Myron L. Weisfeldt

Dissociation between left ventricular untwisting and filling. Accentuation by catecholamines.

Background Efficient early diastolic filling is essential for normal cardiac function. Diastolic suction, as evidenced by a decreasing left ventricular pressure during early filling, could result from restoring forces (the release of potential energy stored during systolic deformation) dependent on myofilament relaxation. Although these restoring forces have been envisioned within individual myofibers, recent studies suggest that gross fiber rearrangement involving the connective tissue network occurs early in diastole. This may lead to the release of potential energy stored during systole and suction-aided filling. Methods and Results To establish precisely the timing and extent of restoration of the systolic torsional deformation of the left ventricle with respect to early filling at baseline and with enhanced relaxation, we studied untwisting during control conditions and with catecholamine stimulation. Using noninvasive and nondestructive magnetic resonance tagging, torsional deformation of the left ventricle was measured at 20-msec intervals in 10 open-chest, atrially paced dogs, starting at aortic valve closure. Eight equiangular tags intersected the epicardium and endocardium in three short-axis imaging planes (base, mid, and apex). From the intersection points, epicardial and endocardial circumferential chord and arc lengths were measured and angular twist of mid and apical levels with respect to the base (maximal torsion and its reversal, untwisting) was calculated. Echo-Doppler provided timing of aortic valve closure and of mitral valve opening. Zero torsion was defined at end diastole. Torsion at the apical level reversed rapidly between its maximum and the time immediately after mitral valve opening: from 7.0±5.80 to 3.2±5.40 and 12.0±8.50 to 6.9±7.80 (mean±SD, both p < 0.01) at the epicardium and endocardium, respectively. During the same period, no significant circumferential segment length changes occurred. As expected, after mitral valve opening, filling resulted in significant circumferential segment lengthening, whereas further reversal of torsion was small and nonsignificant. During dobutamine infusion, torsion at end systole was greater and reversal during isovolumic relaxation was much more rapid and greater in extent (p < 0.01). Torsion reversed from 11.5±4.3° to 5.7±4.8° and 17.4±6.4° to 6.9±7.7° at epicardium and endocardium. Conclusions Untwisting occurs principally during isovolumic relaxation before filling and is markedly enhanced in speed and magnitude by catecholamines. This partial return of the left ventricle to its preejection configuration before mitral valve opening could represent an important mechanism for the release of potential energy stored in elastic elements during the systolic deformation. These myocardial restoring forces would be markedly enhanced by physiological changes consequent to catecholamines such as during exercise, offsetting the concomitant shortening of the filling period.

Relation of regional cross-fiber shortening to wall thickening in the intact heart. Three-dimensional strain analysis by NMR tagging.

BACKGROUNDnThe mechanism by which small amounts of myofiber shortening lead to extensive wall thickening is unknown. When isolated fibers shorten, they thicken in the two orthogonal directions. In situ fibers, however, vary in their orientation through the wall, and each is tethered to near or distant neighbors, which allows shortening to occur both in the direction of the fibers and also perpendicular to them. This cross-fiber shortening may enable the wall to shorten in two directions and thereby thicken extensively in the third.nnnMETHODS AND RESULTSnNuclear magnetic resonance tagging is a noninvasive method of labeling and tracking myocardium of the entire heart in three dimensions that does not interfere with myocardial motion. To investigate the presence and importance of cross-fiber shortening in the intact left ventricle, 10 closed-chest dogs were studied by nuclear magnetic resonance tagging. Five short-axis and four long-axis images were acquired to reconstruct 32 cubes of myocardium in each dog at end diastole and end systole. Pathological dissection was performed to determine the fiber direction at the epicardium, midwall, and endocardium of each cube. Strain was computed from the three-dimensional cube coordinates in the fiber and cross-fiber directions for epicardial and endocardial surfaces, and thickening of the full wall and its epicardial and endocardial halves was determined. Shear deformations were also calculated. Fiber strain at the epicardium and endocardium was -6.4 +/- 0.7% and -8.5 +/- 0.6% (mean +/- SEM), respectively (difference, P > .05). Cross-fiber strain at epicardium and endocardium was -0.6 +/- 0.5% and -25 +/- 0.6%, respectively (difference, P < .05). Thickening of the full wall reached 32.5 +/- 1.0%, composed of epicardial thickening of 25.5 +/- 0.6% and endocardial thickening of 43.3 +/- 1.0% (difference, P < .05). Fiber/cross-fiber shear strain was small (< 3%). Significant regional differences were present in all strains. A significant correlation was found between the extents of regional thickening and cross-fiber shortening.nnnCONCLUSIONSnCross-fiber shortening at the endocardium, therefore, far exceeds cross-fiber shortening at the epicardium and fiber shortening at both epicardium and endocardium. Since no active shortening can occur locally in the cross-fiber direction, the extensive endocardial cross-fiber shortening must result from interaction with differently aligned fibers at a distance. The correlation between regional thickening and cross-fiber shortening supports the hypothesis that this interaction is the mechanism for amplifying small amounts of fiber shortening to cause extensive endocardial thickening.

Improvement of postischemic myocardial function and metabolism induced by administration of deferoxamine at the time of reflow: the role of iron in the pathogenesis of reperfusion injury.

Reperfusion of ischemic myocardium has been postulated to result in a specific oxygen radical-mediated component of tissue injury. In a previous study we demonstrated improved recovery of ventricular function and metabolism when the superoxide radical scavenger superoxide dismutase was administered at the time of postischemic reflow. Studies in vitro, have suggested that superoxide toxicity might be mediated via the generation of more reactive hydroxyl radicals in an iron-catalyzed reaction. The present study was designed to test the hypothesis that myocardial reperfusion injury might be reduced by administration of the iron chelator deferoxamine at the time of reflow, most likely by preventing hydroxyl radical formation. Sixteen isolated Langendorff rabbit hearts, perfused within the bore of a superconducting magnet, were subjected to 30 min of normothermic (37 degrees C) total global ischemia followed by 45 min of reperfusion. At reflow eight treated hearts received a 10 ml bolus containing 50 mumol of deferoxamine followed by an infusion of 11 mumol/min for the first 15 min of reflow. The hearts were then perfused with standard perfusate for an additional 30 min. Eight untreated control hearts received a similar bolus of perfusate followed by 45 min of standard reperfusion. Serial 5 min 31P nuclear magnetic resonance spectra were recorded. Myocardial phosphocreatine (PCr) content fell to 5% to 7% of control during ischemia in both groups of hearts. Deferoxamine-treated hearts recovered 99 +/- 10% of control PCr content, while untreated hearts recovered 60 +/- 16% (p less than .05). Intracellular pH fell to 5.9 during ischemia in both groups, before showing more rapid and complete recovery in treated hearts (p less than .01). Recovery of developed pressure reached 70 +/- 6% of control in treated hearts compared with 35 +/- 10% in untreated hearts (p less than .05). Iron content of the perfusate was 7 microM, and by electron paramagnetic resonance spectroscopy was in the form of Fe3+-EDTA complexes. In the effluent of treated hearts iron was in the form of Fe3+-deferoxamine chelates. In summary, administration of the iron chelator deferoxamine at the time of postischemic reflow results in greater recovery of myocardial function and energy metabolism, which supports the hypothesis that iron plays an important role in the pathogenesis of reperfusion injury.

Quantification of and correction for left ventricular systolic long-axis shortening by magnetic resonance tissue tagging and slice isolation.

BackgroundMeasurement of regional left ventricular (LV) function is predicated on the ability to compare equivalent LV segments at different time points during the cardiac cycle. Standard techniques of short-axis acquisition in two-dimensional echocardiography, cine computed tomography, and standard magnetic resonance imaging (MRI) acquire images from a fixed plane and fail to compensate for through-plane motion. The shortening of the left ventricle along its long axis during systole results in planar images of two different levels of the ventricle, leading to error in any derived functional measurements. LV systolic long-axis motion was measured in 19 normal volunteers using MRI. Methods and ResultsWith a selective radio frequency (RF) tissue-tagging technique, three short-axis planes were labeled at end diastole and standard spin-echo images were acquired at end systole in the two- and four-chamber orientations. Persistence of the tags through systole allowed visualization of the intersecting short-axis tags in the long-axis images and allowed precise quantification of long-axis motion of the septum, lateral, anterior, and inferior walls at the base, mid, and apical LV levels. The total change in position along the long axis between end diastole and end systole was greatest at the base, which moved toward the apex 12.8 ± 3.8 mm. The mid left ventricle moved 6.9 ± 2.6 mm, and the apex was nearly stationary, moving only 1.6 ± 2.2 mm (p < 0.001). Having quantified the normal range of long-axis shortening, we developed a technique that isolates a slice of tissue between selective RF saturation planes at end diastole. Combining this with a wide end-systolic image slice, end-systolic images were acquired without contamination of signal from adjacent tissue moving into the imaging plane. This technique was validated in a moving phantom and in normal volunteers. ConclusionsSignificant LV systolic long-axis shortening exists, and this effect is seen the most at the base and the least at the apex. At a given ventricular level, shortening varied significantly according to location. A method using selective saturation pulses and gated spin-echo MRI automatically corrects for this motion and thus eliminates misregistration artifact from regional function analysis.

Results of a randomized prospective trial of intraaortic balloon counterpulsation and intravenous nitroglycerin in patients with acute myocardial infarction

A randomized prospective clinical trial compared combined treatment with intraaortic balloon pumping and intravenous nitroglycerin for 4 to 5 days with routine clinical management in 20 patients with extensive myocardium at risk for infarction as evidenced by a thallium defect score of 7.0 units or greater. No significant differences in mortality or clinical outcome were observed between the 10 patients receiving the combined treatment and the 10 receiving routine management. In 14 patients two-dimensional echocardiograms obtained 6 to 24 hours after the onset of symptoms and at follow-up 6 to 16 days later (after completion of combined intraaortic balloon pumping plus nitroglycerin therapy) were analyzed to determine whether infarct segment or noninfarct segment lengths were affected by therapy. Among these 14 patients, 5 (3 receiving the combined therapy and 2 receiving routine management) demonstrated an increase in infarct segment length of greater than 1.0 cm. Mean infarct segment length increased 0.30 +/- 0.44 cm in patients receiving the combined therapy and 0.29 +/- 0.36 cm in patients on routine management (p = NS). In contrast, noninfarct segment length increased greater than 1.0 cm (mean increase 1.20 +/- 0.39) in five of seven patients on routine management but in none of 7 patients receiving intraaortic balloon pumping plus nitroglycerin therapy (mean decrease 0.22 +/- 0.20 cm) (p less than 0.05). No significant differences were noted in left ventricular ejection fraction, as measured by gated blood pool scintigraphy, or thallium perfusion defect score in a comparison of day 1 (pretreatment) with day 4 thallium or day 7 to 14 gated blood pool scintigrams. Thus, in patients with extensive myocardium at risk, it is unlikely that a reduction in mortality or a significant improvement in myocardial perfusion or ventricular function can be obtained by early intervention with intraaortic balloon pumping in combination with nitroglycerin. Although this combined therapy failed to prevent infarct segment lengthening (infarct expansion), the combined afterload-lowering effects of intraaortic balloon pumping and nitroglycerin did appear to prevent dilation or remodeling of noninfarcted segments during the first 2 weeks after acute myocardial infarction.

Perfusate sodium during ischemia modifies post-ischemic functional and metabolic recovery in the rabbit heart

Metabolic and functional recovery following 60 minutes of low flow (0.1 ml/min) ischemia were compared in rabbit hearts perfused with normal sodium and potassium, low sodium (120 mM NaCl replaced by 120 mM LiCl), or zero potassium perfusate during ischemia. During the control, pre-ischemic, and reperfusion periods, all hearts were perfused identically with normal sodium and potassium. 31P NMR was used to monitor intracellular pH (pHi), ATP, and phosphocreatine (PGr). Developed pressure, end diastolic pressure, pHi, and the integrated areas of ATP and PCr were equivalent in the three groups in the pre-ischemic period. The fall in pHi, PCr, ATP, and developed pressure and the rise in end diastolic pressure during 60 min ischemia also did not differ among the three groups. In contrast to the lack of an effect of perfusate sodium and potassium on the decline in parameters of metabolism and function during ischemia, there was a marked difference in the recovery of these indices during reperfusion. Hearts perfused with low sodium during ischemia exhibited the best recovery (expressed as percent of control) of developed pressure (95 +/- 4%), PCr (106 +/- 6%), and ATP (51 +/- 2%) and the smallest rise in end diastolic pressure (229 +/- 50%); hearts perfused with normal sodium and potassium during ischemia had intermediate recovery values for developed pressure (53 +/- 10%), PCr (78 +/- 9%), ATP (45 +/- 4%) and end diastolic pressure (487 +/- 73%) and the hearts perfused with zero potassium solution during ischemia exhibited the poorest recovery of developed pressure (23 +/- 6%), PCr (49 +/- 6%), ATP (39 +/- 5%) and end diastolic pressure (968 +/- 185%).(ABSTRACT TRUNCATED AT 250 WORDS)

Intracellular acidosis and contractility in the normal and ischemic heart as examined by 31P NMR.

Abstract 31P was used to investigate correlations between intracellular pH (pHi) and myocardial contractility in the normal and ischemic isolated, perfused isovolumic rabbit heart. Intracellular pH was calculated from the chemical shift of Pi in hearts perfused with phosphate-free buffer. Normal intracellular pH was 7.22 ± 0.02 (n = 15). To calibrate the relationship between pHi and left ventricular developed pressure (LVDP), respiratory acidosis was induced by mixing 65% O2: 30% N2: 5% CO2 with 65% O2: 35% CO2 using Krebs buffer containing 24 m m HCO3−. The results show that a 0.22 pH unit acidification correlates with a 50% reduction in LVDP. The correlation between pHi and LVDP was also studied in two models of ischemia: total global ischemia and steady state partial ischemia (50% reduction of LVDP). In both ischemic conditions, a 50% lowering in LVDP correlated with only a 0.09 pH unit acidification. Thus, while intracellular acidosis may account for 40 to 50% of the depression of LVDP oberved during the early phases of ischemia, other factor must also play a role. Mass spectrometry was used to examine the potential regulatory role of tissue oxygen (PmO2). The model of steady-state partial ischemia was employed. Changes in LVDP and MVO2 correlated quite closely with reductions in coronary flow. However, up to a 50% reduction in flow, pHi remained near normal, and tissue PmO2 was normal or slightly elevated. These latter results suggest that an efficient autoregulatory mechanism controls both function and MVO2 in close parallel to changes in flow. As a result, the metabolic supply/demand balance is maintained. However, beyond a 50% reduction in flow, this mechanism fails and metabolic indicies of ischemia are expressed.

Phosphorus nuclear magnetic resonance studies of heart physiology

Abstract 31 P NMR at 72.9 MHz using a 25-mm-diameter phosphorus probe has been used to study correlations among cardiac metabolism, tissue pH, and contractile performance. In all studies, isovolumic left ventricular pressure (LVP) was measured in the paced hearts. Under these conditions, excellent spectra were collected in 5 min, on 6-g rabbit hearts. Good spectra were obtained in 30-sec intervals. Rapid sequential spectra illustrate the metabolic and pH events associated with the onset and recovery of total, global ischemia. Tissue pH was stable for the first minute, but then fell from 7.4 to 6.9 by 6 min, and progressed to a value of 6.4 after 40 min. During the first minute, LVP fell 80%. Metabolites and tissue pH recovered within 6 min of reperfusion, a time when ventricular pressure remained depressed by 50%. These results suggest that both the early fall and initial postischernic recovery of ventricular pressure may not be exclusively regulated by tissue pH, as estimated by NMR. We also used NMR to investigate the metabolic changes associated with regional ischemia. The 31 P NMR spectrum of a regionally ischemic, perfused rabbit heart showed two inorganic phosphate (P i ) peaks. Before ligation there was only a single P i signal at a position corresponding to one of the peaks noted during regional ischemia. Since the resonance frequency of the P i peak is determined by pH and since ischemia causes acidosis the two signals in the regionally ischemic heart result from P i at different intracellular pH values in the normal (pH 7.4) and ischemic zones (pH 6.4). And finally, we compared the status of KCl-arrested, ischemic rabbit hearts and non-KCl-treated hearts and correlated the 31 P NMR spectra with the ability of the heart to return to normal function following a period of ischemia. A rabbit heart was arrested by perfusing it with 30 m M KCl and was then made globally ischemic; a second heart was made ischemic without KCl arrest. After 40 min of global ischemia the KCl-arrested heart showed a near-normal level of ATP, low P i and a pH of 7.0. The nonarrested heart, on the other hand, showed low ATP, high P i , and a pH of 6.4. On reperfusion, the KCl-arrested heart recovered 100% of control function within 5 min but the control heart recovered only 70% of control function after 30 min. The 31 P NMR confirms that KCl arrest preserves ischemic myocardial metabolites and suggests that it can be used to test currently untried treatments for functional protection.

Reverse CPR: a pilot study of CPR in the prone position

BACKGROUNDnCardiopulmonary resuscitation (CPR), as described in 1960, remains the cornerstone of therapy for cardiopulmonary arrest. Recent case reports have described CPR in the prone position. We hypothesized rhythmic back pressure on a patient in the prone position with sternal counter-pressure (termed reverse CPR here) would increase intra-thoracic pressure and in turn systolic blood pressure (SBP) during cardiac arrest versus standard CPR.nnnMETHODS AND RESULTSnSix patients from Columbia Presbyterian Medical Centers Cardiac and Medical Intensive Care Units (CICU and MICU) were enrolled. Eligible patients had suffered circulatory arrest and failed standard CPR for at least 30 min. After enrollment the patients received 15 additional min of standard CPR and then reverse CPR for 15 min. The studys primary endpoint, mean SBP, significantly improved from 48 mmHg during standard CPR to 72 mmHg during reverse CPR (mean improvement=23+/-14 mmHg). Mean calculated mean arterial pressure (MAP) was also improved significantly from 32 mmHg during standard CPR to 46 mmHg during reverse CPR (mean improvement=14+/-11 mmHg). The mean diastolic blood pressure (DBP) improved from 24 mmHg during standard to 34 mmHg during reverse CPR (mean improvement=10+/-12 mmHg). This difference did not meet statistical significance. No patients had return of spontaneous circulation.nnnCONCLUSIONSnReverse CPR generates higher mean SBP and higher mean MAP during circulatory arrest than standard CPR. These novel findings justify further research into this technique.

Preservation of ventricular function by treatment of ventricular fibrillation with phenylephrine

Epinephrine promotes resuscitation from ventricular fibrillation because of its peripheral vasoconstrictive effects. However, the beta-adrenergic effects of epinephrine may be detrimental because of the stimulation of myocardial oxygen demand. To test whether functional recovery from fibrillation in hearts treated with a selective alpha-adrenergic agent is greater than in hearts treated with epinephrine, ventricular fibrillation was induced in eight isolated dog hearts while coronary perfusion pressure was maintained at 30 mm Hg. In random order, epinephrine (5 micrograms/min), phenylephrine (50 micrograms/min) or no drug was infused for 5 min. The heart was then defibrillated, the drug infusion stopped and coronary perfusion pressure increased to 100 mm Hg. Coronary blood flow (ml/min per 100 g), arteriovenous oxygen difference (ml O2/dl) and myocardial oxygen consumption (ml O2/min per 100 g) measured after 4 min of ventricular fibrillation were greater with epinephrine (mean +/- SD 30.9 +/- 11.7, 17.5 +/- 1.6 and 5.4 +/- 1.9, respectively) than with phenylephrine (24.4 +/- 6.0, 15.7 +/- 2.6 and 3.8 +/- 1.1, respectively) or no drug (19.8 +/- 5.2, 12.8 +/- 1.8 and 2.6 +/- 0.7, respectively) (p less than 0.05, p less than 0.05 and p less than 0.05, respectively). The slope of the end-systolic pressure-volume relation 10 min after defibrillation and restoration of normal coronary perfusion pressure was depressed (percent of prefibrillation value) most by epinephrine infusion (72 +/- 17%, n = 6), less by no drug infusion (82 +/- 12%, n = 4) and was increased after phenylephrine infusion (143 +/- 17%, n = 6) (p less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)