Normothermic ex vivo perfusion provides superior organ preservation and enables viability assessment of hearts from DCD donors.

The shortage of donors in cardiac transplantation may be alleviated by the use of allografts from donation after circulatory death (DCD) donors. We have previously shown that hearts exposed to 30 min warm ischemic time and then flushed with Celsior supplemented with agents that activate ischemic postconditioning pathways, show complete recovery on a blood-perfused ex vivo working heart apparatus. In this study, these findings were assessed in a porcine orthotopic heart transplant model. DCD hearts were preserved with either normothermic ex vivo perfusion (NEVP) using a clinically approved device, or with standard cold storage (CS) for 4 h. Orthotopic transplantation into recipient animals was subsequently undertaken. Five of six hearts preserved with NEVP demonstrated favorable lactate profiles during NEVP and all five could be weaned off cardiopulmonary bypass posttransplant, compared with 0 of 3 hearts preserved with CS (p < 0.05, Fisher's exact test). In conclusion, DCD hearts flushed with supplemented Celsior solution and preserved with NEVP display viability before and after transplantation. Viability studies of human DCD hearts using NEVP are warranted.

Increasing the tolerance of DCD hearts to warm ischemia by pharmacological postconditioning.

Donation after circulatory death (DCD) offers a potential additional source of cardiac allografts. We used a porcine asphyxia model to evaluate viability of DCD hearts subjected to warm ischemic times (WIT) of 20­40 min prior to flushing with Celsior (C) solution. We then assessed potential benefits of supplementing C with erythropoietin, glyceryl trinitrate and zoniporide (Cs), a combination that we have shown previously to activate ischemic postconditioning pathways. Hearts flushed with C/Cs were assessed for functional, biochemical and metabolic recovery on an ex vivo working heart apparatus. Hearts exposed to 20-min WIT showed full recovery of functional and metabolic profiles compared with control hearts (no WIT). Hearts subjected to 30- or 40-min WIT prior to C solution showed partial and no recovery, respectively. Hearts exposed to 30-min WIT and Cs solution displayed complete recovery, while hearts exposed to 40-min WIT and Cs solution demonstrated partial recovery. We conclude that DCD hearts flushed with C solution demonstrate complete recovery up to 20-min WIT after which there is rapid loss of viability. Cs extends the limit of WIT tolerability to 30 min. DCD hearts with ≤30-min WIT may be suitable for transplantation and warrant assessment in a transplant model.

Combining cariporide with glyceryl trinitrate optimizes cardiac preservation during porcine heart transplantation.

Sodium-hydrogen exchange inhibitors, such as cariporide, are potent cardioprotective agents, however, safety concerns have been raised about intravenously (i.v.) administered cariporide in humans. The aim of this study was to develop a preservation strategy that maintained cariporide's cardioprotective efficacy during heart transplantation while minimizing recipient exposure. We utilized a porcine model of orthotopic heart transplantation that incorporated donor brain death and 14 h static heart storage. Five groups were studied: control (CON), hearts stored in Celsior; CAR1, hearts stored in Celsior with donors and recipients receiving cariporide (2 mg/kg i.v.) prior to explantation and reperfusion, respectively; CAR2, hearts stored in Celsior supplemented with cariporide (10 mumol/L); GTN, hearts stored in Celsior supplemented with glyceryl trinitrate (GTN) (100 mg/L); and COMB, hearts stored in Celsior supplemented with cariporide (10 mumol/L) plus GTN (100 mg/L). A total of 5/5 CAR1 and 5/6 COMB recipients were weaned from cardiopulmonary bypass compared with 1/5 CON, 1/5 CAR2 and 0/5 GTN animals (p = 0.001). Hearts from the CAR1 and COMB groups demonstrated similar cardiac function and troponin release after transplantation. Supplementation of Celsior with cariporide plus GTN provided superior donor heart preservation to supplementation with either agent alone and equivalent preservation to that observed with systemic administration of cariporide to the donor and recipient.

Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat.

OBJECTIVE: Diabetic cardiomyopathy is an increasingly recognized cause of cardiac failure despite preserved left ventricular systolic function. Given the over-expression of angiotensin II in human diabetic cardiomyopathy, we hypothesized that combining hyperglycaemia with an enhanced tissue renin-angiotensin system would lead to the development of diastolic dysfunction with adverse remodeling in a rodent model. METHODS: Homozygous (mRen-2)27 rats and non-transgenic Sprague Dawley (SD) rats were randomized to receive streptozotocin (diabetic) or vehicle (non-diabetic) and followed for 6 weeks. Prior to tissue collection, animals underwent pressure-volume loop acquisition. RESULTS: Diabetic Ren-2 rats developed impairment of both active and passive phases of diastole, accompanied by reductions in SERCA-2a ATPase and phospholamban along with activation of the fetal gene program. Structural features of diabetic cardiomyopathy in the Ren-2 rat included interstitial fibrosis, cardiac myocyte hypertrophy and apoptosis in conjunction with increased activity of transforming growth factor-beta (p<0.01 compared with non-diabetic Ren-2 rats for all parameters). No significant functional or structural derangements were observed in non-transgenic, SD diabetic rats. CONCLUSION: These findings indicate that the combination of enhanced tissue renin-angiotensin system and hyperglycaemia lead to the development of diabetic cardiomyopathy. Fibrosis, and myocyte hypertrophy, a prominent feature of this model, may be a consequence of activation of the pro-sclerotic cytokine, transforming growth factor-beta, by the diabetic state.

The effects of hormone resuscitation on cardiac function and hemodynamics in a porcine brain-dead organ donor model.

We compared the effects of hormone resuscitation (HR) with a norepinephrine-based protocol on cardiac function, hemodynamics and need for vasopressor support after brain death in a porcine model. Following brain death induction, animals were treated with norepinephrine and fluids for 3 h. In the following 3 h, they continued on norepinephrine and fluids (control) or received additional HR (triiodothyronine, methylprednisolone, vasopressin, insulin). Data were collected pre-brain death, 3 and 6 h post-brain death. At 6 h, median norepinephrine use was higher in controls (0.563 vs. 0 microg/kg/min; p < 0.005), with 6/8 HR animals weaned off norepinephrine compared with 0/9 controls. Mean arterial pressure was higher in HR animals at 6 h (74 +/- 17 vs. 54 +/- 14 mmHg; p < 0.05). Cardiac contractility was also significantly higher in HR animals at 6 h (stroke work index 1.777 vs. 1.494). After collection of 6 h data, all animals were placed on the same low dose of norepinephrine. At 6.25 h, HR animals had higher stroke work (3540 +/- 1083 vs. 1536 +/- 702 mL.mmHg; p < 0.005), stroke volume (37.2 +/- 8.2 vs. 21.5 +/- 9.8 mL; p < 0.01) and cardiac output (5.8 +/- 1.4 vs. 3.2 +/- 1.2 L/min; p < 0.005). HR in a porcine model of brain death reduces norepinephrine requirements, and improves hemodynamics and cardiac function. These results support the use of HR in the management of the brain-dead donor.

Sustained augmentation of cardiac alpha1A-adrenergic drive results in pathological remodeling with contractile dysfunction, progressive fibrosis and reactivation of matricellular protein genes.

We previously reported that transgenic (TG) mice with cardiac-restricted alpha(1A)-adrenergic receptor (alpha(1A)-AR)-overexpression showed enhanced contractility, but no hypertrophy. Since chronic inotropic enhancement may be deleterious, we investigated if long-term, cardiac function and longevity are compromised. alpha(1A)-TG mice, but not their non-TG littermates (NTLs), showed progressive loss of left ventricular (LV) hypercontractility (dP/dt(max): 14,567+/-603 to 11,610+/-915 mmHg/s, P<0.05, A1A1 line: 170-fold overexpression; and 13,625+/-826 to 8322+/-682 mmHg/s, respectively, P<0.05, A1A4 line: 112-fold overexpression, at 2 and 6 months, respectively). Both TG lines developed LV fibrosis, but not LV dilatation or hypertrophy, despite activation of hypertrophic signaling pathways. Microarray and real time RT-PCR analyses revealed activation of matricellular protein genes, including those for thrombospondin 1, connective tissue growth factor and tenascin C, but not transforming growth factor beta1. Life-span was markedly shortened (mean age at death: 155 days, A1A1 line; 224 days, A1A4 line compared with NTLs: >300 days). Telemetric electrocardiography revealed that death in the alpha(1A)-AR TG mice was due to cardiac standstill preceded by a progressive diminution in QRS amplitude, but not by arrhythmias. The QRS changes and sudden death could be mimicked by alpha(1)-AR activation, and reversed preterminally by alpha(1)-AR blockade, suggesting a relationship to stress- or activity-associated catecholamine release. Thus, long-term augmentation of cardiac alpha(1A)-adrenergic drive leads to premature death and progressive LV fibrosis with reactivation of matricellular protein genes. To our knowledge this is the first evidence in vivo for a role of the alpha(1A)-AR in ventricular fibrosis and in pathological cardiac remodeling.

Load-sensitive measures may overestimate global systolic function in the presence of left ventricular hypertrophy: a comparison with load-insensitive measures.

Transgenic animal models have provided a vital insight into the pathogenesis of cardiovascular disease, but functional cardiac assessment is often limited by high heart rates and small heart size. We hypothesized that in the presence of concentric left ventricular (LV) hypertrophy (LVH), load-sensitive measures of contractility may be misinterpreted as overestimating global cardiac function, because the normal function of excess sarcomeres may displace a greater volume of blood during contraction. Conductance catheter technology was used to evaluate pressure-volume (P-V) relationships as a load-insensitive method of assessing cardiac function in vivo in 18-wk-old heterozygous (mRen-2)27 transgenic rats (a model of LVH), compared with age-matched Sprague-Dawley (SD) controls. Anesthetized animals underwent echocardiography followed by P-V loop analysis. Blood pressure, body weight, and heart rate were higher in the Ren-2 rats (P < 0.05). Load-sensitive measures of systolic function, including fractional area change, fractional shortening, ejection fraction, and positive peak rate of LV pressure development, were greater in the Ren-2 than control animals (P < 0.05). Load-insensitive measures of systolic function, including the preload recruitable stroke work relationship and the end-systolic P-V relationship, were not different between Ren-2 and SD rats. Regional wall motion assessed by circumferential shortening velocity suggested enhanced circumferential fiber contractility in the Ren-2 rats (P = 0.02), but tissue Doppler imaging, used to assess longitudinal function, was not different between groups. Although conventional measures suggested enhanced systolic function in the Ren-2 rat, load-insensitive measures of contractility were not different between Ren-2 and SD animals. These findings suggest that the normal range of values for load-sensitive indexes of contractility needs to be altered according to the degree of LVH. To accurately identify changes in systolic function, we suggest that a combination of echocardiography with assessment of load-insensitive measures be used routinely.

Targeted alpha(1A)-adrenergic receptor overexpression induces enhanced cardiac contractility but not hypertrophy.

Activation of the alpha(1A)-adrenergic receptor (alpha(1A)-AR)/Gq pathway has been implicated as a critical trigger for the development of cardiac hypertrophy. However, direct evidence from in vivo studies is still lacking. To address this issue, transgenic mice with cardiac-targeted overexpression of the alpha(1A)-AR (4- to 170-fold) were generated, using the rodent alpha-myosin heavy chain promoter. Heterozygous animals displayed marked enhancement of cardiac contractility, evident from increases in dP/dt(max) (80%, P<0.0001), dP/dt(max)/LVP(inst) (76%, P<0.001), dP/dt(max):dP/dt(min) (104%, P<0.0001), and fractional shortening (33%, P<0.05). Moreover, changes in the dP/dt(max)-end-diastolic volume relationship provided load-independent evidence of a primary increase in contractility. Blood pressure and heart rate were largely unchanged, and there was a small increase in (-)norepinephrine-stimulated, but not basal, phospholipase C activity. Increased contractility was directly related to the level of receptor overexpression and could be completely reversed by acute alpha(1A)- but not beta-AR blockade. Despite the robust changes in contractility, transgenic animals displayed no morphological, histological, or echocardiographic evidence of left ventricular hypertrophy. In addition, apart from an increase in atrial natriuretic factor mRNA, expression of other hypertrophy-associated genes was unchanged. To our knowledge, these data provide the first in vivo evidence for an inotropic action of the alpha(1A)-AR.

Effect of acutely increased left ventricular afterload on work output from the right ventricle in conscious dogs.

OBJECTIVE: To determine the effect of acute increments in left ventricular afterload on the stroke work output of the right ventricle in vivo. METHODS: After pharmacologic attenuation of autonomic reflexes, left and right ventricular pressure-volume data were obtained in 9 conscious dogs during vena caval occlusions performed before and during aortic constriction. RESULTS: The relationship between right ventricular stroke work and end-diastolic volume during vena caval occlusion was highly linear (r = 0.97 +/- 0.02), but the slope decreased by 20% +/- 13% during aortic constriction sufficient to increase left ventricular mean ejection pressure by 25% +/- 14% (P <.05). The volume-axis intercept remained constant. Similarly, the slope of the linear relationship between right ventricular free wall regional segment work and end-diastolic segment length declined by 22% +/- 10% during aortic constriction (P <.05), without significant change in the length-axis intercept. The reduction in both global and regional right ventricular stroke work at any given preload with increased left ventricular afterload was due entirely to decreased right ventricular stroke volume and free wall shortening, because right ventricular mean ejection pressure was unchanged. Additional experiments were performed in 5 open-chest dogs to produce a greater reduction in left ventricular free wall shortening than observed with aortic constriction by transient constriction of the left circumflex coronary artery. However, this intervention had no effect on right ventricular free wall segment work output. CONCLUSION: Increased left ventricular afterload decreases global and regional right ventricular stroke work at any given preload, a direct, negative systolic ventricular interaction.

Limitations of unidimensional indexes of right ventricular contractile function in conscious dogs.

OBJECTIVE: Our goal was to examine the validity of unidimensional indexes of right ventricular contractile performance in vivo. METHODS: Unidimensional indexes and global measurements of right ventricular volume and contractile performance were compared in 6 conscious dogs. Vena caval occlusions were performed before (control) and during pulmonary arterial or aortic constriction. RESULTS: Moderately strong relationships were demonstrated between right ventricular septal-free wall indexes and global measurements of right ventricular end-diastolic and end-systolic volumes, stroke volume, stroke work, and the slope of the preload recruitable stroke work relationship, respectively, under control conditions (mean r (2) range 0.69-0.94). These relationships were shifted significantly, however, by increased right ventricular afterload. Increased left ventricular afterload significantly shifted the relationships between right ventricular septal-free wall dimensions and end-diastolic and end-systolic volumes. Relationships between the corresponding regional right ventricular free wall segmental indexes and global measurements under control conditions were weaker (mean r (2) range 0.12-0.65) and were significantly more sensitive to distortion by both increased right and left ventricular afterload, the effects of which were generally in opposite directions. These observations are consistent with significant ventricular interactive effects on the relationship between single right ventricular dimensions and right ventricular volume. CONCLUSION: Unidimensional right ventricular measurements are not reliable surrogates for right ventricular volume when assessing right ventricular contractile performance in the intact heart.

Single-beat determination of preload recruitable stroke work relationship: derivation and evaluation in conscious dogs.

OBJECTIVES: To derive and evaluate a method of estimating the slope (Mw) of the preload recruitable stroke work (PRSW) relationship between left ventricular stroke work (SW) and end-diastolic volume (EDV) from a single beat. BACKGROUND: Mw is a load-insensitive index of contractile function, but its clinical application has been limited by the need to record multiple beats over a wide volume range. METHODS: Pressure-volume loops were recorded over a variable preload and afterload range by vena caval and aortic constrictions in 12 conscious dogs instrumented with epicardial dimension transducers and micromanometers. Single-beat Mw (SBMw) was determined as the ratio SW/(EDV-Vw), where the volume-axis intercept of the PRSW relationship (Vw)(EDV at zero SW) was estimated as k x EDVB + (k - 1)LVwall, k is the ratio of the epicardial shell volumes corresponding to Vw and baseline EDV (EDVB) and LVwall is wall volume. RESULTS: In the first six dogs, k was found to be essentially constant at 0.7, SBMw estimates were insensitive to wide preload variation, and the relationship between SBMw and multibeat Mw determined during caval and aortic constrictions did not differ significantly from the line of identity. When the same constant k value was applied to SBMw estimation in a different group of six dogs, SBMw did not differ significantly from multibeat Mw (83 +/- 12 erg x cm(-3) x 10(3) and 77 +/- 12 erg x cm(-3) x 10(3), respectively), neither changed significantly during aortic constriction and both increased significantly with calcium infusion (107 +/- 18 erg x cm(-3) x 10(3) and 95 +/- 19 erg x cm(-3) x 10(3), respectively, both p < 0.05). Single-beat Mw was less load-dependent, more reproducible and a more sensitive index of inotropic state than two previously described single-beat indexes, single-beat elastance and maximum power divided by EDV2. CONCLUSIONS: Mw can be determined accurately from a single, steady-state beat in the normal canine heart and is sensitive to inotropic alterations while being insensitive to wide variations in preload and afterload. Single-beat Mw estimation should facilitate noninvasive, load-independent assessment of contractile function.

A brain dead donor model of porcine orthotopic cardiac transplantation for assessment of cardiac allograft preservation.

BACKGROUND: We aimed to develop a large animal model of orthotopic cardiac transplantation, incorporating donor brain death, to assess new methods of preservation of the donor heart. METHODS: Brain death was achieved in the donor pig by inflation of a 20 cc subdural balloon 1 h prior to harvest. The donor heart was stored for 6 h with conventional hypothermic ischaemic preservation. It was then transplanted orthotopically into the recipient pig using the Lower and Shumway technique. One hour after reperfusion, the transplanted heart was weaned from cardiopulmonary bypass with dobutamine support. Dobutamine support was continued for up to 4 h, if required. After 6 h of physiological and biochemical evaluation, the recipient was euthanased and the heart excised for histological assessment. RESULTS: All pigs experienced the classical haemodynamic changes associated with brain death. This resulted in the release of Troponin I, consistent with myocardial injury. The donor operation was successfully completed in 11 out of 13 pigs. Six out of 11 transplanted hearts were successfully weaned from cardiopulmonary bypass, but required ongoing dobutamine support. CONCLUSIONS: This porcine model of orthotopic cardiac transplantation is a relevant and practical large animal model for the assessment of new methods of preservation of the donor heart.

Salmonella prosthetic valve endocarditis.

We report the case of a 69-year-old man with an aortic valve bioprosthesis in whom a diagnosis of Salmonella typhimurium prosthetic valve endocarditis was made. During the prolonged hospital admission early aggressive antibiotic therapy and early valve replacement surgery were the deciding factors enabling him to survive this otherwise lethal condition.

Left ventricular chamber function during inhaled nitric oxide in patients with dilated cardiomyopathy.

Inhaled nitric oxide is a potent and selective pulmonary vasodilator. However, when used in patients with congestive cardiac failure, the decrease in pulmonary vascular resistance is associated with an increase in pulmonary capillary wedge pressure (PCWP). This study examined load-independent indexes of left ventricular chamber function during inhaled nitric oxide in 10 patients with dilated cardiomyopathy (mean ejection fraction, 30.2+/-7.8%, mean +/- SD). Etiology of cardiomyopathy was idiopathic in six and ischemic in four. Pulmonary hemodynamics in seven patients revealed normal resting pulmonary vascular resistance. Chamber function was defined by recording pressure-volume loops at steady state and during inferior vena caval occlusion during inhalation of 20 ppm nitric oxide for 10 min. We found no effect of inhaled nitric oxide on steady-state left ventricular pressures, volumes, contractility (end-systolic elastance or preload recruitable stroke work), contraction duration, or active (tau, dP/dt(min)) or passive (end-diastolic pressure-volume relation) diastolic function. Right heart filling pressures did not change. We therefore conclude that 20 ppm inhaled nitric oxide does not affect left ventricular chamber function in patients with controlled heart failure. Previously described elevations in PCWP during inhaled nitric oxide are most likely due to altered left ventricular loading conditions related to secondary pulmonary hypertension in severe heart failure.

Response of the intact canine left ventricle to increased afterload and increased coronary perfusion pressure in the presence of coronary flow autoregulation.

BACKGROUND: Increased left ventricular (LV) contractile force or oxygen consumption has been documented with increased coronary arterial pressure (CAP) and flow (Gregg phenomenon). We investigated whether the increase in contractile force with increased LV afterload might be mediated by the concomitant increase in CAP when coronary autoregulation is intact. METHODS AND RESULTS: The LV of 6 autonomically blocked open-chest dogs was perfused through the left main coronary artery by a cannula with a side gate to the aortic root. With the gate open, CAP increased from 77+/-20 to 93+/-20 mm Hg (P<0.05) with aortic constriction (AC). With the gate closed, CAP was maintained at a constant level of 100 mm Hg. A small reduction in the slope of the preload recruitable stroke work (PRSW) relationship was observed with AC, but this response was not altered by the coronary perfusion gate position. The end-systolic pressure-volume (ESPV) relationship shifted upward significantly with AC (P<0.001), but this shift was not greater with open-gate perfusion than with closed-gate perfusion. Furthermore, with coronary autoregulation intact, wide changes in CAP (between 60 and 180 mm Hg, n=5) did not alter either the PRSW or ESPV relationship. In contrast, when autoregulation was abolished with intracoronary adenosine (n=6), both indexes of contractility increased progressively with increased CAP. CONCLUSIONS: The concomitant increase in CAP with increased afterload in the intact canine LV does not contribute to the afterload-induced increase in contractile force. Coronary perfusion pressure per se does not influence LV contractile function. Coronary perfusion pressure influences contractility only when coronary flow changes.

Late systolic pressure augmentation: role of left ventricular outflow patterns.

Late systolic augmentation of the ascending aortic pressure waveform is believed to be caused by particular impedance patterns but also could be caused by particular left ventricular outflow patterns. Using a linear mathematical model of the entire human arterial tree, we derived realistic impedance patterns by altering 1) Young's modulus of the arterial wall of the individual branches, 2) peripheral reflection coefficients, and 3) distal compliances at the terminations. These calculated impedance patterns were then coupled to realistic left ventricular outflow patterns determined by unique 1) end-diastolic and end-systolic pressure-volume relationships, 2) preload-recruitable stroke work relationships, and 3) shortening paths simulated by altered aortic flow contours. As determined by the ratio of the individual parameter coefficient of determination (r(2)) to the overall model r(2), late systolic pressure augmentation was more strongly determined by left ventricular outflow patterns than by arterial impedance parameters (r(2) ratio: 53% vs. 33%). Thus left ventricular outflow patterns are at least as important as impedance parameters in determining late systolic pressure augmentation in this model.

On-line synthesis of the human ascending aortic pressure pulse from the finger pulse.

Although systolic pressure in the ascending aorta (AA) can be determined accurately from the radial arterial waveform using a single generalized transfer function (TF) of the upper limb, a better on-line methods is needed for accurate noninvasive synthesis of the AA pressure contour to characterize left ventricular contractile function and ventricular-vascular coupling. AA, tonometric carotid (CA), and photoplethysmographic finger (FA) arterial pressure waveforms were recorded in 12 subjects (10 male, aged 59.1+/-10.3 years, mean+/-SD) during cardiac catheterization. The AA-FA TF was estimated using (1) a single generalized TF (GAA), (2) individualized TFs directly determined from CA-FA recordings in each patient (DAA), and (3) individualized TFs computed from CA-FA recordings in each patient with a mathematical model of the human upper limb (MAA). AA pressure waveforms were synthesized from FA recordings in real time using convolution windows derived from these TFs. Under steady state conditions, the root mean square error (RMSE) between measured and synthesized AA was lower by DAA (3.3+/-1.3 mm Hg) and MAA (3.9+/-1.2 mmHg) than by GAA (4.8+/-2.0 mm Hg, P<.05). During dynamic load alteration induced by the Valsalva maneuver, however, the MAA method performed better (5.4+/-2.8 mm Hg) than both the GAA (5.8+/-3.3 mm Hg, P<.05) and DAA (6.5+/-2.7 mm Hg, P<.01) methods. The beat-to-beat AA contour can be accurately and noninvasively synthesized on-line using individualized TFs. During dynamic load alteration, individualized TFs derived with an upper limb arterial model provide greater accuracy.

Effect of inhaled nitric oxide on normal human left ventricular function.

OBJECTIVES: This study determined the effects of inhaled nitric oxide (NO) on load-independent indexes of normal human left ventricular (LV) function. BACKGROUND: Inhaled NO is a potent and selective pulmonary vasodilator. However, when it is used in patients with congestive heart failure, the decrease in pulmonary vascular resistance (PVR) is often associated with an increase in pulmonary capillary wedge pressure. NO has been shown to have a negative inotropic action, but it is not known whether it affects LV chamber function when delivered by inhalation. METHODS: Eleven subjects (51 to 69 years old) with normal LV function (mean ejection fraction 72% [range 60% to 80%]) were studied. Four patients had concomitant coronary artery disease. Pressure-volume loop recordings were used to determine end-systolic and end-diastolic pressure-volume and preload recruitable stroke work relations. NO was delivered at 20 ppm for 10 min. In an additional group of patients with normal LV function, PVR (n = 5) and NO metabolites (n = 9) were measured. RESULTS: There was no effect of inhaled NO on steady state LV pressures, volumes, contractility, contraction duration, active relaxation (time constant of relaxation, peak negative first derivative of left ventricular pressure), diastolic compliance or PVR. NO metabolites (methemoglobin and nitrate) were present in the LV cavity at the same concentration as right atrial venous blood, suggesting inactivation of free NO before arrival in the LV chamber. This study had a power of 0.995 to detect a 5% change in contractility (slope of preload recruitable stroke work relation) for alpha = 0.05, based on the multiple linear regression model used. CONCLUSIONS: These results indicate that 20 ppm of inhaled NO does not have significant effects on normal LV function. This lack of effect may be due in part to rapid inactivation of free NO in transit to the heart.

Direct effects of DC cardioversion on blood echogenicity: an in vitro study.

Exacerbation of left atrial spontaneous echo contrast (SEC) after cardioversion of atrial fibrillation has been attributed to left atrial mechanical dysfunction induced by the procedure ("atrial stunning"). An in vitro model was devised to determine whether electrically induced changes in blood properties might contribute to SEC formation after cardioversion. Human blood echogenicity was examined quantitatively by videodensitometry before and after shocks of 1, 2, 5, and 20 J. Changes in blood cell numbers, cell morphology, and erythrocyte sedimentation rate were determined by haematological analysis. Immediately following electrical discharges, transient and dose-related, highly echogenic microbubbles were noted, but shocks of increasing intensity did not induce SEC at high blood velocity or alter the severity of SEC at low blood velocity. No quantitative or qualitative changes in haematological parameters were observed. These results suggest that direct effects of electrical shock on blood do not contribute to SEC after cardioversion. Systemic haematological responses to electric shock that might indirectly promote red cell aggregation in vivo cannot be excluded by this in vitro study.

Left ventricular adaptation to aortic regurgitation in conscious dogs.

OBJECTIVE: Cardiac failure as a result of valvular heart disease remains a major clinical problem that frequently leads to ventricular dysfunction, myocardial failure, and even death. The development of irreversible myocardial damage may be especially insidious in volume overload as a result of aortic or mitral regurgitation. METHODS AND RESULTS: Left ventricular wall volume, ventricular function, and myocardial performance were assessed in 10 chronically instrumented conscious dogs before and after creation of aortic regurgitation. Left ventricular wall volume was measured by serial echocardiography. Left ventricular function was assessed by total cardiac output, stroke work, the slope of the Frank-Starling relationship, and the slope of the end-systolic pressure-volume relationship. Myocardial performance was assessed by the slope of the myocardial power output versus end-diastolic strain relationship. End-diastolic wall stress and volume both increased acutely and remained elevated after creation of aortic regurgitation. Peak systolic wall stress increased initially (1 to 3 weeks) from 336 +/- 30 to 369 +/- 55 mm Hg but returned to control values as left ventricular wall volume increased from 78 +/- 13 to 88 +/- 16 ml after development of compensatory hypertrophy. Left ventricular systolic function remained constant or increased and was maintained initially by increased myocardial performance, which returned to baseline levels after the development of compensatory hypertrophy. CONCLUSIONS: Myocardial performance and ventricular function vary independently in aortic regurgitation. Measures of myocardial performance such as the myocardial power output versus end-diastolic strain relationship may be useful in clinical assessment of aortic regurgitation.