bluuebunny/crossref_metadata_2025 huggingface dataset:
Elimination of atrioventricular nodal reentrant tachycardia using discrete slow potentials to guide application of radiofrequency energy.
Authors: Haissaguerre M , Gaita F , Fischer B , Commenges D , Montserrat P , d'Ivernois C , Lemetayer P , Warin J F
Published: June 2012

BACKGROUND

Ablation of the slow pathway has been performed to eliminate atrioventricular (AV) nodal reentrant tachycardia (AVNRT) either by a surgical approach or by using radiofrequency catheter technique guided by retrograde slow pathway activation mapping. From previous experience of midseptal and posteroseptal mapping, we were aware of the existence of peculiar slow potentials in most humans. Postulating their role in AVNRT, we studied these potentials and the effects of radiofrequency energy.

METHODS AND RESULTS

Sixty-four patients (mean age, 48 +/- 19 years) with the usual form of AVNRT were studied. Slow, low-amplitude potentials were recorded when using the anterograde AV conducting system. Slow potentials occupied all (giving a continuum of electrograms) or some of the time between the atrial and ventricular electrograms. Their most specific patterns were their progressive response to increasing atrial rates, which resulted in a dramatic decline in amplitude and slope, a corresponding increase in duration, and a separation from preceding atrial potentials until the disappearance of any consistent activity. Slow potentials were recorded along a vertical band at the mid or posterior part of the septum near the tricuspid annulus. Radiofrequency energy applied at the slow potential site resulted in interruption of induced tachycardia within a few seconds and rendered tachycardia noninducible in all patients. A median of two impulses was delivered to each patient. In 69% of patients, postablation atrial stimulation cannot achieve a long atrial-His interval, which previously was critical for tachycardia induction or maintenance. No patient had AVNRT over a follow-up period of 1-16 months, and all had preserved AV conduction. In all except two patients, the PR interval was unchanged. In 47 patients, long-term electrophysiological studies confirmed the efficacy of ablation and the nonreversibility of results by isoproterenol; however, echo beats remained inducible in 40% of patients.

CONCLUSIONS

An area showing slow potentials is present at the perinodal region in humans. In patients with AVNRT, application of radiofrequency energy renders tachycardia noninducible through the preferential modification of the anterograde slow pathway. With present clinical methods, the exact origin and significance of these physiological potentials cannot be specified.
Thrombolysis in patients with unstable angina improves the angiographic but not the clinical outcome. Results of UNASEM, a multicenter, randomized, placebo-controlled, clinical trial with anistreplase.
Authors: Bär F W , Verheugt F W , Col J , Materne P , Monassier J P , Geslin P G , Metzger J , Raynaud P , Foucault J , de Zwaan C
Published: June 2012

BACKGROUND

The value of thrombolytic therapy in unstable angina is unclear.

METHODS AND RESULTS

To study this problem, 159 patients were studied in a double-blind, placebo-controlled multicenter trial. Patients without a previous myocardial infarction, with a typical history of unstable angina, and ECG abnormalities indicative of ischemia were included. After baseline angiography, study medication (anistreplase or placebo) was given. Angiography was repeated after 12-28 hours. A significant decrease occurred in diameter stenosis between the first and second angiogram in the anistreplase group compared with the placebo group (11% versus 3%, p = 0.008). This difference was caused by reopening of occluded vessels in the thrombolytic group. However, no beneficial clinical effects of thrombolytic treatment were found. Bleeding complications were significantly higher in patients who received thrombolytic therapy (21 versus seven patients, p = 0.001).

CONCLUSIONS

Thus, angiographic but no clinical improvement after thrombolytic treatment with anistreplase was found in patients with unstable angina with an excess of bleeding complications. Therefore, thrombolytic treatment cannot be recommended in patients diagnosed as having unstable angina until proven otherwise.
Estimation of left ventricular cavity area with an on-line, semiautomated echocardiographic edge detection system.
Authors: Vandenberg B F , Rath L S , Stuhlmuller P , Melton H E , Skorton D J
Published: June 2012

BACKGROUND

Automated edge detection of endocardial borders in echocardiograms provides objective, reproducible estimation of cavity area; however, most methods have required off-line analysis. A recently developed prototype echocardiographic imaging system permits real-time automated edge detection during imaging and thus, the potential for measurement of cyclic changes in cavity area and the assessment of left ventricular function on-line. Our purpose was to compare measurements of endocardial area manually traced from conventional echocardiograms with those obtained with the real-time automated edge detection system in normal subjects.

METHODS AND RESULTS

Two training sets of images were used to establish optimal methods of gain setting; the settings were then evaluated in a test set of images. In the high-gain training group (n = 8 subjects, 119 images), gain settings were adjusted sufficiently high to display at least 90% of the endocardial border. Manually drawn and real-time area measurements correlated at r = 0.92, but manually drawn areas were underestimated by computer. In the low-gain training group (n = 7 subjects, 104 images), gain settings were adjusted sufficiently low to avoid cavity clutter despite the presence of dropout of endocardial edges. Manually drawn and real-time areas again correlated (r = 0.79), but manually drawn areas were overestimated by computer. In the intermediate-gain test group (n = 7 subjects, 105 images), gain settings were balanced between maximal endocardial definition (greater than or equal to 90%) and minimal cavity clutter (less than or equal to 1 cm2). Manually drawn and real-time areas correlated at r = 0.91 for the group, and r ranged from 0.94 to 0.99 in individual subjects. Interobserver variability was 9.5% for manually traced areas and 10.6% for real-time area measurements.

CONCLUSIONS

Real-time on-line automated edge detection provides accurate estimation of manually drawn cavity areas. Although the method is gain dependent, measurements are reproducible. The system should have clinical application in settings in which measurements of left ventricular function are important.
Myocardial viability in patients with Q wave myocardial infarction and no residual ischemia.
Authors: Montalescot G , Faraggi M , Drobinski G , Messian O , Evans J , Grosgogeat Y , Thomas D
Published: June 2012

BACKGROUND

Coronary revascularization in patients with persistent angina after myocardial infarction reduces the incidence of recurrent angina pectoris and myocardial infarction and improves left ventricular function. The results of revascularization after a Q wave myocardial infarction when there is no residual ischemia may depend on myocardial viability.

METHODS AND RESULTS

To determine whether there was viable myocardium in the infarct area in the absence of clinical and scintigraphic evidence of myocardial ischemia, 15 asymptomatic patients with a Q wave myocardial infarction, no redistribution on stress 201Tl test, and single-vessel disease (greater than 70% stenosis) with persistent anterograde blood flow were randomized to percutaneous transluminal coronary artery angioplasty (PTCA) or conservative medical treatment. After 2 months of follow-up, mean coronary blood flow measured by Doppler catheter in the infarct-related artery was higher in the PTCA treatment group (33 +/- 6 ml/min, n = 8) than in the conservative treatment group (16 +/- 4 ml/min, n = 7; p less than 0.05 between groups). The 201Tl pathological-to-normal ratios measured on postexercise images did not change in patients treated conservatively during the follow-up period (delta = +1.1 +/- 2.2%; NS from baseline) but increased significantly in patients treated by PTCA (delta = +8.5 +/- 2.3%; p less than 0.01 from baseline; p less than 0.05 between groups). Segmental wall motion improved on left ventricular angiography 2 months after PTCA (delta = +11.5 +/- 2.2%; p less than 0.001 from baseline) significantly more than in the conservative treatment group (delta = +4.1 +/- 1.4%; p less than 0.05 between both groups). Improvements of 201Tl ratios and segmental wall motion indexes correlated significantly (r = 0.73, p = 0.002). The mild improvement of global left ventricular ejection fraction measured in the PTCA treatment group did not differ significantly from changes in the conservative treatment group.

CONCLUSIONS

Successful angioplasty of the stenotic infarct artery in patients with a Q wave myocardial infarction and no residual ischemia improved coronary flow, 201Tl uptake in the infarct area, and regional wall motion. Therefore, myocardial viability may last several weeks, as long as residual blood flow persists in the infarct-related artery. Optimal assessment of viability by imaging techniques should identify patients who are most likely to benefit from revascularization.
Structural remodeling of cardiac myocytes in patients with ischemic cardiomyopathy.
Authors: Gerdes A M , Kellerman S E , Moore J A , Muffly K E , Clark L C , Reaves P Y , Malec K B , McKeown P P , Schocken D D
Published: June 2012

BACKGROUND

Chronic ischemic heart disease may lead to ventricular dilation and congestive heart failure (ischemic cardiomyopathy [ICM]). The changes in cardiac myocyte shape associated with this dilation, however, are not known.

METHODS AND RESULTS

Left ventricular myocyte dimensions were assessed in cells isolated from explanted human hearts obtained from patients with ICM (n = 6) who were undergoing heart transplantation. Cells were also examined from three nonfailing donor hearts with normal coronary arteries (NCA). Compared with cells from patients with NCA, myocyte length was 40% longer in hearts from patients with ICM (197 +/- 8 versus 141 +/- 9 microns, p less than 0.01), cell width was not significantly different, and cell length/width ratio was 49% greater (11.2 +/- 0.9 versus 7.5 +/- 0.6, p less than 0.01). Sarcomere length was the same in myocytes from both groups. The extent of myocyte lengthening is comparable to the increase in end-diastolic diameter commonly reported in patients with ICM.

CONCLUSIONS

These data suggest that increased myocyte length (an intracellular event), instead of myocyte slippage (an extracellular event), is largely responsible for the chamber dilation in ICM. Furthermore, maladaptive remodeling of myocyte shape (e.g., increased myocyte length/width ratio) may contribute to the elevated wall stress (e.g., increased chamber radius/wall thickness) in ICM.
Effect of balloon angioplasty on femoral artery evaluated with intravascular ultrasound imaging.
Authors: The S H , Gussenhoven E J , Zhong Y , Li W , van Egmond F , Pieterman H , van Urk H , Gerritsen G P , Borst C , Wilson R A
Published: June 2012

BACKGROUND

Intravascular ultrasound was used to assess the immediate effect of balloon angioplasty on the superficial femoral artery.

METHODS AND RESULTS

In 16 consecutive patients, corresponding ultrasonic cross sections (n = 72) before and after balloon angioplasty were qualitatively and quantitatively analyzed. The qualitative data were compared with angiographic findings. Before intervention, the angiographically demonstrated obstructive lesions were confirmed by intravascular ultrasound. Ultrasound enabled discrimination between soft (n = 43) and hard (n = 29) lesions, as well as between eccentric (n = 57) and concentric (n = 15) lesions. After balloon angioplasty, the presence of a dissection assessed angiographically in 14 patients was confirmed by intravascular ultrasound. Additional morphological information provided by ultrasound included plaque rupture in 14 patients and internal lamina rupture in six patients. Quantitative ultrasound data revealed an increase in free lumen area from 9.7 +/- 4.7 to 18.3 +/- 7.0 mm2 (p less than or equal to 0.01), an increase in minimal lumen diameter from 2.8 +/- 0.7 to 3.6 +/- 1.2 mm (p less than or equal to 0.01), and an increase in media-bounded area from 21.7 +/- 5.4 to 28.3 +/- 5.8 mm2 (p less than or equal to 0.01). The lesion area for the majority of cases (n = 32) remained unchanged (13.0 +/- 4.9 mm2 versus 12.9 +/- 4.6 mm2), or the lesion disappeared partially (from 9.1 +/- 0.9 to 4.3 +/- 1.4 mm2, n = 4, p less than or equal to 0.01) or totally (from 10.1 +/- 4.2 to 0 mm2, n = 6). Stretching of the arterial wall was further evidenced by medial thinning from 0.55 +/- 0.19 to 0.34 +/- 0.11 mm (p less than or equal to 0.01).

CONCLUSIONS

Luminal enlargement by balloon dilatation is achieved primarily by overstretching the arterial wall, with the lesion volume remaining practically unchanged. Overstretching is accompanied almost always by dissection and plaque rupture and occasionally by an internal lamina rupture.
Effects of aging, sex, and physical training on cardiovascular responses to exercise.
Authors: Ogawa T , Spina R J , Martin W H , Kohrt W M , Schechtman K B , Holloszy J O , Ehsani A A
Published: June 2012

BACKGROUND

The relative contributions of decreases in maximal heart rate, stroke volume, and oxygen extraction and of changes in body weight and composition to the age-related decline in maximal oxygen uptake (VO2max) are unclear and may be influenced by sex and level of physical activity.

METHODS AND RESULTS

To investigate mechanisms by which aging, sex, and physical activity influence VO2max, we quantified VO2, cardiac output, and heart rate during submaximal and maximal treadmill exercise and assessed weight and fat-free mass in healthy younger and older sedentary and endurance exercise-trained men and women. For results expressed in milliliters per kilogram per minute, a three-to-four-decade greater age was associated with a 40-41% lower VO2max in sedentary subjects and a 25-32% lower VO2max in trained individuals (p less than 0.001). A smaller stroke volume accounted for nearly 50% of these age-related differences, and the remainder was explained by a lower maximal heart rate and reduced oxygen extraction (all p less than 0.001). Age-related effects on maximal heart rate and oxygen extraction were attenuated in trained subjects (p less than 0.05). After normalization of VO2max and maximal cardiac output to fat-free mass, age- and training-related differences were reduced by 24-47% but remained significant (p less than 0.05). For trained but not sedentary subjects, maximal cardiac output and stroke volume normalized to fat-free mass were greater in men than in women (p less than 0.05).

CONCLUSIONS

A lower stroke volume, heart rate, and arteriovenous oxygen difference at maximal exercise all contribute to the age-related decline in VO2max. Effects of age and training on VO2max, maximal cardiac output, and stroke volume cannot be fully explained by differences in body composition. In sedentary subjects, however, the sex difference in maximal cardiac output and stroke volume can be accounted for by the greater percentage of body fat in women than in men.
Effective arterial elastance as index of arterial vascular load in humans.
Authors: Kelly R P , Ting C T , Yang T M , Liu C P , Maughan W L , Chang M S , Kass D A
Published: June 2012

BACKGROUND

This study tested whether the simple ratio of ventricular end-systolic pressure to stroke volume, known as the effective arterial elastance (Ea), provides a valid measure of arterial load in humans with normal and aged hypertensive vasculatures.

METHODS AND RESULTS

Ventricular pressure-volume and invasive aortic pressure and flow were simultaneously determined in 10 subjects (four young normotensive and six older hypertensive). Measurements were obtained at rest, during mechanically reduced preload, and after pharmacological interventions. Two measures of arterial load were compared: One was derived from aortic input impedance and arterial compliance data using an algebraic expression based on a three-element Windkessel model of the arterial system [Ea(Z)], and the other was more simply measured as the ratio of ventricular end-systolic pressure to stroke volume [Ea(PV)]. Although derived from completely different data sources and despite the simplifying assumptions of Ea(PV), both Ea(Z) and Ea(PV) were virtually identical over a broad range of altered conditions: Ea(PV) = 0.97.Ea(Z) + 0.17; n = 33, r2 = 0.98, SEE = 0.09, p less than 0.0001. Whereas Ea(PV) also correlated with mean arterial resistance, it exceeded resistance by as much as 25% in older hypertensive subjects (because of reduced compliance and wave reflections), which better indexed the arterial load effects on the ventricle. Simple methods to estimate Ea (PV) from routine arterial pressures were tested and validated.

CONCLUSIONS

Ea(PV) provides a convenient, useful method to assess arterial load and its impact on the human ventricle. These results highlight effects of increased pulsatile load caused by aging or hypertension on the pressure-volume loop and indicate that this load and its effects on cardiac performance are often underestimated by mean arterial resistance but are better accounted for by Ea.
Low-molecular-weight heparin reduces neointimal proliferation after coronary stent implantation in hypercholesterolemic minipigs.
Authors: Buchwald A B , Unterberg C , Nebendahl K , Gröne H J , Wiegand V
Published: June 2012

BACKGROUND

Intracoronary stents have been suggested as a method of reducing the restenosis rate after balloon angioplasty. Proliferation of vascular smooth muscle cells is a major contributing factor to the restenosis process. Heparin and some of its derivatives have been shown to inhibit smooth muscle cell proliferation. We investigated the effect of low-molecular-weight heparin on the proliferative response after implantation of a balloon-expandable tantalum stent in previously deendothelialized coronary artery segments of hypercholesterolemic minipigs.

METHODS AND RESULTS

Minipigs were fed a diet containing 2% cholesterol, starting 1 month before balloon denudation of the endothelium in a coronary artery. One month later, a stent was implanted at this site. Animals were killed after 4 weeks (group 1, n = 6) or 3 months (group 2, n = 6). Animals in group 3 (n = 6), also followed for 4 weeks after stenting, received subcutaneous low-molecular-weight heparin at a dose of 200-300 units/kg anti-factor Xa activity per day in addition to the chronic acetylsalicylic acid (100 mg/day) also administered to groups 1 and 2. Eighteen of 22 animals survived to the end of the study. Angiography revealed patent stents in all surviving animals. In group 1, histological analysis showed extensive neointimal proliferation around stent struts. Maximal neointimal thickness seen in group 1 averaged 0.93 +/- 0.11 mm, was lower after 3 months (0.8 +/- 0.14 mm) in group 2, but was significantly reduced (0.44 +/- 0.18 mm, p less than 0.01) in group 3.

CONCLUSIONS

These data show a significant reduction of the neointimal proliferative response to coronary stent implantation by low-molecular-weight heparin.
Inhibition of smooth muscle cell proliferation by an antisense oligodeoxynucleotide targeting the messenger RNA encoding proliferating cell nuclear antigen.
Authors: Speir E , Epstein S E
Published: June 2012

BACKGROUND

The process by which normally quiescent vascular smooth muscle cells (SMCs) change into proliferating cells, which express and respond to multiple growth factors, plays a major role in restenosis after coronary angioplasty. We are attempting to inhibit SMC proliferation by interventions that inhibit specific factors involved in signal transduction pathways leading to cell division. To date, all studies taking this approach have attempted to block the effects of mitogens acting on the cell surface. In contrast, we have focused on a strategy that bypasses cell surface-mediated events by directly inhibiting the expression of proliferating cell nuclear antigen (PCNA), an intranuclear protein that functions in a final common pathway shared by diverse mitogen-induced signals. In the present investigation, we determined whether antisense oligodeoxynucleotides (ODNs) complementary to the messenger RNA of PCNA will inhibit PCNA expression and thereby reduce SMC proliferation.

METHODS AND RESULTS

When antisense ODNs (15- or 18-mer), modified to inhibit their degradation, are introduced into the medium of rat aortic SMCs in concentrations ranging from 10 to 100 microM, the 18-mer ODN, in a concentration-related manner, decreases SMC growth (as assessed by cell counting) by more than 50%. This effect persists for at least 9 days. An ODN with the same nucleotides but a scrambled sequence has little effect. Western blots and immunocytochemistry indicate that the antisense ODN reduces expression of PCNA protein.

CONCLUSIONS

Our results demonstrate that an antisense ODN directed at the messenger RNA of PCNA decreases expression of the PCNA gene product and reduces SMC proliferation. In addition, these results provide an important impetus to initiating in vivo studies to determine the feasibility of antisense strategies in the prevention of coronary restenosis.
Influence of loading conditions and contractile state on pulmonary venous flow. Validation of Doppler velocimetry.
Authors: Hoit B D , Shao Y , Gabel M , Walsh R A
Published: June 2012

BACKGROUND

Although recent studies suggest that pulmonary venous flow velocities may be used to evaluate left ventricular diastolic function, the influence of loading conditions and contractile state on the magnitude and pattern of pulmonary venous flow are poorly understood.

METHODS AND RESULTS

Fourteen anesthetized open-chest mongrel dogs were instrumented with pulmonary venous flow probes, atrial sonomicrometer crystal paris, and high-fidelity micromanometers; transesophageal Doppler echocardiography was used to obtain simultaneous pulmonary venous flow velocities. Measurements were made over a wide range of left atrial pressure obtained by either intravascular volume infusion and inferior vena caval balloon inflation (n = 8), halothane inhalation (n = 6), or phenylephrine infusion (n = 5). There was an excellent correlation for pulmonary venous systolic (J) to diastolic (K) time integral between the Doppler and flow probe signal (r = 0.94; SEE, 0.18). When left atrial pressure was increased by volume infusion, there was a significant linear relation between mean left atrial pressure and the Doppler J/K peak (r = 0.64; SEE, 3.4 mm Hg) and flow velocity-time integral ratio (r = 0.75; SEE, 2.9 mm Hg). By contrast, when left atrial pressure was elevated by halothane-induced cardiac depression, there was no correlation. The independent determinants of the pattern of pulmonary venous flow (stepwise multiple linear regression analysis) under all conditions were atrial systolic shortening, aortic systolic pressure, heart rate, and left ventricular end-systolic dimension (cumulative r = 0.80).

CONCLUSIONS

The pattern of pulmonary venous flow can be measured accurately with Doppler velocities and is differentially influenced by loading conditions and myocardial contractile state; in the absence of myocardial contractile dysfunction, the pattern of pulmonary venous flow may provide an estimate of left atrial pressure; and pulmonary venous flow is determined largely by atrial systolic function.
Transesophageal echocardiography in infants and children with congenital heart disease.
Authors: Weintraub R , Shiota T , Elkadi T , Golebiovski P , Zhang J , Rothman A , Ritter S B , Sahn D J
Published: June 2012

TEE applications for children and infants with congenital heart disease are now clinically established and TEE is being used in most major pediatric cardiovascular centers. This technology has evolved to the point that it is capable of providing diagnostic quality imaging, even for small infants. With expanding technology and increasing experience, new and more sophisticated applications will be found for pediatric TEE.
Transient intermittent lymphocyte activation is responsible for the instability of angina.
Authors: Serneri G G , Abbate R , Gori A M , Attanasio M , Martini F , Giusti B , Dabizzi P , Poggesi L , Modesti P A , Trotta F
Published: June 2012

BACKGROUND

Blood clotting activation is an important component of the inflammatory response; the outbursts of unstable angina are usually associated with increased thrombin formation and coronary mural thrombosis.

METHODS AND RESULTS

To investigate 1) whether monocyte activation is responsible for the enhanced thrombin formation during bursts of unstable angina and 2) what mechanism(s) might be responsible for monocyte activation, we studied patients with unstable angina (n = 31), stable effort angina (n = 23), left endoventricular thrombosis (n = 8), and control subjects (n = 44), measuring plasma fibrinopeptide A (FPA) levels and the capacity of monocytes to express procoagulant activity (PCA) and of lymphocytes to modulate this expression. Patients with unstable angina and patients with endoventricular thrombosis had significantly (p less than 0.0001) higher FPA plasma levels than patients with effort angina and control subjects. However, only monocytes from unstable angina patients expressed significantly increased PCA characterized as tissue factor-like activity (units/10(5) monocytes, median and range; 120, 1.1-463.2 versus 10.8, 0.8-39.1 in control subjects; p less than 0.0001 versus the other groups). When 14 patients with unstable angina were restudied 8-12 weeks later, they showed neither elevated plasma FPA levels nor monocyte PCA. In unstable angina patients, there was a correlation between FPA and PCA (r = 0.56, p less than 0.001). For expression of PCA by monocytes, both an incubation of at least 2 hours with lymphocytes and direct monocyte-lymphocyte contact were needed. In reconstitution and cross-mixing experiments, only lymphocytes from patients with active unstable angina induced the expression of PCA by monocytes from both control and patient groups.

CONCLUSIONS

The results demonstrate that the increased thrombin formation in unstable angina patients is due to the expression of tissue factor-like activity by activated monocytes. The monocyte activation appears to be a part of a lymphocytic cell-instructed response intermittently triggered by unknown factors.
Respiratory muscle function and dyspnea in patients with chronic congestive heart failure.
Authors: Mancini D M , Henson D , LaManca J , Levine S
Published: June 2012

BACKGROUND

Patients with heart failure (HF) frequently experience exertional dyspnea. Using near-infrared spectroscopy, we have previously demonstrated accessory respiratory muscle deoxygenation during exercise in these patients by monitoring changes in light absorption at 760-800 nm.

METHODS AND RESULTS

To investigate whether low-frequency respiratory muscle fatigue occurs, we performed supramaximal bilateral transcutaneous phrenic nerve stimulation before and after maximal bicycle exercise in 10 patients with HF (age, 62 +/- 10 years; ejection fraction, 18 +/- 7%) and six normal subjects (age, 50 +/- 8 years). Maximal rates of contraction and relaxation, peak twitch tension, and maximal transdiaphragmatic pressure (Pdi) were derived before and after exercise from analysis of six to 12 twitches obtained at functional residual capacity. Pdi, time in inspiration (Ti), time per breath (TTOT), respiratory gases, ratings of perceived dyspnea and fatigue, and 760-800 nm near-infrared spectroscopy absorbency changes of the serratus anterior muscle were measured throughout exercise. The tension time index (TTdi) of the diaphragm was derived. In both normal and HF subjects, all parameters of diaphragmatic function (i.e., maximal rates of contraction and relaxation, peak twitch tension, and maximal Pdi) were unchanged before and after exercise. Mean Pdi was comparable at rest (normal, 3.7 +/- 1; HF, 5.8 +/- 2.9 cm H2O; p = NS) but significantly greater in patients with HF at peak exercise (normal, 12.1 +/- 3; HF, 18.3 +/- 6.6 cm H2O; p less than 0.05). Ti/TTOT of both groups was similar at rest and throughout exercise. TTdi was significantly greater at rest (normal, 0.01 +/- 0.01; HF, 0.03 +/- 0.02; p less than 0.05) and at peak exercise (normal, 0.03 +/- 0.02; HF, 0.10 +/- 0.03; p less than 0.04) in patients with HF. Significant accessory respiration muscle deoxygenation was noted only in patients with HF (peak exercise; normal, -1 +/- 13; HF, 28 +/- 15 arbitrary units; p less than 0.01). Linear correlation analysis was performed between ratings of perceived dyspnea and parameters of pulmonary and diaphragmatic function. Significant correlations were observed between ratings of perceived dyspnea and maximal inspiratory and expiratory pressure, the TTdi of the diaphragm, near-infrared absorption changes, and forced expiratory volume in 1 second (FEV1) (all r greater than 0.5; p less than 0.05). Thus, respiratory muscle strength, work, and oxygenation were significantly correlated with the degree of dyspnea.

CONCLUSIONS

We conclude that low-frequency diaphragmatic muscle fatigue does not occur despite accessory respiratory muscle deoxygenation during exercise in patients with HF. However, diaphragmatic work as assessed by the TTdi is dramatically increased in patients with HF and approaches levels previously shown to generate fatigue. The sensation of dyspnea appears closely related to respiratory muscle function.
Molecular biology of the natriuretic peptides and their receptors.
Authors: Koller K J , Goeddel D V
Published: June 2012

After the description in the past 5 years of BNP and CNP, interest in the natriuretic peptide family has dramatically increased. Molecular characterization of the receptors for this hormone family has identified a heterogeneity in the receptor subtypes not previously alluded to by pharmacological or biochemical studies. Much has been published on the physiology of ANP, but the major roles for BNP and CNP remain to be elucidated. Some experiments indicate that ANP and BNP may act synergistically, especially during cardiac stress; however, the high level of structural diversity of BNP among species and the ability of porcine BNP, but not human BNP, to activate human NPR-B suggest that an as yet unidentified receptor may exist that specifically recognizes BNP. Localization studies have implied that CNP is the most prominent neuropeptide in the natriuretic peptide family, and the restriction of its receptor, NPR-B, to the nervous system suggests that CNP and NPR-B may act in the brain to coordinate the central aspects of body fluid homeostasis. Of the three known NPRs, two, NPR-A and NPR-B, are capable of synthesizing their own second messenger, cGMP. The domain within these receptors that has high homology to protein kinases has been demonstrated to be essential for regulating this activity. No kinase activity has been measured in these proteins, but it is possible that this region is important for ATP regulation of guanylyl cyclase activity. This possibility raises interesting parallels with receptor-mediated cAMP signaling within cells. Seven transmembrane receptors, once activated by ligand, associate with G proteins to affect the activity of adenylyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
Neurohormonal inhibition and hemodynamic unloading during prolonged inhibition of ANF degradation in patients with severe chronic heart failure.
Authors: Münzel T , Kurz S , Holtz J , Busse R , Steinhauer H , Just H , Drexler H
Published: June 2012

BACKGROUND

The purpose of this study was to investigate the therapeutic potential of prolonged inhibition of atrial natriuretic factor (ANF) degradation in patients with severe chronic heart failure.

METHODS AND RESULTS

The effects of repeated doses of the endopeptidase inhibitor candoxatrilat (150 mg i.v.) were examined over a 24-hour period in patients with severe chronic heart failure (New York Heart Association class III-IV). Plasma alpha-hANF(99-126) was elevated at baseline (235 +/- 59 pg/ml), increased 2.5-fold at 2 hours after the first dose, and remained significantly elevated throughout the 24-hour protocol. In contrast, pro-hANF(31-67) decreased from 3,151 +/- 616 to 2,072 +/- 362 pg/ml (p less than 0.05). Cardiac index (CI) increased only transiently after the first dose of candoxatrilat (CI, 2.11 +/- 0.2 to 2.67 +/- 0.28 l/min/m2, p less than 0.05). Sodium excretion increased sixfold (p less than 0.05) 2 hours after the first dose of candoxatrilat and remained significantly elevated throughout the protocol. Degree of natriuresis and diuresis in response to candoxatrilat was closely related to baseline cardiac output. Glomerular filtration rate and volume excretion did not change significantly. Pulmonary capillary wedge pressure fell from 23 +/- 3 to 18 +/- 3 mm Hg (p less than 0.05) and remained below baseline throughout the 24 hours. Arterial pressure, heart rate, and total peripheral resistance did not change significantly during the 24-hour period. Urinary cGMP excretion increased fivefold (p less than 0.05), whereas urinary ANF immunoreactivity and plasma cGMP levels remained unchanged. Excretion of prostacyclin metabolite 6-keto-PGF-1 alpha increased 3.3-fold (p less than 0.05). Plasma norepinephrine and epinephrine levels decreased significantly after candoxatrilat and remained suppressed over the 24-hour period. There was also a transient reduction in plasma vasopressin, aldosterone levels, and plasma renin activity. Hematocrit, total protein content, and plasma albumin concentrations did not change, indicating that no fluid shift into the extravascular space had occurred.

CONCLUSIONS

1) The inhibition of ANF degradation causes sustained drop in left and right atrial pressures that appears to be mediated by an inhibition of neurohumoral activity; 2) concomitant inhibition of bradykinin breakdown (which in turn stimulates renal prostacyclin synthesis) contributes to natriuresis; 3) the close correlation between renal response and baseline cardiac index indicates that an inadequate renal perfusion secondary to low cardiac output diminishes the efficacy of this treatment modality. This spectrum of action would be advantageous for a first-line diuretic agent early in the course of disease rather than in patients with advanced chronic heart failure.
Detection of unique transmural architecture of human idiopathic cardiomyopathy by ultrasonic tissue characterization.
Authors: Wong A K , Verdonk E D , Hoffmeister B K , Miller J G , Wickline S A
Published: June 2012

BACKGROUND

Noninvasive approaches to the evaluation of idiopathic cardiomyopathy are limited. Recent work from our laboratory has used quantitative ultrasound to define the three-dimensional structure of normal human myocardium and the myocardial remodeling associated with infarction. Our goal was to define the role of ultrasonic tissue characterization for detection of specific alterations in the three-dimensional transmural architecture of idiopathic dilated cardiomyopathy.

METHODS AND RESULTS

We measured frequency-dependent backscatter from 22 cylindrical biopsy specimens from nine explanted fixed hearts of patients who underwent heart transplantation for idiopathic cardiomyopathy, seven specimens from normal portions, and 12 specimens of infarcted tissue from six explanted fixed human hearts. Consecutive transmural levels from each specimen were insonified with a 5-MHz broadband transducer. The dependence of apparent (uncompensated for attenuation) backscatter, B(f), on frequency (f) was computed from radiofrequency (rf) data as: magnitude of B(f)2 = afn, where n is an index that reflects in part the size of the dominant scatterers in myocardial tissue. Myofiber diameter and percentage fibrosis were determined at each transmural level for each specimen. For cardiomyopathic tissue, the frequency dependence of backscatter (n) increased progressively from epicardial to endocardial (0.02 +/- 0.37 to 1.01 +/- 0.12, p less than 0.05) levels in conjunction with a progressive decrease in myofiber diameter (29.5 +/- 0.9 to 21.4 +/- 0.6 microns, p less than 0.0001). In contrast, in tissue from areas of infarction, the frequency dependence decreased progressively from epicardium to endocardium (0.91 +/- 0.20 to 0.23 +/- 0.21, p less than 0.05) in conjunction with a progressive increase in the percentage of fibrosis (23.5 +/- 9.4% to 54.5 +/- 4.9%, p less than 0.005). Normal tissue exhibited no significant transmural trend for frequency dependence, myofiber diameter, or percentage fibrosis.

CONCLUSIONS

These data indicate the presence of a heterogenous transmural distribution of scattering structures associated with human idiopathic cardiomyopathy and myocardial infarction that may be detected by ultrasonic tissue characterization. The divergence of these transmural trends for frequency dependence of backscatter reflects distinct mechanisms of structural heterogeneity for different pathological processes that comprise a transmural gradation of cell size and fibrosis for idiopathic cardiomyopathy and infarction, respectively.
Transcatheter ablation of ectopic atrial tachycardia in young patients using radiofrequency current.
Authors: Walsh E P , Saul J P , Hulse J E , Rhodes L A , Hordof A J , Mayer J E , Lock J E
Published: June 2012

BACKGROUND

Ectopic atrial tachycardia (EAT) is a reversible cause of cardiomyopathy but may be quite difficult to control with conventional therapy. Transcatheter ablation with radiofrequency current was tested as an alternative to medical or surgical treatment of this condition.

METHODS AND RESULTS

Twelve young patients (aged 10 months to 19 years) with drug-resistant EAT were treated with direct transcatheter ablation of the ectopic focus using radiofrequency (RF) energy. All had depressed left ventricular contractility by echocardiographic criteria, involving shortening fractions of 10-26% (median, 20%; normal, 28-35%). The EAT was mapped to the left atrium in seven cases and to the right atrium in five. Local atrial activation at the ectopic site preceded the onset of the surface P wave by 20-60 msec (median, 42 msec). Tachycardia terminated 0.5-13.0 seconds (median, 2.0 seconds) into a successful RF application. The ablation effectively eliminated EAT in 11 of 12 patients (92%), all of whom were discharged in sinus rhythm without medications after a median hospital stay of 48 hours. Ablation was unsuccessful in one patient with diffuse dysplasia of the anterior right atrium, who eventually did well after surgical resection of abnormal atrial tissue. Transient depression of sinus node function was noted in one patient who had successful ablation of an EAT focus in close proximity to the sinus node, although normal sinus node function returned within 72 hours. No other complications were encountered. During follow-up (3-21 months; median, 13 months), one patient had recurrence of a slower and less-sustained EAT that was successfully eliminated at a second ablation session. All others remained in sinus rhythm, and all 12 subjects recovered normal ventricular function.

CONCLUSIONS

RF ablation appears to be a safe and effective therapeutic option for drug-resistant ectopic atrial tachycardia and may be the preferred first-line therapy for those patients with depressed ventricular function.
Myocardial function and transmural blood flow during coronary venous retroperfusion in pigs.
Authors: Oh B H , Volpini M , Kambayashi M , Murata K , Rockman H A , Kassab G S , Ross J
Published: June 2012

BACKGROUND

The degree of recovery of regional myocardial contraction during coronary venous retroperfusion has not been well established, particularly in the absence of coronary collateral channels. Therefore, the maximal functional benefit attainable with coronary venous retroperfusion was assessed in pigs by means of using selective pump retroperfusion of the left anterior descending vein, with venting of the left anterior descending artery to zero pressure.

METHODS AND RESULTS

In eight anesthetized open-chest pigs during selective left anterior descending venous retroperfusion over a range of retroperfusion flows, regional myocardial function (percent systolic wall thickening by sonomicrometry) increased progressively to an average of 62% of control values at a retroperfusion flow rate 200% of control arterial flow. Progressive thickening of the end-diastolic dimension of the anterior wall was observed with increasing retroperfusion flow (from 8.7 +/- 0.9 to 10.7 +/- 2.3 mm, p less than 0.001). Perfusion pressures within the left anterior descending vein increased linearly with increased retroperfusion flow rates (up to 132 +/- 57 mm Hg with retroperfusion flow 200% of control). A gradual increase of retrograde left anterior descending arterial outflow was observed with increasing retroperfusion flows; however, the absolute amount (maximum, 8.3 +/- 4.1 ml/min) was much too low to explain the extent of functional recovery. Transmural myocardial capillary blood flows in the anterior wall with retroperfusion flows of 100% and 200% of control arterial flow were 0.22 and 0.42 ml/min/g with corresponding subendocardial blood flows of 0.14 and 0.29 ml/min/g; ratios of endocardium to epicardium were 0.51 and 0.61, respectively. Thus, capillary blood flows during selective retroperfusion were relatively low despite considerable restoration of regional systolic wall thickening, and a significant difference was noted in the slopes of the relations between regional systolic wall thickening and myocardial blood flow during retroperfusion and anterograde arterial perfusion (p less than 0.05). With retrograde injection of silicone elastomer at different retroperfusion pressures (50, 75, and 100 mm Hg) in three pigs, capillaries were well visualized, and profuse intramyocardial venous anastomotic connections were seen at the highest retroperfusion pressure (100 mm Hg), whereas there was filling of small venules but little capillary filling at the lowest retroperfusion pressure (50 mm Hg).

CONCLUSIONS

Considerable recovery of regional myocardial function with low regional capillary blood flows were observed during acute venous retroperfusion with high retroperfusion flows with arterial blood. These findings together with low levels of retrograde arterial outflow and visualization of retrograde capillary filling with a rich venous network provide evidence for possible oxygen delivery via the intramyocardial venous plexus.
Role of myocardial ATP-sensitive potassium channels in mediating preconditioning in the dog heart and their possible interaction with adenosine A1-receptors.
Authors: Grover G J , Sleph P G , Dzwonczyk S
Published: June 2012

BACKGROUND

A brief period of myocardial ischemia can result in an increased resistance to subsequent, more severe episodes of ischemia. Recent studies have indicated that activation of adenosine A1-receptors may mediate this preconditioning effect. It is also known that A1-activation can lead to ATP-sensitive potassium channel (KATP) opening via a G(i) protein-mediated effect. Thus, we determined whether the KATP blocker glyburide could abolish preconditioning or the protective effects of A1-receptor activation.

METHODS AND RESULTS

Anesthetized dogs were subjected to 5 minutes of left circumflex coronary artery (LCx) occlusion (or sham) followed by 10 minutes of reperfusion. The hearts were then subjected to 60 minutes of LCx occlusion and 5 hours of reperfusion. Glyburide (5 micrograms/kg/min) or vehicle was given directly into the LCx 20 minutes before preconditioning or sham preconditioning. Preconditioning resulted in a significantly reduced infarct size compared with nonpreconditioned animals. Glyburide abolished the protective effect of preconditioning. To establish a link between KATP and A1-receptor activation, the effect of the A1-agonist R-PIA with or without glyburide on infarct size was determined. R-PIA (0.4 microgram/kg/min, directly into the LCx) significantly reduced infarct size, and this protective effect was abolished by glyburide. None of the treatments described above had a significant effect on peripheral hemodynamic status or myocardial blood flow.

CONCLUSIONS

Preconditioning may be mediated by KATP activation, and this may be linked to A1-receptor stimulation.
Left atrial contribution to ventricular filling during the course of evolving heart failure.
Authors: Kono T , Sabbah H N , Rosman H , Alam M , Stein P D , Goldstein S
Published: June 2012

BACKGROUND

Abnormal left ventricular (LV) filling has been observed in patients with heart failure and is characterized by marked heterogeneity of mitral inflow velocity. In the present study, the contribution of the left atrium to LV filling was examined in eight dogs during the course of evolving heart failure.

METHODS AND RESULTS

Heart failure was produced by multiple sequential intracoronary embolizations with microspheres. Pulsed Doppler echocardiography was used to measure mitral inflow velocity at baseline, before embolization, and at 3, 8, 15, 23, and 33 weeks after initiation of microembolization. The early rapid LV filling (Ei) and late left atrial filling (Ai) components were quantitated based on the time-velocity integral of the early and late mitral inflow velocity waveforms, respectively. Ei decreased progressively from 7.6 +/- 1.5 cm at baseline to 4.0 +/- 0.4 cm at 33 weeks (p less than 0.01). In contrast, Ai initially increased from 1.8 +/- 0.9 cm at baseline to 2.7 +/- 0.4 cm at 3 weeks (p less than 0.01) and subsequently decreased gradually to below baseline values reaching 0.8 +/- 0.4 cm at 33 weeks (p less than 0.01). These temporal changes of Ei and Ai were accompanied by a gradual reduction of LV ejection fraction (56 +/- 5% versus 22 +/- 2%) (p less than 0.01) (baseline versus 33 weeks) and by a gradual increase of LV end-diastolic wall stress (24 +/- 7 versus 92 +/- 8 g/cm2) (p less than 0.01), left atrial dimension (2.4 +/- 0.2 cm to 3.3 +/- 0.3 cm) (p less than 0.01), and left atrial fractional shortening (22 +/- 3% versus 15 +/- 2%) (p less than 0.01).

CONCLUSIONS

The initial rise in left atrium contribution to LV filling may represent a compensatory response to the diminution of the rapid early component of LV filling. With further progression of LV dysfunction, the left atrium contribution to LV filling gradually decreased. This reduction may be mediated by increased workload imposed on the left atrial myocardium due to increased LV diastolic wall stress, which, over time, may have lead to intrinsic left atrium dysfunction.