Echocardiographic diagnosis of left ventricular diastolic dysfunction: Impact of coronary artery disease.

BACKGROUND: In 2016, the American Society of Echocardiography (ASE) released guidelines for identifying left ventricular (LV) diastolic dysfunction (DD), but its ability to detect early hemodynamic abnormalities is not well established, especially in the setting of subclinical coronary artery disease (CAD). We hypothesize that the accuracy of ASE categorization of early LVDD is affected by knowledge of whether CAD history is present. METHODS: We studied 34 patients (age 62 ± 7 years) with NYHA class I to II symptoms and with transthoracic echocardiography without findings suggesting myocardial disease (all with preserved LV ejection fraction), who underwent cardiac catheterization with high-fidelity LV pressure measurement. Echocardiographic images were evaluated for LVDD using ASE algorithm without and with knowledge of CAD history and angiography findings. CAD was considered as having DD for the algorithm. RESULTS: CAD was identified in 22 patients at catheterization (65%). Using ASE guidelines without including history of CAD or angiographic results, 29 patients were DD-, 3 were DD+ (all grade II), and 2 were indeterminate. Inclusion of CAD history recategorized 59% (n = 20) patients to DD+ (all grade I) from DD- (P < .0001). Nineteen of the recategorized patients (95%) had increased isovolumetric relaxation time (IVRT). The addition of echocardiographic IVRT improved discrimination between DD- and DD+, when the presence of CAD is unknown. CONCLUSIONS: 2016-ASE algorithm reasonably accurately identifies early LVDD at rest as reflected by LV catheterization when CAD is disclosed, but without knowledge of the presence of CAD, it underdiagnoses DD+ grade I. The addition of IVRT may improve early LVDD diagnostics.

Impact of clinical input variable uncertainties on ten-year atherosclerotic cardiovascular disease risk using new pooled cohort equations.

BACKGROUND: Recently released American College of Cardiology/American Heart Association (ACC/AHA) guideline recommends the Pooled Cohort equations for evaluating atherosclerotic cardiovascular risk of individuals. The impact of the clinical input variable uncertainties on the estimates of ten-year cardiovascular risk based on ACC/AHA guidelines is not known. METHODS: Using a publicly available the National Health and Nutrition Examination Survey dataset (2005-2010), we computed maximum and minimum ten-year cardiovascular risks by assuming clinically relevant variations/uncertainties in input of age (0-1 year) and ±10 % variation in total-cholesterol, high density lipoprotein- cholesterol, and systolic blood pressure and by assuming uniform distribution of the variance of each variable. We analyzed the changes in risk category compared to the actual inputs at 5 % and 7.5 % risk limits as these limits define the thresholds for consideration of drug therapy in the new guidelines. The new-pooled cohort equations for risk estimation were implemented in a custom software package. RESULTS: Based on our input variances, changes in risk category were possible in up to 24 % of the population cohort at both 5 % and 7.5 % risk boundary limits. This trend was consistently noted across all subgroups except in African American males where most of the cohort had ≥7.5 % baseline risk regardless of the variation in the variables. CONCLUSIONS: The uncertainties in the input variables can alter the risk categorization. The impact of these variances on the ten-year risk needs to be incorporated into the patient/clinician discussion and clinical decision making. Incorporating good clinical practices for the measurement of critical clinical variables and robust standardization of laboratory parameters to more stringent reference standards is extremely important for successful implementation of the new guidelines. Furthermore, ability to customize the risk calculator inputs to better represent unique clinical circumstances specific to individual needs would be highly desirable in the future versions of the risk calculator.

Spironolactone improves left atrial function and atrioventricular coupling in patients with resistant hypertension.

To determine the blood pressure independent effects of spironolactone on left atrial (LA) size and function in patients with resistant hypertension (RHTN). Patients with RHTN (n = 36, mean age 55 ± 7) were prospectively recruited. Spironolactone was initiated at 25 mg/day and increased to 50 mg/day after 4 weeks. Other antihypertensives were withdrawn to maintain constant blood pressure. Cardiac magnetic resonance imaging was performed at baseline and after 6 months of spironolactone treatment and changes in LA functional metrics were assessed. LA size and function parameters were improved (p < 0.05) from baseline to month-6: LA volumes indexed to body surface area (LAVI) were reduced (LAVImaximum 41.4 ± 12 vs. 33.2±9.7 mL/m2; LAVIpre-A 32.6 ± 9.8 vs. 25.6 ± 8.1 mL/m2; median LAVIminimum 18.5 [13.9-24.8] vs. 14.1 [10.9-19.2] mL/m2); left atrioventricular coupling index was reduced (28.2 ± 11.5 vs. 22.7 ± 9.2%); LA emptying fractions (LAEF) were increased (median total LAEF 52.4 [48.7-60.3] vs. 55.9 [50.3-61.1] %; active LAEF 40.2 ± 8.6 vs. 43.1 ± 7.8%). LA global longitudinal strain in the active phase was increased (16.3 ± 4.1 vs. 17.8 ± 4.2%). The effect of spironolactone was similar in patients with high (N = 18) and normal (N = 18) aldosterone status (defined by plasma renin activity and 24-h urine aldosterone). Treatment of RHTN with spironolactone is associated with improvements in LA size and function, and atrioventricular coupling, regardless of whether aldosterone levels were normal or high at baseline. This study suggests the need for larger prospective studies examining effects of mineralocorticoid receptor antagonists on atrial function and atrioventricular coupling.

Cationic peptide mR18L with lipid lowering properties inhibits LPS-induced systemic and liver inflammation in rats.

The cationic single domain peptide mR18L has demonstrated lipid-lowering and anti-atherogenic properties in different dyslipidemic mouse models. Lipopolysaccharide (LPS)-mediated inflammation is considered as one of the potential triggers for atherosclerosis. Here, we evaluated anti-inflammatory effects of mR18L peptide against LPS-mediated inflammation. First, we tested the efficacy and tolerance of 1, 2.5 and 5mg/kg mR18L in normolipidemic rats stimulated with 5mg/kg LPS. LPS and then mR18L were injected in different intraperitoneal regions. By 2h post LPS, mR18L inhibited LPS-mediated plasma TNF-α elevation at all doses, with the effect being stronger for 2.5mg/kg (P<0.05 vs. 1mg/kg, non-significant vs. 5mg/kg). In a similar model, 2.5mg/kg mR18L reduced LPS-mediated inflammation in the liver, as assessed by microscopic examination of liver sections and measurements of iNOS expression in the liver tissue. In plasma, 2.5mg/kg mR18L decreased levels of TNF-α and IL-6, decreased endotoxin activity and enhanced HDL binding to LPS. In another similar experiment, mR18L administered 1h post LPS, prevented elevation of plasma triglycerides by 6h post LPS and increased plasma activity of anti-oxidant enzyme paraoxonase 1, along with noted trends in reducing plasma levels of endotoxin and IL-6. Surface plasmon resonance study revealed that mR18L readily binds LPS. We conclude that mR18L exerts anti-endotoxin activity at least in part due to direct LPS-binding and LPS-neutralizing effects. We suggest that anti-endotoxin activity of mR18L is an important anti-inflammatory property, which may increase anti-atherogenic potential of this promising orally active lipid-lowering peptide.

Coronary artery disease is associated with impaired atrial function regardless of left ventricular filling pressure.

BACKGROUND: Left atrial (LA) strain is impaired in left ventricular (LV) diastolic dysfunction, associated with increased LV end diastolic pressure (LVEDP). In patients with preserved LV ejection fraction (LVEF), coronary artery disease (CAD) is known to impair LV diastolic function. The relationship of LVEDP with CAD and impact on LA strain is not well studied. METHODS AND RESULTS: Patients with LVEF >50% (n = 37, age 61 ± 7 years) underwent coronary angiography, high-fidelity LV pressure measurements and cardiac magnetic resonance imaging. LA volumes, LA emptying fraction (LAEF), LA reservoir strain (LARS) and LA long-axis shortening (LALAS) were measured. By coronary angiography, patients were assigned into 3 groups: severe-CAD (n = 19, with obstruction of major coronary arteries >70% and/or history of coronary revascularization), mild-to-moderate-CAD (n = 10, obstruction of major coronary arteries 30-60%), and no-CAD (n = 8, obstruction of major coronary arteries and branches <30%). Overall, LVEF was 65 ± 8% and LVEDP was 14.4 ± 5.6 mmHg. Clinical characteristics, LVEDP and LV function measurements were similar in 3 groups. Severe-CAD group had lower LAEF, LALAS and LARS than those in no-CAD group (P < 0.05 all). In regression analysis, LARS and LALAS were associated with CAD severity and treatment with Nitrates, whereas LAEF and LAEFactive were associated with CAD severity, treatment with Nitrates and LA minimum volume (P < 0.05 all). LAEFpassive was associated with LVED volume (P < 0.05). CONCLUSIONS: LA functional impairment may be affected by coexistent CAD severity, medications, in particular, Nitrates, and loading conditions, which should be considered when assessing LA function and LA-LV interaction. Our findings inspire exploration in a larger cohort.

Electrocardiogram to Determine Mitral and Aortic Valve Opening and Closure.

PURPOSE: Knowledge of the timing of cardiac valve opening and closing is important in cardiac physiology. The relationship between valve motion and electrocardiogram (ECG) is often assumed, however is not clearly defined. Here we investigate the accuracy of cardiac valve timing estimated using only the ECG, compared to Doppler echocardiography (DE) flow imaging as the gold standard. METHODS: DE was obtained in 37 patients with simultaneous ECG recording. ECG was digitally processed and identifiable features (QRS, T, P waves) were examined as potential reference points to determine opening and closure of aortic and mitral valves, as compared to DE outflow and inflow measurement. Timing offset of the cardiac valves opening and closure between ECG features and DE was measured from derivation set (n = 19). The obtained mean offset in combination with the ECG features model was then evaluated on a validation set (n = 18). Using the same approach, additional measurement was also done for the right sided valves. RESULTS: From the derivation set, we found a fixed offset of 22 ± 9 ms, 2 ± 13 ms, 90 ± 26 ms, and - 2 ± - 27 ms when comparing S to aortic valve opening, Tend to aortic valve closure, Tend to mitral valve opening, and R to mitral valve closure respectively. Application of this model to the validation set showed good estimation of aortic and mitral valve opening and closure timing value, with low model absolute error (median of the mean absolute error of the four events = 19 ms compared to the gold standard DE measurement). For the right-sided (tricuspid and pulmonic) valves in our patient set, there was considerably higher median of the mean absolute error of 42 ms for the model. CONCLUSION: ECG features can be used to estimate aortic and mitral valve timings with good accuracy as compared to DE, allowing useful hemodynamic information to be derived from this easily available test.

Diastolic function: modeling left ventricular untwisting as a damped harmonic oscillator.

Objective.We developed a method using cardiovascular magnetic resonance imaging to model the untwisting of the left ventricle (LV) as a damped torsional harmonic oscillator to estimate shear modulus (intrinsic myocardial stiffness) and frictional damping, then applied this method to evaluate the torsional stiffness of patients with resistant hypertension (RHTN) compared to a control group.Approach.The angular displacement of the LV during diastole was measured. Myocardial shear modulus and damping constant were determined by solving a system of equations modeling the diastolic untwisting as a damped, unforced harmonic oscillator, in 100 subjects with RHTN and 36 control subjects.Main Results.Though overall torsional stiffness was increased in RHTN (41.7 (27.1-60.7) versus 29.6 (17.3-35.7) kdyn*cm;p = 0.001), myocardial shear modulus was not different between RHTN and control subjects (0.34 (0.23-0.50) versus 0.33 (0.22-0.46) kPa;p= 0.758). RHTN demonstrated an increase in overall diastolic frictional damping (6.13 ± 3.77 versus 3.35 ± 1.70 kdyn*cm*s;p< 0.001), but no difference in damping when corrected for the overlap factor (74.3 ± 25.9 versus 68.0 ± 24.0 dyn*s/cm3;p = 0.201). There was an increase in the polar moment (geometric component of stiffness; 11.47 ± 6.95 versus 7.58 ± 3.28 cm4;p<0.001).Significance.We have developed a phenomenological method, estimating the intrinsic stiffness and relaxation properties of the LV based on restorative diastolic untwisting. This model finds increased overall stiffness in RHTN and points to hypertrophy, rather than tissue- level changes, as the major factor leading to increased stiffness.

Spironolactone Reduces Aortic Stiffness in Patients With Resistant Hypertension Independent of Blood Pressure Change.

Background Aortic stiffness is an independent predictor of cardiovascular events in patients with arterial hypertension. Resistant hypertension is often linked to hyperaldosteronism and associated with adverse outcomes. Spironolactone, a mineralocorticoid receptor antagonist, has been shown to reduce both the arterial blood pressure (BP) and aortic stiffness in resistant hypertension. However, the mechanism of aortic stiffness reduction by spironolactone is not well understood. We hypothesized that spironolactone reduces aortic stiffness in resistant hypertension independently of BP change. Methods and Results Patients with uncontrolled BP (≥140/90 mm Hg) despite use of ≥3 antihypertensive medications (including diuretics) were prospectively recruited. Participants were started on spironolactone at 25 mg/d, and increased to 50 mg/d at 4 weeks while other antihypertensive medications were withdrawn to maintain constant mean BP. Phase-contrast cardiac magnetic resonance imaging of the ascending aorta was performed in 30 participants at baseline and after 6 months of spironolactone treatment to measure aortic pulsatility, distensibility, and pulse wave velocity. Pulse wave velocity decreased (6.3±2.3 m/s to 4.5±1.8 m/s, P<0.001) and pulsatility and distensibility increased (15.9%±5.3% to 22.1%±7.9%, P<0.001; and 0.28%±0.10%/mm Hg to 0.40%±0.14%/mm Hg, P<0.001, respectively) following 6 months of spironolactone. Conclusions Our results suggest that spironolactone improves aortic properties in resistant hypertension independently of BP, which may support the hypothesis of an effect of aldosterone on the arterial wall. A larger prospective study is needed to confirm our findings.

Emerging role of cardiovascular magnetic resonance imaging in the management of pulmonary hypertension.

Pulmonary hypertension (PH) is a clinical condition characterised by elevation of pulmonary arterial pressure (PAP) above normal range due to various aetiologies. While cardiac right-heart catheterisation (RHC) remains the gold standard and mandatory for establishing the diagnosis of PH, noninvasive imaging of the heart plays a central role in the diagnosis and management of all forms of PH. Although Doppler echocardiography (ECHO) can measure a range of haemodynamic and anatomical variables, it has limited utility for visualisation of the pulmonary artery and, oftentimes, the right ventricle. Cardiovascular magnetic resonance (CMR) provides comprehensive information about the anatomical and functional aspects of the pulmonary artery and right ventricle that are of prognostic significance for assessment of long-term outcomes in disease progression. CMR is suited for serial follow-up of patients with PH due to its noninvasive nature, high sensitivity to changes in anatomical and functional parameters, and high reproducibility. In recent years, there has been growing interest in the use of CMR derived parameters as surrogate endpoints for early-phase PH clinical trials. This review will discuss the role of CMR in the diagnosis and management of PH, including current applications and future developments, in comparison to other existing major imaging modalities.

Impact of medical therapy for cardiovascular disease on left ventricular diastolic properties and remodeling.

BACKGROUND: Left ventricular (LV) remodeling and diastolic properties are affected by both underlying cardiovascular disease/cardiovascular disease risk factors (CVDRFs) and corresponding medication therapy. However, these effects may not be apparent in patients with multiple CVDRFs. We evaluated the effect of medication classes on hemodynamics in a patient cohort with normal LV dimensions and systolic function. METHODS: In 38 participants (61 ±â€¯7 years, 64 ±â€¯9% LV ejection fraction) undergoing coronary angiography, LV pressure measurement and cardiac magnetic resonance imaging was performed. The effects of coronary artery disease (CAD), CVDRFs and their corresponding medication therapy on LV parameters were analyzed considering the number of CAD/CVDRFs and 'adequacy' of medication therapy to address each existing condition with specific indication-based medication classes. RESULTS: Of the patients studied, 68% had CAD, 87% had hypertension, 87% had dyslipidemia, and 45% had diabetes. Neither individual or total number of CAD/CVDRFs were associated with overall differences in LV diastolic parameters. However, those without (n = 20) and with (n = 18) 'adequate' medication therapy for underlying CAD/CVDRFs differed in values of LV end diastolic pressure (17 ±â€¯4 vs. 11 ±â€¯5 mm Hg, P < 0.001), wall stress (3.9 ±â€¯1.6 vs. 2.2 ±â€¯1.2 x1000 N/m2, P < 0.001), pressure/volume ratio (0.13 ±â€¯0.04 vs. 0.08 ±â€¯0.03 mm Hg/ml, P < 0.01), and mass/volume ratio (0.77 ±â€¯0.20 vs. 0.92 ±â€¯0.24 g/ml, P < 0.05), but not in systolic blood pressure or LV mass index. CONCLUSIONS: Our results suggest an association between the degree of LV diastolic impairment and LV remodeling with the intensity of treatment for CAD/CVDRFs. Comprehensive treatment of all identified CAD/CVDRFs may be an important factor for the preservation of diastolic function.

Novel Noninvasive Assessment of Pulmonary Arterial Stiffness Using Velocity Transfer Function.

Background Pulmonary artery ( PA ) stiffness is associated with increased pulmonary vascular resistance ( PVR ). PA stiffness is accurately described by invasive PA impedance because it considers pulsatile blood flow through elastic PA s. We hypothesized that PA stiffness and impedance could be evaluated noninvasively by PA velocity transfer function ( VTF ), calculated as a ratio of the frequency spectra of output/input mean velocity profiles in PA s. Methods and Results In 20 participants (55±19 years, 14 women) undergoing clinically indicated right-sided heart catheterization, comprehensive phase-contrast and cine-cardiac magnetic resonance imaging was performed to calculate PA VTF , along with right ventricular mass and function. PA impedance was measured as a ratio of frequency spectra of invasive PA pressure and echocardiographically derived PA flow waveforms. Mean PA pressure was 29.5±13.6 mm Hg, and PVR was 3.5±2.8 Wood units. A mixed-effects model showed VTF was significantly associated with PA impedance independent of elevation in pulmonary capillary wedge pressure ( P=0.005). The mean of higher frequency moduli of VTF correlated with PVR (ρ=0.63; P=0.003) and discriminated subjects with low (n=10) versus elevated PVR (≥2.5 Wood units, n=10), with an area under the curve of 0.95, similar to discrimination by impedance (area under the curve=0.93). VTF had a strong inverse association with right ventricular ejection fraction (ρ=-0.73; P<0.001) and a significant positive correlation with right ventricular mass index (ρ=0.51; P=0.02). Conclusions VTF , a novel right ventricular- PA axis coupling parameter, is a surrogate for PA impedance with the potential to assess PA stiffness and elevation in PVR noninvasively and reliably using cardiac magnetic resonance imaging.

Optical measurements of intramural action potentials in isolated porcine hearts using optrodes.

BACKGROUND: Measurements of intramural membrane potential (Vm) would greatly increase knowledge of cardiac arrhythmias and defibrillation. Optrodes offer the possibility for three-dimensional Vm mapping, but their signal quality has been inadequate. OBJECTIVE: The purpose of this work was to improve optrode signal quality and use optrodes to measure intramural distribution of action potentials and shock-induced Vm changes in porcine hearts. METHODS: Optrodes were made from seven optical fibers 225 or 325 microm in diameter. Fiber ends were polished at a 45 degrees angle, which improved light collection and allowed their insertion without a needle. Fluorescent measurements were performed in isolated porcine hearts perfused with Tyrode's solution or blood using Vm-sensitive dye RH-237 and a 200-W Hg/Xe lamp. RESULTS: The signal-to-noise ratio for 325-microm fibers was 44 +/- 23 in blood-perfused hearts (n = 5) and 106 +/- 45 in Tyrode's-perfused hearts (n = 3), which represents an approximately four-fold improvement over previously reported data. There was close correspondence between optical and electrical measurements of activation times and action potential duration (APD). No significant intramural APD gradients were observed at cycle lengths up to 4 s and in the presence of dofetilide or d-sotalol. Application of shocks (5-50 V/cm) produced large intramural Vm changes (up to approximately 200% action potential amplitude), possibly reflecting a combined effect of tissue discontinuities and optrode geometry. CONCLUSIONS: A substantial improvement of optrode signal quality was achieved. Optical measurements of APD and activation times matched electrical measurements. Optrode measurements revealed no significant intramural APD gradients. Application of shocks caused large intramural Vm changes that could be influenced by the optrode geometry.

What Is the Evidence That the Tissue Doppler Index E/e' Reflects Left Ventricular Filling Pressure Changes After Exercise or Pharmacological Intervention for Evaluating Diastolic Function? A Systematic Review.

BACKGROUND: Noninvasive echocardiographic tissue Doppler assessment (E/e') in response to exercise or pharmacological intervention has been proposed as a useful parameter to assess left ventricular (LV) filling pressure (LVFP) and LV diastolic dysfunction. However, the evidence for it is not well summarized. METHODS AND RESULTS: Clinical studies that evaluated invasive LVFP changes in response to exercise/other interventions and echocardiographic E/e' were identified from PubMed, Scopus, Embase, and Cochrane Library databases. We grouped and evaluated studies that included patients with preserved LV ejection fraction (LVEF), patients with mixed/reduced LVEF, and patients with specific cardiac conditions. Overall, we found 28 studies with 9 studies for preserved LVEF, which was our primary interest. Studies had differing methodologies with limited data sets, which precluded quantitative meta-analysis. We therefore descriptively summarized our findings. Only 2 small studies (N=12 and 10) directly or indirectly support use of E/e' for assessing LVFP changes in preserved LVEF. In 7 other studies (cumulative N=429) of preserved LVEF, E/e' was not useful for assessing LVFP changes. For mixed/reduced LVEF groups or specific cardiac conditions, results similar to preserved LVEF were found. CONCLUSIONS: We find that there is insufficient evidence that E/e' can reliably assess LVFP changes in response to exercise or other interventions. We suggest that well-designed prospective studies should be conducted for further evaluation.

Left Ventricular Torsion Shear Angle Volume Approach for Noninvasive Evaluation of Diastolic Dysfunction in Preserved Ejection Fraction.

BACKGROUND: Accurate noninvasive diagnostic tools for evaluating left ventricular (LV) diastolic dysfunction (LVDD) are limited in preserved LV ejection fraction. We previously proposed the relationship of normalized rate of change in LV torsion shear angle (φ') to corresponding rate of change in LV volume (V') during early diastole (represented as -dφ'/dV') as a measure of LV diastolic function. We prospectively evaluated diagnostic accuracy of -dφ'/dV' in respect to invasive LV parameters. METHODS AND RESULTS: Participants (n=36, age 61±7 years) with LV ejection fraction ≥50% and no acute myocardial infarction undergoing coronary angiography for chest pain and/or dyspnea evaluation were studied. High-fidelity invasive LV pressure measurements and cardiac magnetic resonance imaging with tissue tagging were performed. τ, the time constant of LV diastolic relaxation, was 58±10 milliseconds (mean±SD), and LV end-diastolic pressure was 14.5±5.5 mm Hg. Cardiac magnetic resonance imaging-derived -dφ'/dV' was 5.6±3.7. The value of -dφ'/dV' correlated with both τ and LV end-diastolic pressure (r=0.39 and 0.36, respectively, P<0.05). LVDD was defined as τ>48 milliseconds and LV end-diastolic pressure >12 mm Hg (LVDD1), or, alternatively, τ>48 milliseconds and LV end-diastolic pressure >16 mm Hg (LVDD2). Area under the curve (AUC) of -dφ'/dV' for identifying LVDD1 was 0.83 (0.67-0.98, P=0.001), with sensitivity/specificity of 72%/100% for -dφ'/dV' ≥6.2. AUC of -dφ'/dV' for identifying LVDD_2 was 0.82 (0.64-1.00, P=0.006), with sensitivity/specificity of 76%/85% for -dφ'/dV' ≥6.9. There were good limits of agreement between pre- and post-nitroglycerin -dφ'/dV'. CONCLUSIONS: The -dφ'/dV' obtained from the LV torsion volume loop is a promising parameter for assessing global LVDD with preserved LV ejection fraction and requires further evaluation.

Role of intramural virtual electrodes in shock-induced activation of left ventricle: optical measurements from the intact epicardial surface.

BACKGROUND: According to one hypothesized mechanism of defibrillation, shocks directly excite the bulk of ventricular myocardium in the excitable state due to intramural virtual electrodes; however, this hypothesis has not been examined in intact myocardium. OBJECTIVES: The purpose of this study was examine the role of intramural virtual electrodes in shock-induced activation of intact left ventricular (LV) tissue. METHODS: Twelve isolated porcine LV preparations were stained with a transmembrane potential (V(m))-sensitive dye by two methods: (1) surface staining and (2) global staining via coronary perfusion. Shocks (E approximately 0.8-48 V/cm, duration = 10 ms) were applied across the wall from epicardium to endocardium during diastole via transparent electrodes. Shock-induced V(m) responses were measured optically from the intact epicardial surface after surface staining and global staining. RESULTS: Surface-staining recordings demonstrated different V(m) responses to cathodal and anodal shocks. Whereas cathodal shocks caused depolarization and rapid activation of the epicardial surface, anodal shocks induced hyperpolarization and delayed surface activation. In contrast, global-staining V(m) responses to cathodal and anodal shocks were qualitatively similar. Both responses were characterized by activation with small latency and rapid propagation. Weak shocks of both polarities induced monotonic action potential upstrokes; stronger shocks induced nonmonotonic upstrokes with two rising phases at shock onset and end. Such features of global-staining V(m) responses as make activation of the epicardium by anodal shocks and the nonmonotonic action potential upstrokes can be explained by the presence of subepicardial intramural virtual electrodes. CONCLUSION: These data suggest that shocks induce intramural virtual electrodes that directly excite LV tissue and account for the shape of optical V(m) responses recorded from the epicardial surface.

Diagnostic Accuracy of Tissue Doppler Index E/e' for Evaluating Left Ventricular Filling Pressure and Diastolic Dysfunction/Heart Failure With Preserved Ejection Fraction: A Systematic Review and Meta-Analysis.

BACKGROUND: Tissue Doppler index E/e' is used clinically and in multidisciplinary research for estimation of left ventricular filling pressure (LVFP) and diastolic dysfunction (DD)/heart failure with preserved ejection fraction (HFpEF). Its diagnostic accuracy is not well studied. METHODS AND RESULTS: From the PubMed, Scopus, Embase, and Cochrane databases, we identified 24 studies reporting E/e' and invasive LVFP in preserved EF (≥50%). In random-effects models, E/e' had poor to mediocre linear correlation with LVFP. Summary sensitivity and specificity (with 95% CIs) for the American Society of Echocardiography-recommended E/e' cutoffs (lateral, mean, and septal, respectively) to identify elevated LVFP was estimated by using hierarchical summary receiver operating characteristic analysis. Summary sensitivity was 30% (9-48%), 37% (13-61%), and 24% (6-46%), and summary specificity was 92% (82-100%), 91% (80-99%), and 98% (92-100%). Positive likelihood ratio (LR+) was <5 for lateral and mean E/e'. LR+ was slightly >10 for septal E/e' obtained from 4 studies (cumulative sample size <220). For excluding elevated LVFP, summary sensitivity for E/e' (lateral, mean, and septal, respectively) was 64% (38-86%), 36% (3-74%), and 50% (14-81%), while summary specificity was 73% (54-89%), 83% (49-100%), and 89% (66-100%). Because of data set limitations, meaningful inference for identifying HFpEF by using E/e' could not be drawn. With the use of quality assessment tool for diagnostic accuracy studies (Quality Assessment of Diagnostic Accuracy Studies questionnaire), we found substantial risks of bias and/or applicability. CONCLUSIONS: There is insufficient evidence to support that E/e' can reliably estimate LVFP in preserved EF. The diagnostic accuracy of E/e' to identify/exclude elevated LVFP and DD/HFpEF is limited and requires further validation in a well-designed prospective clinical trial.

Intramural virtual electrodes in ventricular wall: effects on epicardial polarizations.

BACKGROUND: Intramural virtual electrodes (IVEs) are believed to play an important role in defibrillation, but their existence in intact myocardium remains unproven. Here, IVEs were detected by use of optical recordings of shock-induced transmembrane potential (V(m)) changes (DeltaV(m)) measured from the intact epicardial heart surface. METHODS AND RESULTS: To detect IVEs, isolated porcine left ventricles were sequentially stained with a V(m)-sensitive dye by 2 methods: (1) surface staining (SS) and (2) global staining (GS) via coronary perfusion. Shocks (2 to 50 V/cm) were applied across the ventricular wall in an epicardial-to-endocardial direction during the action potential plateau via transparent mesh electrodes, and shock-induced DeltaV(m) were measured optically from the same epicardial locations after SS and GS. Optical recordings revealed significant differences between DeltaV(m) of 2 types that became more prominent with increasing shock strength: (1) for weak shocks, SS-DeltaV(m) were larger and faster than GS-DeltaV(m); (2) for intermediate shocks, cathodal GS-DeltaV(m) became multiphasic, whereas SS-DeltaV(m) remained monophasic; and (3) for strong shocks, cathodal GS-DeltaV(m) became uniformly negative, whereas SS-DeltaV(m) typically remained positive. The radical differences in the shape and polarity of SS and GS polarizations can be explained by the contribution of subepicardial IVEs to optical signals. Histological examination revealed a dense network of collagen septa in the subepicardium, which could form the IVE substrate. CONCLUSIONS: Intramural virtual electrodes are reflected in optical measurements of shock-induced DeltaV(m) on the intact epicardial surface. These IVEs could be a result of microscopic resistive discontinuities formed by collagen septa.

Intramural virtual electrodes during defibrillation shocks in left ventricular wall assessed by optical mapping of membrane potential.

BACKGROUND: It is believed that defibrillation is due to shock-induced changes of transmembrane potential (DeltaV(m)) in the bulk of ventricular myocardium (so-called virtual electrodes), but experimental proof of this hypothesis is absent. Here, intramural shock-induced DeltaV(m) were measured for the first time in isolated preparations of left ventricle (LV) by an optical mapping technique. METHODS AND RESULTS: LV preparations were excised from porcine hearts (n=9) and perfused through a coronary artery. Rectangular shocks (duration 10 ms, field strength E approximately 2 to 50 V/cm) were applied across the wall during the action potential plateau by 2 large electrodes. Shock-induced DeltaV(m) were measured on the transmural wall surface with a 16x16 photodiode array (resolution 1.2 mm/diode). Whereas weak shocks (E approximately 2 V/cm) induced negligible DeltaV(m) in the wall middle, stronger shocks produced intramural DeltaV(m) of 2 types. (1) Shocks with E>4 V/cm produced both positive and negative intramural DeltaV(m) that changed their sign on changing shock polarity, possibly reflecting large-scale nonuniformities in the tissue structure; the DeltaV(m) patterns were asymmetrical, with DeltaV-(m)>DeltaV+(m). (2) Shocks with E>34 V/cm produced predominantly negative DeltaV(m) across the whole transmural surface, independent of the shock polarity. These relatively uniform polarizations could be a result of microscopic discontinuities in tissue structure. CONCLUSIONS: Strong defibrillation shocks induce DeltaV(m) in the intramural layers of LV. During action potential plateau, intramural DeltaV(m) are typically asymmetrical (DeltaV-(m)>DeltaV+(m)) and become globally negative during very strong shocks.

Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs.

OBJECTIVES: We studied the effects of beta-adrenergic and cholinergic stimulation and blockade on spontaneous atrial fibrillation (AF) in the intact dog heart. BACKGROUND: Paroxysmal AF is often preceded by changes in autonomic tone, but the relative roles of adrenergic and cholinergic influences on AF induction are not well known. METHODS: Perfusion of catecholamines and acetylcholine (ACh), as well as their combination, through the sinus node artery was used to induce AF in 20 anesthetized open-chest dogs without electrical stimulation of atria. RESULTS: Isoproterenol and adrenaline (10 to 100 micromol/l) induced AF in 21% (3 of 14) and 17% (1 of 6) of dogs, respectively. Atropine (1 to 2 mg) treatment prevented catecholamine-mediated AF, indicating a critical role of cholinergic tone in these AF episodes. Acetylcholine (2.8 +/- 0.3 micromol/l) induced AF in all dogs. Beta-blockade by propranolol (1 mg/kg) did not prevent ACh-induced AF, but increased the threshold ACh concentration for AF induction to 23.5 +/- 3.4 micromol/l (p < 0.05). Acetylcholine-mediated AF was facilitated by isoproterenol (1 to 2 and 10 micromol/l), which decreased the threshold ACh concentration for AF induction to 0.5 +/- 0.1 and 0.4 +/- 0.1 micromol/l, respectively (p < 0.05) and increased the AF duration (from 25 +/- 7 to 141 +/- 54 and 233 +/- 60 s, respectively; p < 0.05). Epicardial mapping of the right atrium (112 unipolar electrodes) demonstrated similar activation patterns during arrhythmias induced by ACh and catecholamines. CONCLUSIONS: These data indicate that although both autonomic systems play a role in AF, cholinergic stimulation is likely the main factor for spontaneous AF initiation in this animal model. Adrenergic tone modulates the initiation and maintenance of cholinergically mediated AF.

High-resolution optical mapping of intramural virtual electrodes in porcine left ventricular wall.

OBJECTIVE: It is believed that shock-induced intramural virtual electrodes (IVE) play a critical role in defibrillation. IVE were recently demonstrated in the porcine left ventricle (LV), but their origin remains unknown. Macroscopic optical mapping showed that strong shocks induce IVE of only one polarity, which contradicts theoretical predictions. It is hypothesized that IVE have a microscopic origin and that microscopic positive and negative IVE are spatially averaged during macroscopic optical mapping. This hypothesis was examined by mapping V(m) responses at the transmural LV surface with increased optical resolution. METHODS: Rectangular shocks (strength=2-48 V/cm; duration=10 ms) were applied across isolated coronary-perfused porcine LV preparations (n=7) during the action potential plateau and diastole. Shock-induced V(m) responses were measured at low resolution (LR; 1.2 mm/diode) and high resolution (HR; 0.11 mm/diode). RESULTS: During plateau shocks with strength > or =20 V/cm, LR recordings demonstrated only negative DeltaV(m) extending to the cathodal preparation edge. In contrast, HR recordings from this area as well as from intramural locations revealed both positive and negative DeltaV(m) at all shock strengths. During diastolic shocks, only positive polarizations were observed at LR, but both positive and negative polarizations were detected at HR. In areas of negative polarization, large activation delays were found at HR, whereas LR recordings at these locations demonstrated fast activation. CONCLUSIONS: High- and low-resolution optical mapping produced radically different patterns of shock-induced polarization and activation. The occurrence of positive and negative polarizations during plateau and diastolic shocks at high but not low resolution provides evidence for microscopic nature of IVE in LV wall.