Organization of atrial fibrillation using a pure sodium channel blocker: Implications of rotor ablation therapy.

Background: Rotors are the source of atrial fibrillation (AF). However, the ablation of rotors for persistent AF is challenging. The purpose of this study was to identify the dominant rotor by accelerating the organization of AF using a sodium channel blocker and detecting the rotor's preferential area that governs AF. Methods: Overall, 30 consecutive patients with persistent AF who underwent pulmonary vein isolation and still sustained AF were enrolled. Pilsicainide 50 mg was administered. An online real-time phase mapping system (ExTRa Mapping™) was used to identify the meandering rotors and multiple wavelets in 11 left atrial segments. The time ratio of non-passive activation (%NP) was evaluated as the frequency of rotor activity in each segment. Results: Conduction velocity became slower-from 0.46 ± 0.14 to 0.35 ± 0.14 mm/ms (p = .004)-and the rotational period of the rotor was significantly prolonged-156 ± 21 to 193 ± 28 ms/cycle (p < .001). AF cycle length was prolonged from 169 ± 19 to 223 ± 29 ms (p < .001). A decrease in %NP was observed in seven segments. Additionally, 14 patients had at least one complete passive activation area. Of them, the use of high %NP area ablation resulted in atrial tachycardia and sinus rhythm in two patients each. Conclusions: A sodium channel blocker organized persistent AF. In selective patients with a wide organized area, high %NP area ablation could convert AF into atrial tachycardia or terminate AF.

Important factors in left atrial posterior wall isolation using 28-mm cryoballoon ablation for persistent atrial fibrillation-Block line or isolation area?

INTRODUCTION: Left atrial (LA) roof ablation using the cryoballoon technique, combined with pulmonary vein isolation (PVI), has been reported to be beneficial for ablation therapy in patients with persistent atrial fibrillation (AF). Left posterior wall ablation also results in improved patient outcomes. However, the contribution of these techniques to the success of cryoballoon ablation (CBA) treatment of AF is not known. The present study examined the influence of the roofline block and isolation area on outcomes after CBA. METHODS AND RESULTS: We enrolled 78 patients with persistent AF. LA roof ablation was performed using a 28-mm cryoballoon with a single freezing of 3 minutes at each region (median number of freezes: 4) after PVI. After CBA, bipolar voltage amplitude mapping was performed during sinus rhythm using the NavX mapping system. Patients were divided into two subgroups according to the voltage and activation map: the roof-conduction (n = 46) and roofline-block groups (n = 32). Atrial tachyarrhythmia recurred in 20 patients of the conduction group and 4 patients of the roofline-block group. The rate of 12-month freedom from tachyarrhythmia after a single ablation procedure was 78% (95% confidence interval [CI], 60%-89%) in the roofline-block group and 45% (95% CI, 30%-60%) in the conduction group (P = .048). Cox proportional hazard analysis revealed that the isolated area was not a significant predictor of recurrence (hazard ratio, 0.94; 95% CI, 0.86-1.02; P = .15). CONCLUSION: Creating a complete roofline block is the major factor predicting the maintenance of sinus rhythm in patients with persistent AF.

Successful catheter cryoablation for premature ventricular contractions originating from the para-Hisian region.

We achieved successful catheter cryoablation in a patient with para-Hisian premature ventricular contractions (PVCs) without conduction disturbance using the freeze-thaw-freeze method while observing the atrial-His bundle interval. Cryoablation could be considered an alternative to radiofrequency ablation for patients with para-Hisian PVCs.

Novel use of a 3-dimensional mapping system in cryoablation of right-sided and septal accessory pathways: playback ablation.

PURPOSE: Despite recent advances in the treatment of eliminating accessory pathways (APs), catheter-induced mechanical block (bump) of APs has been reported to result in a less favorable outcome with high primary failure and recurrence rates. The real bump site cannot always be precisely reapproached under fluoroscopy so physicians can perform ablation to a location different from where the mechanical block was encountered. In this paper, we describe this novel use of a 3-dimensional (3D) mapping system (playback ablation) with a case series. METHODS: The EnSite Velocity system (St. Jude Medical, St. Paul, MN, USA), a 3D mapping system, has a unique function that records the positional information of catheters in a 3D geometric map and the local potential of catheters continuously. This function enables physicians to specify the bump site in a 3D geometric map and apply ablation to the bump site even if the catheter moves away from the bump site. RESULTS: This technique helped us eliminate APs in two patients with bump of APs, and they have been free of preexcitation and arrhythmias without the use of anti-arrhythmic drugs for more than 3 months. CONCLUSIONS: This technique may contribute to improving long-term success in patients with mechanical block of APs.

A relation between ablation area and outcome of ablation using 28-mm cryoballon ablation: Importance of carina region.

INTRODUCTION: Pulmonary vein isolation (PVI) with wide antral ablation leads to better outcomes in atrial fibrillation ablation therapy, but the ablation area is relatively small during cryoballoon ablation (CBA). The present study tested the hypothesis that wide ablation can lead to better outcomes in CBA. METHODS AND RESULTS: Ninety-six patients with atrial fibrillation were enrolled (paroxysmal 76%, 64.1 ± 11.7 years). All patients underwent preprocedural computed tomography and the PV diameter at left atrial PV junction was measured. PV isolation was performed using a 28-mm CB for 3 minutes with single freezing. Sinus rhythm bipolar voltage amplitude maps with the NavX mapping system were generated after ablation. According to the voltage map, patients were divided into 3 subgroups (68 in the extensive isolation group, 17 in the individual isolation group, and 10 in the incomplete isolation group). Atrial tachyarrhythmias recurred in 9 patients of the extensive isolation group and 6 in the individual isolation group. The rate of 12-month freedom from tachyarrhythmia after a single ablation procedure was 84% (95% confidence interval [C.I.], 72%-91%) in the extensive group and 57% (95% C.I., 28%-78%) in the individual group (P = 0.048). Multiple logistic regression analyses revealed that maximal PV diameter was the only predictor to achieve extensive PVI (odds ratio, 1.57; 95% C.I. 1.08-2.29 P = 0.018). CONCLUSION: Extensive isolation is superior to individual isolation for achieving freedom from atrial arrhythmia in long term follow-up by CBA. Evaluating PV diameter at the left atrial PV junction is essential for applying CBA.

A novel guidewire approach for handling acute-angle bifurcations: reversed guidewire technique with adjunctive use of a double-lumen microcatheter.

Guidewire manipulation to negotiate branches originating at an acute angle from the parent artery is a frequently encountered challenge by the interventional cardiologist in clinical practice. To date, several methods have been developed, but none of them has a definitive success rate. Here, we report a technique for negotiating extremely angulated vascular bifurcations, with which we have achieved a high rate of success in percutaneous coronary intervention. This technique involves combining a reversed guidewire technique with a double-lumen multifunctional probing microcatheter. We present the cases of 3 patients successfully treated using this technique.

Long-term pharmacological activation of PPARgamma does not prevent left ventricular remodeling in dogs with advanced heart failure.

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) activators affect the myocardium through inhibition of inflammatory cytokines and metabolic modulation but their effect in the progression of heart failure is unclear. In the present study, we examined the effects of the PPARgamma activator, GW347845 (GW), on the progression of heart failure. METHODS AND RESULTS: Heart failure was produced in 21 dogs by intracoronary microembolizations to LV ejection fraction (EF) less than 30% and randomized to 3 months of therapy with high-dose GW (10 mg/Kg daily, n = 7), low-dose GW (3 mg/Kg daily, n = 7), or no therapy (control, n = 7). In control dogs, EF significantly decreased (28 +/- 1 vs. 22 +/- 1%, p < 0.001) and end-diastolic volume (EDV) and end-systolic volume (ESV) increased during the 3 months of the follow-up period (64 +/- 4 vs. 76 +/- 5; p = 0.003, 46 +/- 3 vs. 59 +/- 4 ml, p = 0.002, respectively). In dogs treated with low-dose GW, EDV increased significantly (69 +/- 4 vs.81 +/- 5 ml, p = 0.01), whereas ESV remained statistically unchanged (50 +/- 3 vs. 54 +/- 3 ml, p = 0.10) resulting in modestly increased ejection fraction (27 +/- 1 vs. 32 +/- 3%, p = 0.05). In dogs treated with high-dose GW, both EDV and ESV increased (72 +/- 4 vs. 79 +/- 5 ml, p = 0.04; 53 +/- 3 vs. 62 +/- 5 ml, p = 0.04) and EF decreased (26 +/- 1 vs. 23 +/- 1%, p = 0.04) as with control dogs. There was significantly increased myocardial hypertrophy as evidenced by increased LV weight to body weight ratio and myocyte cross-section area in the GW treated animals compared to controls. Compared to control, treatment with GW had no effect on mRNA expression of PPARgamma, inflammatory cytokines, stretch response proteins, or transcription factors that may induce hypertrophy. CONCLUSIONS: Long-term PPARgamma activation with GW did not prevent progressive LV remodeling in dogs with advanced heart failure.

Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure.

Matrix metalloproteinases (MMPs) contribute to the progression of left ventricular (LV) dysfunction and remodeling associated with heart failure (HF). The present study examined the long-term effects of a selective MMP inhibitor PG-530742 (PG) on the progression of LV dysfunction and remodeling in dogs with HF. Chronic HF [LV ejection fraction (LVEF),

Long-term effects of non-excitatory cardiac contractility modulation electric signals on the progression of heart failure in dogs.

OBJECTIVE: We previously showed that acute delivery of non-excitatory cardiac contractility modulation (CCM) electric signal during the absolute refractory period improved LV function in dogs with chronic heart failure (HF). In the present study we examined the long-term effects of CCM signal delivery on the progression of LV dysfunction and remodeling in dogs with chronic HF. METHODS: Chronic HF was produced in 12 dogs by multiple sequential intracoronary microembolizations. The CCM signal was delivered using a lead implanted in the distal anterior coronary vein. A right ventricular and a right atrial lead were implanted and used for timing of CCM signal delivery. In six dogs, CCM signals were delivered continuously for 6 h daily with an average amplitude of 3.3 V for 3 months. Six HF dogs did not have leads implanted and served as controls. RESULTS: In control dogs, LV end-diastolic volume (EDV) and LV end-systolic volume (ESV) increased (64+/-5 ml vs. 75+/-6 ml, P=0.003; 46+/-4 ml vs. 57+/-4 ml, P=0.003; respectively), and ejection fraction (EF) decreased (28+/-1% vs. 23+/-1%, P=0.001) over the course of 3 months of follow-up. In contrast, CCM-treated dogs showed a smaller increase in EDV (66+/-4 vs. 73+/-5 ml, P=0.01), no change in ESV, and an increase in EF from 31+/-1 to 34+/-2% (P=0.04) after 3 months of therapy. CONCLUSIONS: In dogs with HF, long-term CCM therapy prevents progressive LV dysfunction and attenuates global LV remodeling. These findings provide compelling rationale for exploring the use of CCM for the treatment of patients with chronic HF.

Hemodynamic unloading of the failing left ventricle using an arterial-to-arterial extracorporeal flow circuit.

We tested the hypothesis that creation of a constant-flow extracorporeal circuit between the proximal and distal aorta will unload the failing left ventricle. Studies were performed in 14 heart failure dogs produced by intracoronary microembolizations. An extracorporeal circuit incorporating a diagonal pump was placed between a femoral and a carotid artery, with flow directed to the carotid. Hemodynamic measurements were made with the pump delivering 0.25 L/min through the circuit for 4 hours (active group). Measurements obtained from 8 sham-operated heart failure dogs were used for comparison (control group). Heart rate, peak left ventricular systolic pressure, left ventricular end-diastolic pressure, end-diastolic volume, end-systolic volume, and ejection fraction were measured at baseline and at 30, 60, 120, and 240 minutes. There were no differences in any of the hemodynamic values during the 4 hours of follow-up in the control group. In the active group, there was no effect on heart rate or peak systolic pressure, but reductions between baseline and 240 minutes were observed in left ventricular end-diastolic pressure (15 +/- 1 vs 6 +/- 1 mm Hg, p < 0.05), end-diastolic volume (61 +/- 3 vs 50 +/- 3 mL, p < 0.05), and end-systolic volume (44 +/- 2 vs 32 +/- 2 mL, p < 0.05), and an increase in ejection fraction (28 +/- 2 vs 37% +/- 2%, p < 0.05). Acute use of this artery-to-artery extracorporeal system effectively unloads the failing left ventricle. The potential benefits of this approach on long-term myocardial recovery in heart failure require further investigation.

Reversal of chronic molecular and cellular abnormalities due to heart failure by passive mechanical ventricular containment.

Passive mechanical containment of failing left ventricle (LV) with the Acorn Cardiac Support Device (CSD) was shown to prevent progressive LV dilation in dogs with heart failure (HF) and increase ejection fraction. To examine possible mechanisms for improved LV function with the CSD, we examined the effect of CSD therapy on the expression of cardiac stretch response proteins, myocyte hypertrophy, sarcoplasmic reticulum Ca2+-ATPase activity and uptake, and mRNA gene expression for myosin heavy chain (MHC) isoforms. HF was produced in 12 dogs by intracoronary microembolization. Six dogs were implanted with the CSD and 6 served as concurrent controls. LV tissue from 6 normal dogs was used for comparison. Compared with normal dogs, untreated HF dogs showed reduced cardiomyocyte contraction and relaxation, upregulation of stretch response proteins (p21ras, c-fos, and p38 alpha/beta mitogen-activated protein kinase), increased myocyte hypertrophy, reduced SERCA2a activity with unchanged affinity for calcium, reduced proportion of mRNA gene expression for alpha-MHC, and increased proportion of beta-MHC. Therapy with the CSD was associated with improved cardiomyocyte contraction and relaxation, downregulation of stretch response proteins, attenuation of cardiomyocyte hypertrophy, increased affinity of the pump for calcium, and restoration of alpha- and beta-MHC isoforms ratio. The results suggest that preventing LV dilation and stretch with the CSD promotes downregulation of stretch response proteins, attenuates myocyte hypertrophy and improves SR calcium cycling. These data offer possible mechanisms for improvement of LV function after CSD therapy.

Hypoxia, angiotensin-II, and norepinephrine mediated apoptosis is stimulus specific in canine failed cardiomyocytes: a role for p38 MAPK, Fas-L and cyclin D1.

BACKGROUND: Apoptosis may contribute to the myocardial dysfunction associated with heart failure (HF). Activation of the p38 MAPK cascade can induce apoptosis in non-cardiac cells through increased expression of Fas-L, or through decreased expression of cyclin D(1). AIMS: We tested the hypothesis that hypoxia (HX), angiotensin-II (A-II) and norepinephrine (NEPI) can mediate apoptosis by activating p38 MAPK, and thus initiating stimulus specific changes in Fas-L and cyclin D(1) expression in failing cardiomyocytes. METHODS AND RESULTS: Cardiomyocytes isolated from ten dogs with HF induced by coronary microembolizations were subjected to HX or A-II or NEPI with and without a p38 MAPK inhibitor (SB 203580). TUNEL staining for DNA fragmentation and Western blots for p38 MAPK, Fas-L and cyclin D(1) detection were performed. HX-induced apoptosis was associated with increased Fas-L expression, A-II-induced apoptosis was associated with increased Fas-L and decreased cyclin D(1) expression, and NEPI-induced apoptosis was associated with decreased cyclin D(1) expression. Inhibition of p38 MAPK activity attenuated stress-induced apoptosis in all experiments and reversed changes in Fas-L and cyclin D(1) expression. CONCLUSIONS: HX, A-II and NEPI mediate apoptosis in failing cardiomyocytes via different effects on Fas-L and cyclin D(1) expression. Inhibition of p38 MAPK reversed these effects, suggesting that apoptosis induced by HX, A-II and NEPI involves activation of p38 MAPK upstream from Fas-L and cyclin D(1).

Cardiac contractility modulation with nonexcitatory electric signals improves left ventricular function in dogs with chronic heart failure.

BACKGROUND: Nonexcitatory electrical, signals termed cardiac contractility modulation (CCM) have been shown to improve contractile force of isolated papillary muscles. In this study, we examined the effects of CCM signal delivery on left ventricular function in dogs with chronic heart failure (HF). METHODS AND RESULTS: Chronic HF (ejection fraction

Effects of the AT1-receptor antagonist eprosartan on the progression of left ventricular dysfunction in dogs with heart failure.

1. We examined the effects of eprosartan, an AT(1) receptor antagonist, on the progression of left ventricular (LV) dysfunction and remodelling in dogs with heart failure (HF) produced by intracoronary microembolizations (LV ejection fraction, EF 30 to 40%). 2. Dogs were randomized to 3 months of oral therapy with low-dose eprosartan (600 mg once daily, n=8), high-dose eprosartan (1200 mg once daily, n=8), or placebo (n=8). 3. In the placebo group, LV end-diastolic (EDV) and end-systolic (ESV) volumes increased after 3 months (68+/-7 vs 82+/-9 ml, P<0.004, 43+/-1 vs 58+/-7 ml, P<0.003, respectively), and EF decreased (37+/-1 vs 29+/-1%, P<0.001). In dogs treated with low-dose eprosartan, EF, EDV, and ESV remained unchanged over the course of therapy, whereas in dogs treated with high-dose eprosartan, EF increased (38+/-1 vs 42+/-1%, P<0.004) and ESV decreased (41+/-1 vs 37+/-1 ml, P<0.006), Eprosartan also decreased interstitial fibrosis and cardiomyocyte hypertrophy. 4. We conclude that eprosartan prevents progressive LV dysfunction and attenuates progressive LV remodelling in dogs with moderate HF and may be useful in treating patients with chronic HF.

Effects of long-term monotherapy with eplerenone, a novel aldosterone blocker, on progression of left ventricular dysfunction and remodeling in dogs with heart failure.

BACKGROUND: In heart failure (HF), aldosterone has been implicated in the formation of reactive interstitial fibrosis, a maladaptation that contributes to left ventricular (LV) remodeling. Eplerenone is a novel selective aldosterone blocker. The present study examined the effects of long-term monotherapy with eplerenone on the progression of LV dysfunction and remodeling in dogs with chronic HF. METHODS AND RESULTS: HF was produced in 14 dogs by intracoronary microembolizations that were discontinued when LV ejection fraction (EF) was between 30% and 40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with eplerenone (10 mg/kg twice daily, n=7) or no therapy at all (control, n=7). Hemodynamic measurements were made just before randomization and were repeated at the end of 3 months of therapy. In control dogs, LV end-diastolic and end-systolic volume increased significantly (62+/-4 versus 68+/-4 mL, P<0.001, and 38+/-3 versus 47+/-3 mL, P<0.001, respectively), and EF decreased significantly (38+/-1% versus 31+/-2%, P<0.001). In contrast, end-diastolic volume, end-systolic volume, and EF remained unchanged during the 3 months of treatment in eplerenone-treated dogs. LV end-diastolic wall stress increased significantly in control dogs but decreased significantly in eplerenone-treated dogs. Compared with control, eplerenone was associated with a 28% reduction in cardiomyocyte cross-sectional area, a 37% reduction of volume fraction of reactive interstitial fibrosis, and a 34% reduction of volume fraction of replacement fibrosis. CONCLUSIONS: Our results indicate that long-term therapy with eplerenone prevents progressive LV dysfunction and attenuates LV remodeling in dogs with chronic HF.

Effects of chronic neutral endopeptidase inhibition on the progression of left ventricular dysfunction and remodeling in dogs with moderate heart failure.

BACKGROUND: The diuretic actions of endogenously produced atrial natriuretic factor (ANF) may be beneficial in the treatment of chronic heart failure (CHF). Neutral endopeptidase (NEP) is the primary enzyme responsible for the degradation of ANF. The present study investigates the effects of long-term NEP inhibition on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure. METHODS: LV dysfunction was produced in 12 dogs by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LV ejection fraction (EF) was between 30-40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with the NEP inhibitor ecadotril (100 mg, once daily, n = 6) or to no therapy at all (control, n = 6). RESULTS: During the 3 months of follow-up, LV EF in control dogs decreased from 37 +/- 1% to 28 +/- 1% (P < 0.01) and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased (EDV: 72 +/- 3 vs. 84 +/- 5 ml, P < 0.01); ESV: 45 +/- 1 vs. 60 +/- 4 ml, P < 0.01). In dogs treated with ecadotril, LV EF (34 +/- 1% vs. 37 +/- 2%), EDV (79+/- 5 vs. 78+/- 6 ml) and ESV (52 +/- 3 vs. 49 +/- 4) remained essentially unchanged after 3 months of therapy. Histomorphometric measurements at the termination of the study showed that ecadotril was associated with significantly reduced cardiomyocyte hypertrophy compared to control. CONCLUSION: Early, long-term NEP inhibition with ecadotril prevents the progression of LV dysfunction and attenuates progressive LV remodeling in dogs with moderate heart failure.

Prediction of functional recovery of the left ventricle after coronary revascularization in patients with prior anterior myocardial infarction: a myocardial integrated backscatter study.

Cyclic variation (CV) of myocardial integrated backscatter (IBS), which reflects intrinsic contractile performance, can predict myocardial viability in patients with a reperfused acute myocardial infarction (MI), but the use of this method has not been validated for chronic left ventricular (LV) dysfunction. The aim of this study was to examine whether myocardial IBS was useful for predicting LV functional recovery after coronary revascularization in 17 patients with prior anterior MI and LV dysfunction (ejection fraction <50%). Within 24 h of the revascularization procedure (percutaneous transluminal coronary angioplasty or coronary stenting), IBS curves were obtained by placing the region of interest on the anterior wall on the short-axis IBS image. The patients had repeat left heart catheterization at 3 or 6 months after the revascularization procedure, and were grouped according to the patterns of the IBS curve within the anterior wall. In 8 patients (group A), the IBS curve had a synchronized pattern with the magnitude of CV > or = 3.5, and in the remaining 9 patients (group B), the curve had either an asynchronized pattern or the magnitude of CV was less than 3.5 dB even in the case of synchronized pattern, or both. At baseline, there were no significant differences in LV functional indices between the 2 groups. After the follow-up period, the LV end-systolic volume decreased (75 +/- 21 ml to 56 +/- 20ml, p = 0.05), LV ejection fraction increased (35 +/- 12% to 50 +/- 14%, p = 0.014), and LV end-diastolic pressure decreased (19 +/- 10 mmHg to 13 +/- 6 mmHg, p = 0.02) in group A, whereas only the LV ejection fraction increased (34 +/- 9% to 40 +/- 11%, p = 0.03) in group B; LV end-systolic volume (72 +/- 19 ml to 66 +/- 16 ml, p = 0.126) and LV end-diastolic pressure (18 +/- 12 mmHg to 14 +/- 8 mmHg, p = 0.184) showed no significant changes. In conclusion, IBS is valuable for predicting LV functional recovery after coronary revascularization in patients with LV dysfunction caused by a remote anterior MI. A large-scale study is be needed to establish these data.

Short-term treatment with ranolazine improves mechanical efficiency in dogs with chronic heart failure.

The present study assesses whether ranolazine increases left ventricular (LV) function without an increase in myocardial oxygen consumption (MVO2) and thus improves LV mechanical efficiency in dogs with heart failure (HF). Ranolazine did not change MVO2 and LV mechanical efficiency increased (22.4+/-2.8% to 30.9+/-3.4% (P<0.05). In contrast, dobutamine significantly increased MVO2 and did not improve mechanical efficiency. Thus, short-term treatment with ranolazine improved LV function without an increase in MO2, resulting in an increased myocardial mechanical efficiency in dogs with HF.

Reverse remodeling and enhanced adrenergic reserve from passive external support in experimental dilated heart failure.

OBJECTIVES: We sought to test the efficacy of a passive elastic containment device to reverse chronic chamber remodeling and adrenergic down-regulation in the failing heart, yet still maintaining preload reserve. BACKGROUND: Progressive cardiac remodeling due to heart failure is thought to exacerbate underlying myocardial dysfunction. In a pressure-volume analysis, we tested the impact of limiting progressive cardiac dilation by an externally applied passive containment device on both basal and adrenergic-stimulated function in failing canine hearts. METHODS: Ischemic dilated cardiomyopathy was induced by repeated intracoronary microembolizations in six dogs. The animals were studied before and three to six months after surgical implantation of a thin polyester mesh (cardiac support device [CSD]) that surrounded both cardiac ventricles. Pressure-volume relations were measured by a conductance micromanometer catheter. RESULTS: Long-term use of the CSD lowered end-diastolic and end-systolic volumes by -19 +/- 4% and -22 +/- 8%, respectively (both p < 0.0001) and shifted the end-systolic pressure-volume relation to the left (p < 0.01), compatible with reverse remodeling. End-diastolic pressure and chamber diastolic stiffness did not significantly change. The systolic response to dobutamine markedly improved after CSD implantation (55 +/- 8% rise in ejection fraction after CSD vs. -10 +/- 8% before CSD, p < 0.05), in conjunction with a heightened adenylyl cyclase response to isoproterenol. There was no change in the density or affinity of beta-adrenergic receptors. Diastolic compliance was not adversely affected, and preload-recruitable function was preserved with the CSD, consistent with a lack of constriction. CONCLUSIONS: Reverse remodeling with reduced systolic wall stress and improved adrenergic signaling can be achieved by passive external support that does not generate diastolic constriction. This approach may prove useful in the treatment of chronic heart failure.

Hemostatic alterations associated with supraceliac aortic cross-clamping.

PURPOSE: The causative role of consumptive coagulopathy in the development of bleeding complications after supraceliac (SC) aortic cross-clamping (AXC) has been challenged by recent reports that ascribe this coagulopathy to primary fibrinolysis. This theory is made on the basis of evidence that tissue plasminogen activator (t-PA) antigen (Ag) levels increase after SC AXC. However, t-PA Ag levels reflect both active and inactive (bound to serum t-PA inhibitors) forms of serum t-PA, and elevations confirm the presence of fibrinolysis only in conjunction with an increase in t-PA activity. METHODS: To investigate the etiology of this coagulopathy, we submitted eight pigs to SC AXC and six pigs to infrarenal (IR) AXC for 30 minutes. Blood was drawn from the portal vein, the hepatic vein, and the carotid artery before AXC, just before unclamping, and 5, 30, and 60 minutes after unclamping. Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen (FBG), platelets (PLT), thrombin-antithrombin complexes (TAT), t-PA Ag, t-PA activity, plasminogen activator inhibitor-1 (PAI-1), and alpha2-antiplasmin (AP) activities were measured. Statistical analysis was performed by using repeated measures analysis of variance and t tests RESULTS: The PT did not differ between the two groups at any point. After unclamping, in the SC group there was a drop in PLT levels (P =.005), a decrease in FBG levels (P <.001), and a trend toward PTT prolongation (P =.06) compared with baseline. In contrast, there were no changes in PTT, PLT levels, or FBG levels in the IR group. TAT, a serum marker of thrombin generation, increased with SC AXC (P =.04), remained elevated 5 minutes after unclamping (P =.08), and returned to normal 30 minutes after unclamping. In contrast, TAT levels did not change in the IR control group. In the SC AXC group, the TAT levels did not differ between the three test sites at any time. SC AXC was associated with an increase in t-PA Ag just before unclamping (P <.001) and 5 minutes after unclamping (P =.002), but IR AXC was not. t-PA activity levels decreased in both experimental groups 30 and 60 minutes after unclamping. Levels of alpha2-AP activity decreased to a similar degree in both groups after unclamping when compared with baseline CONCLUSION: Thirty minutes of SC AXC results in intravascular thrombosis that cannot be localized to the ischemic visceral circulation. This intravascular thrombosis is associated with consumption of clotting factors. Thirty minutes of SC AXC causes an activation of fibrinolytic pathways that does not result in a hyperfibrinolytic state. An increase in t-PA Ag without a rise in t-PA activity does not represent true fibrinolysis, but rather an increase in the bound, inactive forms of serum t-PA. Both IR and SC AXC result in decreased fibrinolytic activity ("fibrinolytic shutdown") after release of the aortic clamp.