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.

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.

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.

Mechanoelectrical feedback: independent role of preload and contractility in modulation of canine ventricular excitability.

Mechanoelectrical feedback, defined as changes in mechanical state that precede and alter transmembrane potential, may have potential importance in understanding the role of altered load and contractility in the initiation and modulation of ventricular arrhythmias. To assess the independent effects of preload and contractility on myocardial excitability and action potential duration, we determined the stimulus strength-interval relationship and recorded monophasic action potentials in isolated canine left ventricles contracting isovolumically. The strength-interval relationship was characterized by three parameters: threshold excitability, relative refractory period, and absolute refractory period. The effects of a threefold increase in left ventricular volume or twofold increase in contractility on these parameters were independently assessed. An increase in preload did not change threshold excitability in 11 ventricles but significantly shortened the absolute refractory period from 205 +/- 15 to 191 +/- 14 ms (P less than 0.001) (mean +/- SD). Similarly, the relative refractory period decreased from 220 +/- 18 to 208 +/- 19 ms (P less than 0.002). Comparable results were observed when contractility was increased as a result of dobutamine infusion in 10 ventricles. That is, threshold excitability was unchanged but the absolute refractory period decreased from 206 +/- 14 to 181 +/- 9 ms (P less than 0.003), and the relative refractory period decreased from 225 +/- 17 to 205 +/- 18 ms (P less than 0.003). Similar results were obtained when contractility was increased with CaCl2, indicating that contractility associated changes were independent of beta-adrenergic receptor stimulation. An increase in preload or contractility was associated with shortening of the action potential. A threefold increase in preload and twofold increase in contractility were associated with a decrease in action potential duration of 22 and 24 ms, respectively. There was a significant linear correlation between action potential duration and excitability (absolute refractory period). The similar effects of increased preload and contractility on threshold excitability and refractoriness can be explained by the action these perturbations have on the time course of repolarization. Therefore, excitability of the ventricle is sensitive to and is modulated by alteration of load or inotropic state. The similar effects of either increased preload or contractility on excitability may be mediated by a common cellular mechanism which results in a rise in intracellular free Ca2+ and secondary abbreviation of the action potential.

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.

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

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.

Hemodynamic effects of direct biventricular compression studied in isovolumic and ejecting isolated canine hearts.

BACKGROUND: Biventricular direct cardiac compression (DCC) can potentially support the failing heart without the complications associated with a blood/device interface. The effect of uniform DCC on left and right ventricular performance was evaluated in 7 isolated canine heart preparations. METHODS AND RESULTS: A computer-controlled afterload system either constrained the isolated heart to contract isovolumically or simulated hemodynamic properties of physiological ejection. Biventricular DCC was provided by a chamber surrounding the heart that allowed adjustment of the compression pressure, onset time, and duration. Through a series of ventricular preloads, the effect of DCC on the end-systolic pressure-volume relationship (ESPVR) was evaluated under isovolumic and ejecting conditions. Under both conditions, DCC shifted the ESPVR of the left and right ventricles upward by an amount approximately equal to the compression pressure. The augmentation of end-systolic pressure for each initial preload tested, however, was less under ejecting conditions, because reductions in end-systolic and end-diastolic volumes occurred with ejection. Nevertheless, the net effect was to increase stroke volume. Measurement of M&f1;O2 demonstrated that at a given ventricular volume, M&f1;O2 did not change with DCC; however, peak ventricular pressure increased substantially, so that the effective pressure-volume area increased. CONCLUSIONS: Biventricular DCC can augment end-systolic pressure with no added costs of M&f1;O2. Under ejecting conditions, this augmentation of ventricular contracting ability manifests as increases in stroke volume. Thus, DCC represents a feasible alternative form of ventricular assist, and devices that support the heart in this manner should be further explored.

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.

Chronic unloading by left ventricular assist device reverses contractile dysfunction and alters gene expression in end-stage heart failure.

BACKGROUND: Left ventricular (LV) assist devices (LVADs) can improve contractile strength and normalize characteristics of the Ca(2+) transient in myocytes isolated from failing human hearts. The purpose of the present study was to determine whether LVAD support also improves contractile strength at different frequencies of contraction (the force-frequency relationship [FFR]) of intact myocardium and alters the expression of genes encoding for proteins involved in Ca(2+) handling. METHODS AND RESULTS: The isometric FFRs of LV trabeculae isolated from 15 patients with end-stage heart failure were compared with those of 7 LVAD-supported patients and demonstrated improved contractile force at 1-Hz stimulation, with reversal of a negative FFR after LVAD implantation. In 20 failing hearts, Northern blot analysis for sarcoplasmic endoreticular Ca(2+)-ATPase subtype 2a (SERCA2a), the ryanodine receptor, and the sarcolemmal Na(+)-Ca(2+) exchanger was performed on LV tissue obtained before and after LVAD implantation. These paired data demonstrated an upregulation of all 3 genes after LVAD support. In tissue obtained from subsets of these patients, Western blot analysis was performed, and oxalate-supported Ca(2+) uptake by isolated sarcoplasmic reticular membranes was determined. Despite higher mRNA for all genes after LVAD support, only SERCA2a protein was increased. Functional significance of increased SERCA2a was confirmed by augmented Ca(2+) uptake by sarcoplasmic reticular membranes isolated from LVAD-supported hearts. CONCLUSIONS: LVAD support can improve contractile strength of intact myocardium and reverse the negative FFR associated with end-stage heart failure. The expression of genes encoding for proteins involved in Ca(2+) cycling is upregulated (reverse molecular remodeling), but only the protein content of SERCA2a is increased.

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.

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.

Factors correlating with risk of mortality after transmyocardial revascularization.

OBJECTIVES: The purpose of this study was to determine factors correlating with the risk of postoperative mortality after transmyocardial laser revascularization (TMR). BACKGROUND: Clinical studies have indicated that TMR reduces angina by an average of two classes in patients with medically refractory symptoms not treatable by coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty. Factors which correlate with mortality after TMR, however, have not been extensively investigated. METHODS: One hundred thirty-two patients with severe angina underwent TMR as sole therapy with a CO2 laser. Age, gender, ejection fraction, prior CABG, unstable angina and the severity of coronary artery disease (graded on the basis of a newly proposed Anatomic Myocardial Perfusion index, AMP) were each determined. Each vascular territory (left anterior descending artery [LAD] left circumflex artery and posterior descending artery [PDA]) was graded as either having (AMP = 1) or not having (AMP = 0) blood flow through an unobstructed major vessel in the territory. Univariate and multivariate analysis determined which factors correlated with mortality. RESULTS: Patients with at least one AMP = 1 vascular territory (overall AMP = 1) had a 5% (4/82) postoperative mortality rate (POM), compared with 25% (12/49) with overall AMP 0 (p = 0.002). Left anterior descending artery AMP (p = 0.03) and previous CABG (p = 0.04) each correlated with the risk of POM. However, multivariate analysis indicated that no factor improved the correlation obtained with overall AMP by itself. With regard to overall mortality (Kaplan-Meier curves), univariate analysis also revealed correlations with overall AMP (p < 0.001), LAD AMP (p = 0.005), previous CABG (p = 0.003) and PDA AMP (p = 0.05) each individually correlated with mortality. Multivariate analysis indicated that overall AMP = 1, female gender and previous CABG together correlated best with lower postoperative mortality. CONCLUSIONS: Patients with good blood flow to at least one region of the heart through a native artery or a patent vascular graft have a markedly reduced risk of perioperative and longer term mortality.

Angiogenesis is enhanced in ischemic canine myocardium by transmyocardial laser revascularization.

OBJECTIVES: This study sought to test whether transmyocardial laser revascularization (TMLR) stimulates angiogenesis in an animal model of chronic ischemia. BACKGROUND: TMLR relieves angina and may also improve blood flow in patients who are not candidates for traditional therapies. The mechanisms of these benefits are not fully defined. METHODS: Ischemia was created in 14 dogs by proximal left anterior descending coronary ameroid constrictors. TMLR was performed in the anterior wall (approximately 1 channel/cm2) of seven dogs; the remaining dogs served as the ischemic control group. Myocardial blood flow was measured (colored microspheres) at rest and during chemical stress (adenosine) in the acute setting and after 2 months. RESULTS: TMLR did not influence blood flow in the acute setting. After 2 months, resting blood flow increased comparably in the anterior wall in both groups to approximately 80% of normal. However, the TMLR-treated dogs demonstrated an approximately 40% increase in blood flow capacity during stress in the ischemic territory compared with untreated dogs (left anterior descending coronary artery/left circumflex coronary artery flow 0.53+/-0.16 in the control group vs. 0.73+/-0.08 in TMLR animals, p < 0.05). Vascular proliferation, assessed by bromodeoxyuridine incorporation and proliferating cell nuclear antigen positivity in endothelial and smooth muscle cells was about four times greater in the TMLR group than in the control group (p < 0.001). The density of vessels with at least one smooth muscle cell layer was approximately 1.4 times greater in the myocardium surrounding the TMLR channel remnants than in control ischemic tissue (p < 0.001). CONCLUSIONS: In this canine model of chronic ischemia, TMLR significantly enhances angiogenesis as evidenced by the increased number of vessels lined with smooth muscle cells, markedly increased vascular proliferation and increased blood flow capacity during stress.

Assessment of right ventricular contractile state with the conductance catheter technique in the pig.

OBJECTIVE: Since the conductance catheter method has facilitated evaluation of left ventricular contractile state in both laboratory and clinical studies, the aim of this study was to determine whether the technique is similarly useful for the right ventricle. METHODS: A series of right ventricular pressure-volume loops was obtained in seven open chest pigs during transient vena caval occlusion using a 12-electrode conductance catheter. End systolic pressure-volume relationships, stroke work-end diastolic volume relationships, and dP/dt-end diastolic volume relationships were compared at control and during infusion of dobutamine and esmolol. RESULTS: Right ventricular pressure-volume loops generated with the conductance catheter were of a shape consistent with those previously reported by other volume measurement techniques, and responded to changes in inotropic state in a predictable fashion. Dobutamine shifted the three contractile relationships leftward, whereas esmolol shifted them rightward. Comparisons of stroke volume derived with the conductance catheter and with a pulmonary artery flow probe demonstrated the ability of the conductance technique to measure relative volume changes. CONCLUSIONS: The conductance catheter provides a continuous measure of right ventricular volume that was used to detect changes in right ventricular contractile state in pigs. This represents a promising and much needed method for the evaluation of right ventricular function.

Mechanically induced action potential changes and arrhythmia in isolated and in situ canine hearts.

Stretch of excised myocardial tissue causes electrophysiological and potentially arrhythmogenic changes in transmembrane action potentials but corresponding data of the intact mammalian heart are lacking. The effects of increases in ventricular volume and pressure on epicardial monophasic action potentials were therefore investigated in isolated, cross circulated and in situ canine hearts. In seven isolated hearts, increases in ventricular volume and pressure resulted in (1) a linearly related decrease in action potential amplitude (r = 0.988; slope = 0.41% amplitude.ml-1; volume intercept = 17.6 ml), mainly due to a decrease in maximum diastolic potential; (2) a decrease in action potential plateau duration (at 20% repolarisation) by 19 (SD 8)%; and (3) appearance of early afterdepolarizations, reaching up to 18% of total action potential amplitude. Afterdepolarizations occurred only when ventricular outflow was obstructed at end diastole but not at end systole. In eight in situ hearts, increase in left intraventricular pressure produced by transient occlusions of the ascending aorta was also accompanied by decrease in maximum diastolic potential and action potential plateau duration, and by appearance of early afterdepolarizations. In both isolated and in situ intact ventricles, the loading induced electrophysiological changes were associated with occurrence of ectopic ventricular beats. These data show that mechanical overload produces significant electrophysiological changes in the intact canine ventricle which may lead to arrhythmia.

Effects of afterload on regional left ventricular torsion.

OBJECTIVE: To determine if left ventricular torsion, as measured by magnetic resonance tissue tagging, is afterload dependent in a canine isolated heart model in which neurohumoral responses are absent, and preload is constant. METHODS: In ten isolated, blood perfused, ejecting, canine hearts, three afterloads were studied, while keeping preload constant: low afterload, high afterload (stroke volume reduced by approx. 50% of low afterload), and isovolumic loading (infinite afterload). RESULTS: There were significant effects of afterload on both torsion (P < 0.05) and circumferential shortening (P < 0.0005). Between low and high afterloads, at the anterior region of the endocardium only, where torsion was maximal, there was a significant reduction in torsion (15.1 +/- 2.2 degrees to 7.8 +/- 1.8 degrees, P < 0.05). Between high afterload and isovolumic loading there was no significant change in torsion (7.8 +/- 1.8 degrees to 6.2 +/- 1.5 degrees, P = NS). Circumferential shortening at the anterior endocardium was significantly reduced both between low and high afterload (-0.19 +/- 0.02 to -0.11 +/- 0.02, P < 0.0005), and also between high afterload and isovolumic loading (-0.11 +/- 0.02 to 0.00 +/- 0.02, P < 0.05). Plots of strains with respect to end-systolic volume demonstrated a reduction in both torsion and shortening with afterload-induced increases in end-systolic volume. Torsion, but not circumferential shortening, persisted at isovolumic loading. CONCLUSIONS: Maximal regional torsion of the left ventricle is afterload dependent. The afterload response of torsion appears related to the effects of afterload on end-systolic volume.

The hemodynamic basis for the cardiac effects of parathyroid hormone (PTH) and PTH-related protein.

PTH and PTH-related protein (PTHrP) have been regarded to have positive inotropic effects on the heart as well as positive chronotropic and vasodilator effects. However, inotropy due to a direct effect of these peptides has not heretofore been distinguished from an indirect inotropic effect as a result of altered heart rate or coronary flow. The aim of this study was to determine whether PTH and PTHrP have direct inotropic effects in isolated perfused rat hearts. Three groups of hearts were studied; in all groups, hearts contracted isovolumically and were perfused with a constant coronary pressure. In the control group, heart rate, coronary flow, peak pressure (LVPmax), peak rate of rise of LV pressure (dP/dtmax), and peak intracellular calcium (measured by aequorin) all increased with PTH and PTHrP in a dose-dependent manner. When heart rate was fixed by pacing in a second group of rats, PTH and PTHrP increased coronary flow, LVPmax, and dP/dtmax significantly, indicating that inotropic actions were not mediated solely by chronotropic effects. However, when heart rate was fixed by pacing and, additionally, coronary flow was held constant (by maximal prevasodilation with nitroprusside) in a third group of rats, there was no significant effect of either PTH or PTHrP on LVPmax, dP/dtmax, or peak intracellular calcium. To demonstrate the responsiveness of this latter preparation to inotropic stimulation, the beta-adrenergic agonist, isoproterenol, increased LVPmax, dP/dtmax, and peak calcium even when heart rate was fixed and vasodilation was maximal. Thus, PTH and PTHrP are inotropic agents by virtue of their influence on coronary flow and heart rate, but not by any direct effect on contractile elements in the 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.

Heart reduction surgery: an analysis of the impact on cardiac function.

OBJECTIVES: Reports of improved ejection fraction, coupled with decreased filling pressures, have prompted a number of centers to begin evaluating the efficacy of heart reduction surgery to ameliorate symptoms of heart failure. However, the impact of this operation on cardiac mechanics is unknown. We applied a multiple compartment elastance model to simulate the effects of excising cardiac mass on heart function. METHODS: The left ventricle was divided into two functional compartments to simulate excision of part of the wall. At multiple increments of mass reduction, the resulting end-systolic elastance, ejection fraction, stroke volume, end-diastolic pressure and volume, and diastolic stiffness were determined. RESULTS: Changes in systolic function were accompanied by offsetting changes in diastolic function; consequently, overall pump function (the Frank-Starling Relationship) was found to be depressed. The geometric rearrangement associated with this operation leads to a reduction in wall stress for a given level of pressure generation, thus implying an increase in the efficiency with which wall stress is transduced into intraventricular pressure. CONCLUSIONS: Overall pump function is depressed in the short run after heart reduction surgery. However, on the basis of theoretic arguments, heart reduction surgery may have long-term beneficial implications. Importantly, this analysis revealed that changes in parameters of ventricular function have different implications during heart reduction surgery than when such changes are observed with inotropism caused by acute pharmacologic therapy.