Resting and exercise haemodynamic characteristics of patients with advanced heart failure and preserved ejection fraction.

AIMS: This study aimed to describe haemodynamic features of patients with advanced heart failure with preserved ejection fraction (HFpEF) as defined by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). METHODS AND RESULTS: We used pooled data from two dedicated HFpEF studies with invasive exercise haemodynamic protocols, the REDUCE LAP-HF (Reduce Elevated Left Atrial Pressure in Patients with Heart Failure) trial and the REDUCE LAP-HF I trial, and categorized patients according to advanced heart failure (AdHF) criteria. The well-characterized HFpEF patients were considered advanced if they had persistent New York Heart Association classification of III-IV and heart failure (HF) hospitalization < 12 months and a 6 min walk test distance < 300 m. Twenty-four (22%) out of 108 patients met the AdHF criteria. On evaluation, clinical characteristics and resting haemodynamics were not different in the two groups. Patients with AdHF had lower work capacity compared with non-advanced patients (35 ± 16 vs. 45 ± 18 W, P = 0.021). Workload-corrected pulmonary capillary wedge pressure normalized to body weight (PCWL) was higher in AdHF patients compared with non-advanced (112 ± 55 vs. 86 ± 49 mmHg/W/kg, P = 0.04). Further, AdHF patients had a smaller increase in cardiac index during exercise (1.1 ± 0.7 vs. 1.6 ± 0.9 L/min/m2 , P = 0.028). CONCLUSIONS: A significantly higher PCWL and lower cardiac index reserve during exercise were observed in AdHF patients compared with non-advanced. These differences were not apparent at rest. Therapies targeting the haemodynamic compromise associated with advanced HFpEF are needed.

Clinical effects of long-term cardiac contractility modulation (CCM) in subjects with heart failure caused by left ventricular systolic dysfunction.

INTRODUCTION: Heart failure is a major cause of morbidity and mortality throughout the world. Despite advances in therapy, nearly half of patients receiving guideline-directed medical therapy remain limited by symptoms. Cardiac contractility modulation (CCM) can improve symptoms in this population, but efficacy and safety in prospective studies has been limited to 12 months of follow-up. We report on the first 2 year multi-site evaluation of CCM in patients with heart failure. METHODS: One hundred and forty-three subjects with heart failure and reduced ejection fraction were followed via clinical registry for 24 months recording NYHA class, MLWHFQ score, 6 min walk distance, LVEF, and peak VO2 at baseline and 6 month intervals as clinically indicated. Serious adverse events, and all cause as well as cardiovascular mortality were recorded. Data are presented stratified by LVEF (all subjects, LVEF <35%, LVEF ≥35%). RESULTS: One hundred and six subjects from 24 sites completed the 24 month follow-up. Baseline parameters were similar among LVEF groups. NYHA and MLWHFQ improved in all 3 groups at each time point. LVEF in the entire cohort improved 2.5, 2.9, 5.0, and 4.9% at 6, 12, 18, and 24 months, respectively. Insufficient numbers of subjects had follow-up data for 6 min walk or peak VO2 assessment, precluding comparative analysis. Serious adverse events (n = 193) were observed in 91 subjects and similarly distributed between groups with LVEF <35% and LVEF ≥35%, and similar to other device trials for heart failure. Eighteen deaths (7 cardiovascularly related) over 2 years. Overall survival at 2 years was 86.4% (95% confidence intervals: 79.3, 91.2%). CONCLUSION: Cardiac contractility modulation provides safe and effective long-term symptomatic and functional improvement in heart failure. These benefits were independent of baseline LVEF and were associated with a safety profile similar to published device trials.

Partial mechanical long-term support with the CircuLite Synergy pump as bridge-to-transplant in congestive heart failure.

BACKGROUND: Full mechanical support with a left ventricular assist device (LVAD) is often limited to very sick patients, as the only survival option. This European multicenter study analyzes the effect of partial mechanical support as bridge-to-transplant in a less sick heart failure patient group. METHODS: The CircuLite Synergy device is implanted via a small right-sided thoracotomy with an inflow cannula in the left atrium and an outflow graft connected to the right subclavian artery without the use of extracorporeal circulation. The pump itself sits in a "pacemaker" pocket subcutaneously in the right clavicular groove. It is able to pump up to 3.0 l/min and partially unload the left ventricle. RESULTS: The device was implanted in 25 patients on the cardiac transplant waiting list (20 males), aged 55.5 +/- 9.6 yrs with an ejection fraction of 21.6 +/- 6.0 %, a mean arterial pressure of 73.5 +/- 8.5 mmHg, a pulmonary capillary wedge pressure of 27.2 +/- 7.8 mmHg and cardiac index of 1.9 +/- 0.4 l/min/m (2). Duration of support ranged from 6 to 238 days. Right heart catheterization showed significant hemodynamic improvement in the short- and intermediate-term after implantation with increases in arterial pressure from 72.6 +/- 11.0 to 79.4 +/- 8.6 mmHg ( P = 0.04) and in cardiac index from 2.0 +/- 0.4 to 2.7 +/- 0.6 l/min/m (2) ( P = 0.003) with a reduction in pulmonary capillary wedge pressure from 28.5 +/- 6.0 to 19.7 +/- 6.9 mmHg ( P = 0.012). CONCLUSIONS: The CircuLite Synergy device is a partial support pump, which is easy to implant and which provides hemodynamic benefits in bridging heart failure patients to cardiac transplant.

beta-adrenergic receptor blockers restore cardiac calcium release channel (ryanodine receptor) structure and function in heart failure.

BACKGROUND: beta-Adrenergic receptor blockade is one of the most effective treatments for heart failure, a leading cause of mortality worldwide. The use of beta-adrenergic receptor blockers in patients with heart failure is counterintuitive, however, because they are known to decrease contractility in normal hearts. The ryanodine receptor (RyR2) on cardiac sarcoplasmic reticulum is the key calcium release channel required for excitation-contraction coupling. In failing hearts, the stoichiometry and function of the RyR2 macromolecular complex is altered. Decreased levels of phosphatases (PP1 and PP2A) and hyperphosphorylation by protein kinase A result in dissociation of the regulatory protein FKBP12.6 and channels with increased open probability. METHODS AND RESULTS: Here, we show that systemic oral administration of a beta-adrenergic receptor blocker reverses protein kinase A hyperphosphorylation of RyR2, restores the stoichiometry of the RyR2 macromolecular complex, and normalizes single-channel function in a canine model of heart failure. CONCLUSIONS: These results may, in part, explain the improved cardiac function observed in heart failure patients treated with beta-adrenergic receptor blockers.

Assessment of left ventricular systolic function using contrast two-dimensional echocardiography with a high-frequency transducer in the awake murine model of myocardial infarction.

The estimation of global left ventricular function using M-mode echocardiography has technical limitations in the murine model of myocardial infarction (MI), but the recent improvements in 2-dimensional (2-D) echocardiography using a high-frequency transducer provide more accessible images. Furthermore, intravenous injection of contrast agent has the additional benefit of enhancing the endocardial border in the murine heart. The present study was designed to evaluate the value of 2-D echocardiography with intravenous injection of contrast agent in the assessment of global systolic function of the murine heart with MI. Two-dimensional and M-mode echocardiography without and with intravenous injection of contrast agent (Optison, 0.1-0.15 ml) were performed in 76 awake mice 2 days before and 2 days after left coronary artery ligation. Fractional shortening (FS) was calculated from the end-diastolic and end-systolic diameters on M-mode echocardiography, and fractional area change (FAC) from the end-diastolic and end-systolic areas on 2-D echocardiography. Both FS and FAC were compared with the areas of hypoperfusion observed in the pathological samples. The use of contrast agent improved the number of hearts that could be evaluated by both the M-mode and 2-D method (M-mode: non-contrast 87% vs contrast 99%, p<0.01; 2-D: non-contrast 26% vs contrast 89%, p<0.001). FAC from the 2-D method correlated better with the region of hypoperfusion in the pathological samples than did FS from the M-mode method (FAC: r=0.84 vs FS: r=0.51). In conclusion, FAC obtained from 2-D contrast echocardiography is useful for noninvasive assessment of global systolic function in infarcted murine hearts and can be used to serially assess systolic function in various models of the murine heart.

Left ventricular volume reduction surgery for heart failure: a physiologic perspective.

BACKGROUND: Ventricular volume reduction surgery for idiopathic cardiomyopathy fails to improve cardiac output and is associated with a high incidence of recurrent heart failure. Volume reduction surgery achieved by removing akinetic or dyskinetic myocardium after myocardial infarction appears to be associated with better outcomes. The reasons for the differences in outcomes are not clear. METHODS AND RESULTS: The hemodynamic effect of the major forms of volume reduction surgery were predicted by using a composite model of the left ventricle in which 20% of the myocardium was given properties of either weak but contracting muscle, an akinetic scar, or a dyskinetic scar (aneurysm). The end-systolic and end-diastolic pressure-volume relationships were determined numerically for each simulated operation. Any volume reduction procedure reduced chamber size, shifting end-systolic and end-diastolic pressure-volume relationships leftward. With resection of weak but contracting muscle, the leftward shift was greater for the end-diastolic than for the end-systolic pressure-volume relationship. Conversely, with resection of dyskinetic scar, the leftward shift was greater for end-systolic than for end-diastolic pressure-volume relationships. In contrast, resection of stiff scar shifted the 2 relationships equally. The effect on overall pump function was indexed by the relationship between total ventricular mechanical work and end-diastolic pressure. There was a beneficial effect on this relationship of resecting dyskinetic tissue, an equivocal effect of akinetic scar resection, and a negative effect of removing contracting myocardium. CONCLUSIONS: The effect of volume reduction surgery on overall ventricular pumping characteristics is determined by the differential effects on end-systolic and end-diastolic properties, which in turn are determined by the material properties of the region being removed.

A growth factor mixture that significantly enhances angiogenesis in vivo.

Studies of therapeutic angiogenesis have generally focused on single growth factor strategies. However, multiple factors participate in angiogenesis. We evaluated the angiogenic potential of a growth factor mixture (GFm) derived from bovine bone. The major components of GFm (SDS-polyacrylamide gel electrophoresis, mass spectrometry, and Western blot) include transforming growth factor-beta1-3, bone morphogenic protein-2-7, and fibroblast growth factor-1. GFm was first shown to induce an angiogenic response in chorioallantoic membranes. Next, myocardial ischemia was induced in 21 dogs (ameroid) that were randomized 3 weeks later to received GFm 1 mg/ml (I), GFm 10 mg/ml (II), or placebo (P) (with investigators blinded to conditions) injected in and adjacent to ischemic myocardium. Dogs were assessed 6 weeks later using quantitative and semiquantitative measures. There were GFm concentration-dependent improvements in distal left anterior descending artery (LAD) opacification by angiography (P: 0.4 +/- 0.2, I: 1.1 +/- 0.14, II: 1.6 +/- 0.3, angiographic score p = 0.014). Histologically, there was also concentration-dependent vascular growth response of relatively large vessels (P: 0.21 +/- 0.15, I: 1.00 +/- 0.22, II: 1.71 +/- 0.18, vascular growth score p = 0.001). Resting myocardial blood flow (colored microspheres) was not significantly impaired in any group. However, maximum blood flow (adenosine) was reduced in ischemic territories and did not improve in GFm-treated hearts. GFm, a multiple growth factor mixture, is a potent angiogenic agent that stimulates large vessel growth. Although blood flow did not improve during maximal vasodilatory stress, large intramyocardial collateral vessels developed and angiographic visualization of the occluded distal LAD improved significantly. The use of multiple growth factors may be an effective strategy for therapeutic angiogenesis provided a more effective delivery strategy is devised that can achieve improved maximum blood flow potential.

Variability of myocardial perfusion defects assessed by thallium-201 scintigraphy in patients with coronary artery disease not amenable to angioplasty or bypass surgery.

OBJECTIVES: We sought to assess the variability of results obtained with thallium scintigraphy as a method for tracking the extent of myocardial ischemia in medically refractory patients with angina who are not suitable for coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty. BACKGROUND: New therapies are being evaluated for patients with "no option" angina in whom medical therapy has failed. Nuclear techniques, like thallium scintigraphy, are used in multicenter trials to evaluate whether such therapies improve myocardial perfusion. However, the variability of test results is unknown in this patient group in a multicenter study. METHODS: The Angina Treatments: Lasers And Normal Therapies In Comparison (ATLANTIC) study was a randomized trial of transmyocardial laser revascularization (n = 182). Patients underwent dipyridamole thallium stress tests at baseline and 3, 6 and 12 months after enrollment. The control group (n = 90) was treated with constant medical therapy during the study and is a relevant group to investigate test variability. Test variability over time was quantified by the mean absolute change in the percentage of reversible perfusion defects between baseline and follow-up. RESULTS: Baseline percent myocardium with ischemia averaged 17.0 +/- 13.7% and did not change during follow-up. However, variations in the percent myocardium with reversible perfusion defects over time amounted to an average of 6 to 8 percentage points, or 43% to 55% of the baseline value. Only approximately 13% of this variability was attributable to variability in image reconstruction and analysis. CONCLUSIONS: As demonstrated in the ATLANTIC study, percent myocardial ischemia in control subjects receiving constant medical therapy varied in individual patients by an average of approximately 50%. This may limit the utility of thallium scintigraphy to detect improved myocardial perfusion over time in response to therapy.

Normalized diastolic properties after left ventricular assist result from reverse remodeling of chamber geometry.

BACKGROUND: Normalization of diastolic properties after left ventricular (LV) assist may result from a change in myocardial material properties, chamber size, or both. This study tested the hypothesis that reported normalization of LV diastolic properties is primarily due to remodeling of chamber geometry. METHODS AND RESULTS: Hearts were obtained at transplantation from 8 patients with dilated cardiomyopathy (DCM), 6 patients with DCM plus 33+/-5 days of LV assist, and 3 patients with no evidence of heart failure. LV assist normalized passive pressure-volume curves. Chamber dimensions decreased without a change in the ratio of radius to wall thickness. Midwall stress-stretch relations predicted from pressure-volume and dimension data were not different for DCM and LV assist hearts. Passive stress-stretch relations were measured in endocardial trabeculae and were not different for DCM and LV assist hearts. Myocyte size and collagen area fraction were unchanged at this brief duration of support. CONCLUSIONS: These findings are all consistent with the hypothesis that early normalization of diastolic properties after LV assist device support results from remodeling of chamber geometry, not from changes in tissue stiffness. These data emphasize the importance of geometry to ventricular mechanics and demonstrate that reduction of heart size does not necessarily produce a reduction in wall stress.

Selective renal vasodilation and active renal artery perfusion improve renal function in dogs with acute heart failure.

Renal failure is common in heart failure due to renovascular constriction and hypotension. We tested whether selective pharmacological renal artery vasodilation and active renal artery perfusion (ARP) could improve renal function without adverse effects on systemic blood pressure in a canine model of acute heart failure (AHF). AHF was induced by coronary microembolization in 16 adult mongrel dogs. In five dogs, selective intrarenal (IR) papaverine (1, 2, and 4 mg/min) was administered into the left renal artery. In six dogs, ARP was performed in the left renal artery to normalize mean renal arterial pressure followed by administration of IR papaverine (2 mg/min). In five dogs, ARP plus intravenous furosemide was tested. Urine output (UO) and cortical renal blood flow decreased during AHF and were restored by 2 mg/min IR papaverine (UO: baseline 4.2 +/- 0.6, AHF 1.6 +/- 1.3, IR papaverine 5.8 +/- 1.1 ml/15 min; cortical blood flow: baseline 4.3 +/- 0.2, AHF 2.4 +/- 0.6, IR papaverine 4.2 +/- 1.2 ml/min/g) with no significant change in aortic pressure. ARP also increased urine output and cortical renal blood flow (UO: baseline 5.0 +/- 1.1, AHF 0.5 +/- 0.4, ARP 3.8 +/- 3.1 ml/15 min; cortical blood flow: baseline 4.0 +/- 0.5, AHF 2.0 +/- 0.8, ARP 3.52 +/- 1.1 ml/min/g). A combination of these methods in AHF further increased urine output to twice the normal baseline (10.5 +/- 7.5 ml/15 min). Addition of furosemide synergistically increased UO above that achieved with ARP alone (5.5 +/- 2.6 versus 40.3 +/- 24.7 ml/15 min, p = 0.03). In conclusion, ARP and selective renal vasodilation may effectively promote salt and water excretion in the setting of heart failure, particularly when systemic blood pressure is low.

Comparison of right and left ventricular responses to left ventricular assist device support in patients with severe heart failure: a primary role of mechanical unloading underlying reverse remodeling.

BACKGROUND: Left ventricular assist devices (LVAD) reverse ventricular, myocardial, and systemic abnormalities characteristic of severe heart failure (reverse remodeling). The relative contributions of hemodynamic unloading and normalized biochemical milieu to reverse remodeling are unknown. METHODS AND RESULTS: Structural and functional characteristics were measured from 53 hearts of patients undergoing transplantation without LVAD support (medical support) and 33 hearts from patients receiving a median of 46 days of LVAD support (range, 8 to 360 days). Compared with medical support alone, patients receiving LVAD support for >/=30 days had higher central venous pressures (11+/-6 versus 8+/-5 mm Hg, P=0.04), lower pulmonary artery diastolic pressures (14+/-9 versus 21+/-9 mm Hg, P=0.01), and higher cardiac outputs (5.1+/-1.6 versus 3.7+/-1.0 L/min, P<0.001). In LVAD versus transplantation hearts, V(30) (ex vivo volume yielding ventricular pressure of 30 mm Hg) was decreased in the left ventricle (LV) (179+/-75 versus 261+/-118 mL, P=0.005) but not in the right ventricle (RV) (140+/-59 versus 148+/-52 mL, P=NS). LV myocyte diameter decreased more significantly after LVAD support (17%, P=0.05) than in the RV (11%, P=NS). Compared with transplantation, LVAD support increased normalized SERCA2a content in the LV (0.51+/-0.26 versus 1.04+/-0.34, P<0.001) but not in the RV (0.48+/-34 versus 0.67+/-0.55, P=NS). Finally, LVAD support improved force-frequency relations of isolated superfused LV trabeculae (P=0.01) but not RV trabeculae. CONCLUSIONS: Reduction of hemodynamic load is a primary factor underlying several important features of reverse remodeling. These findings do not preclude a possible primary role of neurohormonal factors underlying other facets of reverse remodeling during LVAD support.

Mechanoelectrical feedback: role of beta-adrenergic receptor activation in mediating load-dependent shortening of ventricular action potential and refractoriness.

BACKGROUND: Augmented preload increases myocardial excitability by shortening action potential duration (APD). The mechanism governing this phenomenon is unknown. Because myocardial stretch increases intracellular cAMP, we hypothesized that load-dependent changes in myocardial excitability are mediated by beta-adrenergic stimulation of a cAMP-sensitive K(+) current. METHODS AND RESULTS: The effects of propranolol on load-induced changes in electrical excitability were studied in 7 isolated ejecting canine hearts. LV monophasic APD at 50% and 90% repolarization (MAPD(50) and MAPD(90)) and refractoriness were determined at low (9+/-3 mL) and high (39+/-4 mL) load before and after beta-adrenergic blockade. During control, the MAPD(50) decreased from 193+/-26 to 184+/-26 ms with increased load, as did the MAPD(90) (238+/-28 to 233+/-28 ms), P

Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function.

Left ventricular remodeling is a major cause of progressive heart failure and death after myocardial infarction. Although neoangiogenesis within the infarcted tissue is an integral component of the remodeling process, the capillary network is unable to support the greater demands of the hypertrophied myocardium, resulting in progressive loss of viable tissue, infarct extension and fibrous replacement. Here we show that bone marrow from adult humans contains endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts, and that these can be used to directly induce new blood vessel formation in the infarct-bed (vasculogenesis) and proliferation of preexisting vasculature (angiogenesis) after experimental myocardial infarction. The neoangiogenesis resulted in decreased apoptosis of hypertrophied myocytes in the peri-infarct region, long-term salvage and survival of viable myocardium, reduction in collagen deposition and sustained improvement in cardiac function. The use of cytokine-mobilized autologous human bone-marrow-derived angioblasts for revascularization of infarcted myocardium (alone or in conjunction with currently used therapies) has the potential to significantly reduce morbidity and mortality associated with left ventricular remodeling.

Time course of reverse remodeling of the left ventricle during support with a left ventricular assist device.

BACKGROUND: Support with a left ventricular assist device leads to normalization of left ventricular chamber geometry, regression of myocyte hypertrophy, alterations in left ventricular collagen content, and normalized expression of genes involved with excitation-contraction coupling in patients with heart failure. The objective of this study was to investigate the time course of these processes. METHODS: Passive left ventricular pressure-volume relationships were obtained from explanted hearts of 19 patients with heart failure undergoing transplantation without left ventricular assist device support, 25 patients with heart failure supported before transplantation (duration of support ranging between 8 and 155 days), and 5 normal human hearts not suitable for transplantation. Left ventricular size was indexed by the volume at which left ventricular pressure reached 30 mm Hg. Left ventricular tissue samples were probed for sarcoplasmic endoreticular calcium adenosine triphosphatase 2a expression and processed for analysis of myocyte diameter and relative myocardial collagen content. RESULTS: The volume at which left ventricular pressure reached 30 mm Hg was not significantly different between hearts without and with assist device support for less than 40 days. However, the volume at which left ventricular pressure reached 30 mm Hg in patients with assist devices supported for more than 40 days was significantly smaller than that of the hearts without assist devices but was larger than that of normal hearts. A similar pattern was observed for myocyte diameter. Sarcoplasmic endoreticular calcium adenosine triphosphatase 2a expression increased to normal levels by about 20 days of support with an assist device. Relative collagen content was significantly increased in hearts supported for more than 40 days. CONCLUSION: Maximum structural reverse remodeling by left ventricular assist devices is complete by about 40 days. Molecular reverse remodeling of sarcoplasmic endoreticular calcium adenosine triphosphatase 2a expression is quicker, being complete by about 20 days.

Anesthetic inhibition in ischemic and nonischemic murine heart: comparison with conscious echocardiographic approach.

It is well known that the level of anesthesia obtained by intraperitoneal injection is variable and may alter cardiac function. In this study, we compared the effects of different anesthetics on cardiac function with the conscious state using high-resolution two-dimensional echocardiography in nonischemic and ischemic mice. Eighty-four mice were tested before and after surgery with ligation of the coronary artery. All 84 mice were studied in the conscious state and under high-dose intraperitoneal anesthesia. Twenty-two of 84 mice were studied under low-dose intraperitoneal anesthesia. Another 22 mice were also studied under gas anesthesia and spontaneous breathing. Experiments in the conscious state were performed by two investigators before the administration of anesthesia: one investigator held the animal and the transducer and the other operated the ultrasound equipment. Left ventricular systolic function was measured, and measurements obtained after surgery were compared with infarcted areas assessed by histological staining. Results showed that both high- and low-dose intraperitoneal anesthesia significantly reduced heart rates and left ventricular contractility in both pre- and postsurgical mice as opposed to conscious mice (P < 0.01). There were significantly higher correlation coefficients between mean fractional area change (FAC) and infarcted area in conscious state compared with high-dose intraperitoneal anesthesia (P < 0.05). The correlation coefficient between FAC and infarcted area during gas anesthesia was also significantly higher compared with high-dose intraperitoneal anesthesia (P < 0.05). In conclusion, conscious experiments or the use of gas anesthesia is preferred for echocardiographic assessment of cardiac function in mice because intraperitoneal injection significantly induces a significant reduction in heart rate and left ventricular systolic function.

Assessment of segmental wall motion abnormalities using contrast two-dimensional echocardiography in awake mice.

Murine models of cardiac disease are becoming an important tool for studying pathophysiological processes. Development of methods to accurately assess ventricular function are therefore important. The purpose of this study was to evaluate the feasibility of echocardiographic assessment of segmental wall motion abnormalities in a murine model of myocardial infarction. Two-dimensional contrast (C+) and noncontrast (C-) echocardiography were performed in 76 awake mice 2 days before and 2 days after left coronary ligation. The short-axis images obtained with two-dimensional echocardiography and corresponding postmortem cross-sectional histological samples stained with Evans blue dye were each divided into 16 segments, and all matched segments were examined for correlation between wall motion abnormalities and myocardial hypoperfusion. With the use of contrast enhancement, the number of visualized segments was significantly increased (base: C- 86%, C+ 98%; midpapillary: C- 57%, C+ 89%; apex: C- 30%, C+ 74%). Agreement between echocardiographically assessed regional wall motion abnormalities and pathologically determined hypoperfusion in basal, midpapillary, and apical levels were 90%, 93%, and 93%, respectively. Agreement between echocardiographically normal wall motion and pathologically normal findings in basal, midpapillary, and apical levels were 99%, 88%, and 71%, respectively. Thus echocardiographic assessment of segmental wall motion in awake mice was feasible and the accuracy was improved with the use of a contrast agent.

Direct coronary artery perfusion from the left ventricle.

OBJECTIVES: Trends in coronary bypass surgery require less invasive techniques and more conduits. We investigated the ability of direct coronary perfusion from the left ventricle to support regional and global cardiac function. METHODS: A conduit was established between the left ventricle and left anterior descending coronary artery (n = 6) with an interposed Starling resistor that allowed for graded regulation of backward flow. Changes of coronary flow, regional function in the territory of the left anterior descending coronary artery, and reactive hyperemia were studied. In 3 separate dogs, functional tolerance to increased heart rate was tested. In another 3 dogs, left ventricle-left anterior descending and left ventricle-left circumflex coronary artery conduits were established simultaneously (double conduit), and global function was tested. RESULTS: Without flow regulation, flow through the left ventricle-left anterior descending conduit exhibited high peaking (102 +/- 35 mL/min), midsystolic forward flow, and large pandiastolic backward flow (peaking at -47 +/- 22 mL/min). Mean coronary flow and regional function were maintained at 46.0% +/- 7.1% (35.8%-54.2%) and 45.3% +/- 29.1% (-1.8%-74.2%) of their respective normal values. When the Starling resistor was used to regulate backward flow, these values increased to 70.8% +/- 12.5% (56.8%-90.4%) and 70.2% +/- 27.8% (23.6%-107.7%), respectively. Coronary and functional reserve with a left ventricle-left anterior descending conduit were not observed. With the double conduit, global ventricular contractility indexed by end-systolic pressure-volume relation averaged 46% +/- 35% of its normal value. CONCLUSIONS: A left ventricle-coronary artery conduit supplied approximately 45% of normal blood flow and regional function, and both were improved by regulation of backward flow. Therefore, a conduit from the left ventricle to an epicardial vessel could serve as a rapidly deployable means of revascularizing totally occluded coronary vessels for which suitable natural conduits are not available.

Fluorescence changes on contractile activation in TnC(DANZ) labeled skinned rabbit psoas fibers.

The increase in fluorescence of dansylaziridine (DANZ) labeled troponin C (TnC(DANZ) substituted into skinned rabbit psoas fibers was determined as a function of the pCa. The fluorescence data are expressed as the ratio of two wavelength bands, one that sees the fluorescence of TnC(DANZ), and one that sees background fluorescence and scatter. The percent TnC replaced with TnC(DANZ) was varied between 10 and 50% and, the fibers were randomly stretched, at the start of each experiment, between 10 and 50%. A large ratio increase accompanies increase in [Ca2+]. The pCa/force data are best fit by the Hill equation but the pCa/ratio data are best fit by a model in which Ca2+ binds in two phases. The position of the force curve on the pCa axis varies little between fibers, in contrast to that of the ratio or A-fluorescence curve. In accord with previous reports the delta-fluorescence can be left of the force on the pCa axis (type I) or superimpose in part on the force (type II). Not described previously, we find curves in which the second phase of the ratio cross-over the pCa/force curve. This type III relationship is found only in fibers less than 3 weeks postmuscle harvest. We propose that the first, relatively invariant, phase of the biphasic pCa/ratio curve accompanies Ca2+ binding to either of the two low affinity sites on TnC(DANZ) as it does for TnC in solution. The second, highly cooperative, phase of the ratio curve that accompanies muscle contraction and enhanced Ca2+ binding is initiated when sufficient Ca2+ is bound to overcome inhibitory systems. Loose coupling between the initial Ca2+ binding and the cooperative switch point may account for much of the variation in the shape and position of the pCa/ratio curve. There is evidence that, in the overlap zone, weakly attached myosin cross-bridges enhance cooperation between the regulatory units of the thin filaments.