expiration. Right heart catheterization was performed at different pacemaker configurations (biventricular pacing, left ventricular pacing, RV pacing, and unpaced conduction) in a randomly generated sequence with >3 minutes between configuration change and hemodynamic assessment. The right heart catheterization operator was blinded to the sequence. RV maximal change in pressure over time normalized to instantaneous pressure was calculated from digitized hemodynamic waveforms, consistent with a previously validated protocol. Fifteen patients with LVADs who were in sinus rhythm were included. Load-independent RV contractility, as assessed by RV maximal change in pressure over time normalized to instantaneous pressure, was higher in biventricular pacing compared with unpaced conduction (15.7±7.6 versus 11.0±4.0 s-1; P=0.003). Thermodilution cardiac output was higher in biventricular pacing compared with unpaced conduction (4.48±0.7 versus 4.38±0.8 L/min; P=0.05). There were no significant differences in heart rate, ventricular filling pressures, or atrioventricular valvular regurgitation across all pacing configurations. Conclusions Biventricular pacing acutely improves load-independent RV contractility in patients with LVADs. Even in these patients with mechanical left ventricular unloading via LVAD who were relative pacing nonresponders (required LVAD support despite cardiac resynchronization therapy), biventricular pacing was acutely beneficial to RV contractility.

Left ventricular mass index and ventricular contractility improvement in patients with severe obesity following rapid weight loss after bariatric surgery.

BACKGROUND: Obesity is a well-known risk factor for heart disease, resulting in a broad spectrum of cardiovascular changes. Left ventricular mass (LVM) and contractility are recognized markers of cardiac function. OBJECTIVES: To determine the changes of LVM and contractility after bariatric surgery (BaS). SETTING: University hospital, United States METHODS: To determine the cardiac changes in ventricular mass, ventricular contractility, and left ventricular shortening fraction (LVSF), we retrospectively reviewed the 2-dimensional echocardiographic parameters of patients with obesity who underwent BaS at our institution. We compared these results before and after BaS. RESULTS: A total of 40 patients met the inclusion criteria. The majority were females (57.5%; n = 23), with an average age of 63.5 ± 12.1. The excess body mass index (BMI) lost at 12 months was 48.9 ± 28.9%. The percent total weight loss after BaS was 16.46 ± 9.9%. The left ventricular mass was 234.9 ± 88.1 grams before and 181.5 ± 52.7 grams after BaS (P = .002). The LVM index was 101.3 ± 38.3 g/m2 before versus 86.7 ± 26.6 g/m2 after BaS (P = .005). The LVSF was 31% ± 8.8% before and 36.3% ± 8.2% after BaS (P = .007). We found a good correlation between the decrease in LVM index and the BMI after BaS (P = .03). CONCLUSION: Rapid weight loss results in a decrease of the LVM index, as well as improvement in the left ventricular muscle contractility. Our results suggest that there is left ventricular remodeling and an improvement of heart dynamics following bariatric surgery. Further studies are needed to better assess these findings.

Flecainide-induced QRS complex widening correlates with negative inotropy.

BACKGROUND: The negative inotropic effect of Class IC antiarrhythmic drugs limits their use for acute cardioversion of atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to examine, in an intact porcine model, the effects of pulmonary and intravenous (IV) administration of flecainide on left ventricular (LV) contractility and QRS complex width at doses that are effective in converting new-onset AF to sinus rhythm. METHODS: Flecainide (1.5 mg/kg bolus) was delivered by intratracheal administration and compared to 2.0 mg/kg 10-minute IV administration (European Society of Cardiology guideline) and to 0.5 and 1.0 mg/kg 2-minute IV doses in 40 closed-chest, anesthetized Yorkshire pigs. Catheters were fluoroscopically positioned in the LV to monitor QRS complex width and contractility and at the bifurcation of the main bronchi to deliver intratracheal flecainide. RESULTS: Peak flecainide plasma concentrations (Cmax) were similar, but the 30-minute area under the curve (AUC) of plasma levels was 1.4- to 2.8-fold greater for 2.0 mg/kg 10-minute IV infusion than for the lower, more rapidly delivered intratracheal and IV doses. AUC for LV contractility (ie, negative inotropic burden) was 2.2- to 3.6-fold greater for 2.0 mg/kg 10-minute IV dose than for the lower, more rapidly delivered doses. QRS complex widening by flecainide was highly correlated with the decrease in LV contractility (r2 = 0.890, P <.0001, for all IV doses; r2 = 0.812, P = .01, for intratracheal flecainide). CONCLUSION: QRS complex widening in response to flecainide is strongly correlated with decrease in LV contractility. Rapid pulmonary or IV flecainide delivery reduces the negative inotropic burden while quickly achieving Cmax levels associated with conversion of AF.

Insulin and takotsubo syndrome: plausible pathophysiologic, diagnostic, prognostic, and therapeutic roles.

The pathophysiology of takotsubo syndrome (TTS) is elusive. Heightened adrenergic surge via the sympathetic nervous system (mainly by norepinephrine secretion) and/or elevated blood-borne catecholamines (mainly epinephrine, secreted by the adrenals) probably mediate TTS. Patients with TTS have a low prevalence of diabetes mellitus (DM), and it has been postulated that DM, via its associated neuropathy, prevents the emergence of TTS. Insulin, in animal experiments, has been shown to greatly attenuate the effects of NE on the cardiomyocytes; also, insulin in a limited clinical experience, has been found to improve heart function in patients with neurogenic stress-cardiomyopathy and TTS. Accordingly, it is postulated that high levels of insulin encountered in patients with type 2 DM are at the roots of the protective effect of DM for the emergence of TTS. Thus, a role of insulin in the pathophysiology, diagnosis, prognosis, and therapy of TTS appears to be plausible, and needs exploration.

Bioprosthetic interstrut distance subtending the preserved anterior mitral leaflet mitigates left ventricular outflow tract obstruction.

Background: The anterior mitral leaflet (AML) contributes to left ventricular (LV) function but is normally excised at the time of a bioprosthetic valve insertion. This study aimed to investigate methods of safely retaining the AML at the time of mitral valve replacement. Methods: Five adult sheep (57 ± 3.8 kg) each underwent 3 insertions of a bioprosthetic mitral valve (asymmetric interstrut sectors) alternating the wide and narrow interstrut distance under the AML. Each insertion was performed on normothermic beating-heart cardiopulmonary bypass, with full retention of the native valve. After each valve insertion, continuous measurements of LV and aortic pressures were recorded with echocardiographic assessment of mitral valve function. If LV outflow tract obstruction (LVOTO) was not seen on the resumption of normal cardiac output, a bolus of adrenaline was given to precipitate it. Results: Thirteen of 15 valve insertions resulted in LVOTO caused by systolic anterior motion (SAM), independent of valve orientation. The wide interstrut distance subtending the AML was associated with a greater requirement for inotropic stress to precipitate an obstruction and was associated with late systolic rather than holosystolic obstruction. Conclusions: The predisposition to and nature of LVOTO due to SAM were associated with the bioprosthetic valve interstrut distance subtending the fully retained AML and may explain the survival differences in such patients. This model represents an effective method for research into prevention of LVOTO following mitral valve replacement with preservation of the native valve.

Short-term exposure to noise on stroke volume and left ventricular contractility: A repeated-measure study.

Prolonged exposure to noise has been associated with cardiovascular disease, but the possible mechanism for its influence on cardiac activity is unknown. This study investigated the acute effects of noise exposure on 24-h ambulatory cardiac parameters among male workers. We recruited 75 volunteers in an aviation-industry cohort in 2009. Personal noise-exposure levels and individual cardiac parameters, including stroke volume (SV) and left ventricular contractility (LVC), were measured simultaneously over 24 h on working and nonworking days. Linear mixed-effects regression models were used to estimate transient and sustained effects on ambulatory SV and LVC among high-noise-exposure (≥80 A-weighted decibels [dBA]), low-noise-exposure (<80 dBA) and office workers. Every 1-dBA increase in noise exposure was significantly associated with transient changes of -1.50 (95% confidence interval [CI]: -2.18, -1.03) ml/beat in SV and -1.76 (-2.99, -1.03) L/sec in LVC at work on working days only among high-exposure workers. The 1-dBA increase in nocturnal noise exposure was also significantly associated with transiently decreased SV among high-exposure (-1.62 [-2.15, -1.22] ml/beat), low-exposure (-1.27 [-1.57, -1.03] ml/beat) and office workers (-1.09 [-1.18, -1.00] ml/beat), but only the high-exposure group had the transiently reduced LVC (-1.70, [-2.37, -1.22] L/sec) after the current noise exposure on nonworking days. Such decreasing effects persisted to become sustained decreases in 24-h ambulatory SV in high-exposure (-1.10 [-1.20, -1.01] ml/beat) and office workers (-1.13 [-1.22, -1.05] ml/beat) on working days and in all three groups (-1.19 [-1.36, -1.04]; -1.15 [-1.31, -1.02]; -1.08 [-1.13, -1.02] ml/beat, respectively) on nonworking days. No significant effect on 24-h ambulatory LVC was found in any group on working or nonworking days. Occupational and nocturnal noise exposure may have acute effects on 24-h ambulatory SV among male workers, directly influencing the cardiac function related to cardiovascular disease.