Cardiac-directed expression of adenylyl cyclase VI facilitates atrioventricular nodal conduction.

OBJECTIVES: The purpose of this study was to test the hypothesis that cardiac-directed expression of adenylyl cyclase VI (AC(VI)) facilitates atrioventricular (AV) nodal conduction. BACKGROUND: Cardiac-directed expression of AC(VI), unlike other strategies to increase cyclic adenosine monophosphate generation, reduces mortality in murine cardiomyopathy. Recent reports suggest that AC(VI) expression may also protect against lethal bradycardia. METHODS: We performed immunofluorescence staining for AC(VI) in the AV node of transgenic mice. We then performed electrophysiologic studies (EPSs) using a 1.7-F octapolar catheter at the AV junction in 11 transgenic AC(VI) mice and 14 control mice. RESULTS: Immunofluorescence staining revealed increased AC(VI) expression in the AV node of transgenic mice versus controls. During EPS, AV intervals approximated PR intervals (R2 = 0.99) and related linearly to atrial-to-His intervals (R2 = 0.98; both p < 0.0001). Thus, we studied AV intervals to avoid electrocardiogram pacing artifacts and inconsistent inscription of His bundle electrograms. At baseline, AC(VI) mice had shorter AV intervals (47 +/- 9 ms) than controls (57 +/- 11 ms; p = 0.02), despite similar sinus rates. In pacing, AV intervals were shorter in AC(VI) mice than controls for a wide cycle-length range (p < 0.01). The AC(VI) mice also had shorter AV Wenckebach cycle lengths (AC(VI): 114 +/- 12 ms; control: 131 +/- 28 ms; p = 0.05) and ventriculo-atrial effective refractory periods (AC(VI): 97 +/- 21 ms; control: 127 +/- 15 ms; p = 0.05). We observed no differences between groups in sinus node function, and ventricular arrhythmias were not inducible. CONCLUSIONS: Cardiac-directed expression of AC(VI) facilitates AV nodal conduction without altering sinus node function. These results suggest the need to define a role for AC(VI) gene transfer in treating diseases of AV conduction.

Abnormal heart rate turbulence predicts the initiation of ventricular arrhythmias.

BACKGROUND: Abnormal heart rate turbulence (HRT) reflects autonomic derangements predicting all-cause mortality, yet has not been shown to predict ventricular arrhythmias in at-risk patients. We hypothesized that HRT at programmed ventricular stimulation (PVS) would predict arrhythmia initiation in patients with left ventricular dysfunction. METHODS: We studied 27 patients with coronary disease, left ventricular ejection fraction (LVEF) 26.7 +/- 9.1%, and plasma B-type natriuretic peptide (BNP) 461 +/- 561 pg/mL. Prior to arrhythmia induction at PVS, we measured sinus cycles after spontaneous or paced premature ventricular contractions (PVCs) for turbulence onset (TO; % cycle length change following PVC) and slope (TS; greatest slope of return to baseline cycle). T-wave alternans (TWA) was also measured during atrial pacing. RESULTS: At PVS, abnormal TO (> or =0%) predicted inducible ventricular tachycardia (VT; n = 10 patients; P < 0.05). TO was greater in inducible than in noninducible patients (2.3 +/- 3.1% vs -0.02 +/- 2.8%, P < 0.05) and correlated with LVEF (P < 0.05) but not with BNP. TS did not differ between groups. Conversely, ambulatory HRT differed significantly from HRT at PVS (TO -0.55 +/- 1.08% vs 0.85 +/- 3.02%, P < 0.05; TS 2.63 +/- 2.09 ms/RR vs 8.70 +/- 6.56 ms/RR, P < 0.01), and did not predict inducible VT but trended (P = 0.05) to predict sustained VT on 739 +/- 179 days follow-up. TWA predicted inducible (P < 0.05) and spontaneous (P = 0.0001) VT but did not co-migrate with HRT. CONCLUSIONS: Abnormal HRT measured at PVS predicted the induction of sustained ventricular arrhythmias in patients with ischemic cardiomyopathy. However, HRT at PVS did not correlate with ambulatory HRT, nor with TWA, both of which predicted spontaneous ventricular arrhythmias. Thus, HRT may reflect the influence of autonomic milieu on arrhythmic susceptibility and is likely complementary to traditional arrhythmic indices.

Separating atrial flutter from atrial fibrillation with apparent electrocardiographic organization using dominant and narrow F-wave spectra.

OBJECTIVES: The purpose of this study was to separate atrial flutter (AFL) with atypical F waves from fibrillation (AF) with "apparent organization." BACKGROUND: We hypothesized that F-wave spectra should reveal a dominant and narrow peak in AFL, reflecting its single macro-re-entrant wave front, but broad spectra in AF, reflecting multiple wave fronts. METHODS: We identified 39 patients with electrocardiograms (ECGs) of "AFL/AF" or "coarse AF" from 134 consecutive patients referred for ablation: 21 had AFL (18 atypical, 3 typical), 18 had AF, and all were successfully ablated. Filtered atrial ECGs were created by cross-correlating F waves to successive ECG time points. Dominant peaks between 3 and 10 Hz were identified from power spectra of X (lead V5), Y (aVF), and Z (V1) axes, and for each, we calculated height (relative to two adjacent spectral points) and area ratio to envelopes of bandwidth 0.625, 1.25, 2.5, 3.75, and 5 Hz (range 0 to 1, where higher ratios reflect narrower peaks). RESULTS: Dominant peaks had greater relative height for AFL than AF (three-axis mean: 14.2 +/- 6.4 dB vs. 6.6 +/- 2.1 dB; p < 0.001). Peak area ratios were also higher for AFL than AF for all envelopes (p < 0.001). For the 2.5-Hz envelope, the separation (0.61 +/- 0.14 vs. 0.35 +/- 0.05, respectively; p < 0.001) enabled a ratio > or =0.44 to identify all cases of AFL from AF (p < 0.001). A panel of seven cardiologists blinded to clinical data provided lower diagnostic accuracy (82.1%; p < 0.01). CONCLUSIONS: In ambiguous ECGs with atypical F waves, spectral evidence for a solitary activation cycle separates AFL from AF with "apparent organization." This approach might improve bedside ECG diagnosis and shed light on intra-atrial organization of both rhythms.

Separating non-isthmus- from isthmus-dependent atrial flutter using wavefront variability.

OBJECTIVES: The aim of this study was to separate isthmus-dependent atrial flutter (IDAFL) from non-isthmus-dependent atrial flutter (NIDAFL) from the electrocardiogram (ECG) based on functional differences. BACKGROUND: The ECG analyses of F-wave shape suboptimally separate NIDAFL from IDAFL. The authors hypothesized that anatomic and functional differences may result in greater wavefront variability in NIDAFL than IDAFL, allowing their separation. The authors tested this hypothesis in patients undergoing ablation for atrial flutter using a novel ECG algorithm to detect subtle F-wave variability, validated by intracardiac measurements. METHODS: In 62 patients (23 NIDAFL, 39 IDAFL) ECG atrial wavefronts were represented as correlations of an F-wave template to the ECG over time. Correlations in orthogonal ECG lead-pairs were plotted at each time point to yield loops reflecting temporal and spatial regularity in each plane. The ECG analyses were compared with intracardiac standard deviations of: 1) atrial electrograms (temporal variability), and 2) bi-atrial activation time differences (spatial variability). RESULTS: Atrial ECG temporospatial loops were reproducible in IDAFL, but varied in NIDAFL (p < 0.01) suggesting greater variability that correctly classified IDAFL (39 of 39 cases) from NIDAFL (22 of 23 cases; p < 0.001). Intra-atrial mapping confirmed greater temporal variability for NIDAFL versus IDAFL, in lateral (p < 0.01) and septal (p = 0.03) right atrium, and proximal (p = 0.02) and distal (p < 0.01) coronary sinus. Spatial variability was greater in NIDAFL than IDAFL (p = 0.02). CONCLUSIONS: Greater cycle-to-cycle atrial wavefront variability separates NIDAFL from IDAFL and is detectable from the ECG using temporospatial analyses. These results have implications for guiding ablation and support the concept that IDAFL and NIDAFL lie along a spectrum of intracardiac organization.

Quantifying intracardiac organization of atrial arrhythmias using temporospatial phase of the electrocardiogram.

INTRODUCTION: Separating nonisthmus-dependent atrial flutter (AFL) from "organized" atrial fibrillation (AF), or isthmus-dependent AFL, may be difficult using ECG characteristics alone. We hypothesized that temporal and spatial phase analysis of ECG atrial waveforms could effectively separate these rhythms by quantifying subtle variations in ECG atrial activation during supraventricular tachycardias (SVT). METHODS AND RESULTS: We studied 52 patients at electrophysiologic study (EPS) who demonstrated isthmus-dependent (n = 15) and nonisthmus-dependent (n = 9) AFL, atrial tachycardia (n = 6), AV nodal reentry (n = 9), orthodromic reciprocating tachycardia (n = 6), and AF (n = 7). Atrial activity was represented as a series of correlations of an atrial template to successive time samples of the arrhythmia ECG. Spatial phase was analyzed as a reproducible relationship of this atrial activity between leads over time; temporal regularity was measured from power spectra. Spatial phase was maintained (coherent) in lead planes V5/aVF (XY), V5/V1 (XZ), and aVF/V1 (YZ) in 15 of 15 cases of isthmus-dependent AFL, but in only 1 of 9 cases of nonisthmus-dependent AFL (P < 0.01; chi2). Temporally, all cases of AFL showed one dominant peak on correlation spectra (magnitude >6 dB), suggesting one activation wavefront, although this was smeared in nonisthmus-dependent cases. In contrast, AF showed inconsistent spatial phase in all planes and broad band spectra, consistent with multiple and/or variable activation paths. All other SVTs showed spatial coherence and one dominant spectral peak. CONCLUSION: Coherence of temporal and spatial phase is a powerful approach to measure the spatial organization of intracardiac activation from the ECG that reveals a spectrum from SVT to isthmus-dependent and nonisthmus-dependent AFL, to AF.

Conduction velocity around the tricuspid valve annulus during type 1 atrial flutter: defining the location of areas of slow conduction by three-dimensional electroanatomical mapping.

BACKGROUND: Conduction velocity (CV) around the tricuspid valve annulus (TVA) during type 1 atrial flutter (AFL) has been shown to be slowest in the tricuspid valve-inferior vena cava (TV-IVC) isthmus, compared to the septal or free wall segments of the TVA. However, fiber orientation in the triangle-of-Koch suggests that the inferior septum and medial TV-IVC isthmus should be the most slowly conducting segments around the TVA. METHODS: To test this hypothesis we evaluated CV around the TVA during type 1 atrial flutter in 11 patients, using an electro-anatomical mapping system (Carto). CV was first calculated in 4 segments around the TVA including the TV-IVC isthmus, lateral free wall, superior free wall and septum, and then calculated in 8 segments around the TVA including medial (MI) and lateral isthmus (LI), inferior (IL) and superior lateral (SL) free wall, lateral (LS) and medial superior (MS) free wall, and superior (SS) and inferior septum (IS). Statistical comparison of CV from these multiple segments was made by one-way analysis of variance. RESULTS: Measured in 4 segments around the TVA, mean CV (m/sec) in the TV-IVC isthmus (0.81 +/- 0.23) and the septum (0.93 +/- 0.18) was significantly slower than CV in the lateral free wall (1.16 +/- 0.23) and superior free wall (1.10 +/- 0.20), and CV in the TV-IVC isthmus was significantly slower than in the septum (p < 0.05). However, when analyzed in 8 segments, mean CV in the MI (0.56 +/- 0.16) and IS (0.59 +/- 0.24) was significantly (p < 0.05) slower than in all other segments including the LI (1.06 +/- 0.46), IL (1.17 +/- 0.40), SL (1.15 +/- 0.40), LS (1.04 +/- 0.25), MS (1.15 +/- 0.28), and SS (1.26 +/- 0.36) segments. CONCLUSIONS: Consistent with previous reports, CV around the TVA during type 1 AFL was slowest in the TV-IVC isthmus, compared to the septum, superior and lateral free wall regions. However, when the TVA was further subdivided into 8 segments, CV in the MI and IS segments was significantly slower than in all other segments around the TVA. These observations more precisely define the regions of slow conduction in human type 1 AFL, and are consistent with the known anisotropy and slow conduction in the Triangle of Koch.

Calcific aortic stenosis in the elderly: a brief overview.

Aortic stenosis is the most common valvular lesion in patients above the age of 65. The etiology, presentation, and management of aortic stenosis differs in the elderly compared to younger patients in many ways. Many of the classic physical findings are absent in the elderly, making the diagnosis of critical aortic stenosis more difficult. Due to coexisting morbidity in many elderly patients, there is often a reluctance to recommend aortic valve replacement despite the dismal prognosis of medical therapy. In the following review, the authors discuss the pathophysiology, presentation, and management of aortic stenosis in the elderly.

Correlation of left ventricular diastolic filling characteristics with right ventricular overload and pulmonary artery pressure in chronic thromboembolic pulmonary hypertension.

OBJECTIVES: This study was designed to determine a quantitative relationship between right ventricular (RV) pressure overload and left ventricular (LV) diastolic filling characteristics in patients with chronic thromboembolic pulmonary hypertension (CTEPH). BACKGROUND: Right ventricular pressure overload in patients with CTEPH causes abnormal LV diastolic filling. However, a quantitative relationship between RV pressure overload and LV diastolic function has not been established. METHODS: We analyzed pre- and postoperative diastolic mitral inflow velocities and right heart hemodynamic data in 39 consecutive patients with CTEPH over the age of 30 (55 +/- 11 years) with mean pulmonary artery pressure >30 mm Hg who underwent pulmonary thromboendarterectomy (PTE). RESULTS: After PTE, mean pulmonary artery pressure (mPAP) decreased from 50 +/- 11 to 28 +/- 9 mm Hg (p < 0.001) while cardiac output (CO) increased from 4.4 +/- 1.1 to 5.7 +/- 0.9 l/m (p < 0.001). Mitral E/A ratio (E/A) increased from 0.74 +/- 0.22 to 1.48 +/- 0.69 (p < 0.001). E/A was < 1.25 in all patients pre-PTE. After PTE, all patients with E/A >1.50 had mPAP <35 mm Hg and CO >5.0 l/min. E/A correlated inversely with mPAP (r = 0.55, p < 0.001) and directly with CO (r = 0.53, p < 0.001). CONCLUSIONS: E/A is consistently abnormal in patients with CTEPH and increases post-PTE. Moreover, E/A varies inversely with mPAP and directly with CO. Following PTE, E/A >1.5 correlates with the absence of severe pulmonary hypertension (mPAP >35 mm Hg) and the presence of normal cardiac output (> 5.0 l/m).