Combined transplantation of skeletal myoblasts and bone marrow stem cells for myocardial repair in rats.

OBJECTIVES: To prove whether intramyocardial transplantation of combined skeletal myoblasts (SM) and mononuclear bone marrow stem cells is superior to the isolated transplantation of these cell types after myocardial infarction in rats. METHODS: In 67 male Fischer rats myocardial infarction was induced by direct ligature of the LAD. Seven days postinfarction baseline echocardiography and intramyocardial cell transplantation were performed. Via lateral thoracotomy 200 microl containing either 10(7) SMs or 10(7) bone marrow-derived mononuclear cells (BM-MNC) or a combination of 5x10(6) of both cell types (MB) were injected in 10-15 sites in and around the infarct zone. In controls (C) 200 microl of cell-free medium were injected in the same manner. Before injection both cell types were stained using a fluorescent cell linker kit (PKH, Sigma). In addition, SMs were transfected with green fluorescent protein. Nine weeks postinfarction follow-up echocardiography was performed and animals were sacrificed for further analysis. RESULTS: At baseline echocardiography there was no difference in left ventricular ejection fraction (LVEF; C, SM, BM-MNC, MB: 60.1+/-3.2, 53.3+/-10.2, 53.1+/-8.7, 49+/-9.0%) and left ventricular end diastolic diameter (LVEDD; C, SM, BM-MNC, MB: 6.5+/-0.8, 5.17+/-0.8, 5.77+/-1.4, 6.25+/-0.8 mm) between the different therapeutic groups. Eight weeks after cell transplantation LVEDD was significantly increased in all animals except those that received a combination of myoblasts and bone marrow stem cells (MB; C, SM, BM-MNC, MB: 7.7+/-0.6 mm, P=0.001; 7.7+/-1.5 mm, P<0.001; 7.7+/-1.1 mm, P=0.005; 6.6+/-1.7 mm, P=0.397. At the same time LVEF decreased significantly in the control group (C), stayed unchanged in animals that received bone marrow stem cells (BM-MNC) and increased in animals that received myoblasts (SM) and a combination of both cell types (MB; C, SM, BM-MNC, MB: 45.3+/-7.0%, P=0.05; 63.9+/-15.4%, P=0.044; 54.3+/-6.3%, P=0.607; 63.0+/-11.5%, P=0.039). CONCLUSIONS: The present data show that the concept of combining SMs with bone marrow-derived stem cells may be of clinical relevance by merging the beneficial effects of each cell line and potentially reducing the required cell quantity. Further studies are required to identify the exact mechanisms underlying this synergy and to allow full exploitation of its therapeutic potential.     

Increased engraftment and GVHD after in utero transplantation of MHC-mismatched bone marrow cells and CD80low, CD86(-) dendritic cells in a fetal mouse model.

BACKGROUND: Bone marrow transplantation (BMT) is the only known cure for a variety of inherited diseases and requires the administration of high doses of immunosuppressive and myeloablative therapy. Because the fetus is immunoincompetent early in gestation, in utero stem cell transplantation (IUT) could avoid the need for this toxic conditioning. A major limitation to date of IUT is the low level of engraftment and failure to induce tolerance. Dendritic cells (DC) are considered very potent antigen-presenting cells, but DC progenitors (pDC) are strongly tolerogenic. METHODS: We examined the effect of donor pDC on the degree of engraftment and tolerance induction after IUT. Bone marrow-derived pDC (CD80low, CD86-) from male C57BL/6 mice (H2b) were injected with and without donor bone marrow (BM) intraperitoneally into 13 to 15-day BALB/c (H2d) fetuses. Engraftment was determined by flow cytometry and quantitative polymerase chain reaction and tolerance by skin grafts and the mixed lymphocyte reaction. RESULTS: At 1-month posttransplant, mice that received BM+pDC showed a higher degree of engraftment (29+/-46%) than mice that received pDC-enriched cells or BM cells alone (0.11+/-0.70% and 1.71+/-1.66%, respectively, P<0.001). However, 5/19 recipients of BM+pDC died within 6 weeks; 4/5 had significant donor cell engraftment in blood and/or tissues. Also, these mice had evidence of graft-versus-host disease (GVHD). Two mice out of 15 long-term survivors in the BM+pDC group had virtually complete replacement of host with donor hematopoietic cells. Skin grafts and mixed lymphocyte reaction studies showed no durable tolerance induction other than in the two fully engrafted recipients of BM+pDC. CONCLUSIONS: These results suggest that donor pDC, along with donor BM, can have a significant impact on engraftment of MHC-mismatched donor cells associated with an increased incidence of GVHD. However, marrow-derived pDC do not result in an increase in tolerance induction in utero even when microchimerism is present.     

Reduction of tricuspid annular doppler tissue velocities in pediatric heart transplant patients.

BACKGROUND: Orthotopic heart transplantation is a life-saving therapy for children with end-stage heart disease. However, 50% of these transplanted children die or require re-transplantation 12 years later. Progressive deterioration of cardiac function is a common feature of long-term survivors; however, quantitative evaluation of the state of the right ventricle has been lacking. Tissue Doppler imaging (TDI) has been used to measure alterations in right ventricular (RV) function in other illnesses. The purpose of this study was to quantitate abnormalities in tricuspid annular systolic and diastolic velocities as an indicator of RV dysfunction, and to evaluate if time since transplantation and the presence of tricuspid regurgitation are associated with quantitative changes in tricuspid annular velocities in pediatric heart transplant recipients. METHODS: TDI was performed and velocities recorded during systole and early and late diastole at the tricuspid annulus, septum and mitral annulus in transplanted patients and in a control group with normal hearts. Pulsed wave Doppler mitral and tricuspid inflows were also measured and the severity of tricuspid regurgitation was estimated using color flow mapping. Patients with biopsy evidence of active cellular rejection or left ventricular ejection fraction of <60% were excluded from study. RESULTS: Thirty-five patients were divided into a normal heart group (n = 14) and a transplant group (n = 21), aged from 1 to 23 years. Systolic and early diastolic velocities at the tricuspid annulus and septum in the transplant group were reduced significantly compared with the normal group (p < 0.05): tricuspid annular systolic, 5.8 +/- 1.4 vs 9.4 +/- 1.7 cm/sec; early diastolic, -6.4 +/- 2.6 vs -9.7 +/- 2.6 cm/sec; septum systolic, 3.9 +/- 1.5 vs 5.8 +/- 1.4 cm/sec; and early diastolic, -6.3 +/- 2.4 vs -9.1 +/- 2.5 cm/sec. Patients were divided into early (<5 years) and late (>5 years) term groups since transplantation. Tissue velocities at the tricuspid annulus in the late term group had further reduction in systole, 4.9 +/- 1.4 vs 6.4 +/- 1.1 cm/sec, and early diastole, -5.3 +/- 1.5 vs -7.1 +/- 2.9 cm/sec (p < 0.05). Patients with severe tricuspid regurgitation had systolic and early diastolic velocities at the tricuspid annulus that were further reduced. Left ventricular mitral inflow Doppler early/late diastolic ratios became significantly different from the normal group 5 years after transplantation (p < 0.05). CONCLUSIONS: TDI demonstrated that tricuspid annular systolic and early diastolic velocities were abnormal in children after transplantation and became significantly more abnormal with prolonged time after transplantation. These alterations were not dependent on the presence of severe tricuspid regurgitation but appeared to be exacerbated by its presence. Evidence of diastolic left ventricular dysfunction was not detected before 5 years after transplantation in this unselected group. A prospective study may be required to define the evolution and progression of right and left ventricular dysfunction in children after heart transplantation.     

Myogenic cell transplantation improves in vivo regional performance in infarcted rabbit myocardium

BACKGROUND: Although cardiac transplantation is an ideal treatment for end-stage heart disease, inadequate donor availability has stimulated efforts to manage terminally injured myocardium by other innovative methods. Autologous skeletal myoblast transplantation, or cellular cardiomyoplasty, is one method to potentially mediate myocardial repair within chronically injured hearts. However, few investigators have documented the ability of myogenic cells to alter load-insensitive indices of systolic and diastolic performance in vivo. In this study, both systolic and diastolic regional myocardial function were evaluated following left ventricular cryoinjury and compared with function after myogenic cell transplantation. METHODS: Left ventricular pressure and segment length were determined in 9 rabbits by micromanometry and sonomicrometry 1 week following cryoinjury and 3 weeks after myoblast transplantation. At study termination, the extent of myoblast engraftment was determined by histologic analysis. Systolic performance was based on the linear regression of stroke work and end-diastolic segment length. Diastolic properties were evaluated by the curvilinear relationships between left ventricular pressure and strain, and left ventricular pressure and end-diastolic segment length. RESULTS: Although mean indices of systolic performance were unchanged after cell transplantation, systolic performance improved in 3 animals. In contrast, myoblast engraftment was associated with significantly improved diastolic properties (strain and dynamic stiffness) in all animals. CONCLUSIONS: These data quantify temporal changes in regional myocardial performance and suggest that cellular cardiomyoplasty improves diastolic compliance prior to affecting systolic performance. Cellular cardiomyoplasty, a potential therapeutic option for ischemic heart disease, appears to reverse diastolic creep and thus may represent a clinical alternative to transplantation in the near future.     

Functional consequences of the right ventricular isolation procedure

The right ventricular free wall was surgically isolated from the remainder of the heart in eight dogs to evaluate the functional consequences of this procedure. Each dog was instrumented with ultrasonic dimension transducers in the right and left ventricular free walls, intracavitary micromanometers, and pulmonary artery flow probes. Volume loading and vena caval occlusions were performed to assess diastolic compliance and systolic function. Right ventricular unstressed myocardial segment length increased from 14.2 +/- 0.7 to 15.0 +/- 0.8 mm (p less than 0.5). There was an accompanying significant postoperative loss of right ventricular diastolic compliance (p less than 0.005). Regional right ventricular systolic function and regional left ventricular diastolic compliance and systolic function were preserved after the procedure. Postoperatively, when the right ventricular free wall was not paced and left silent, right ventricular stroke work decreased from 7.0 +/- 0.8 to 2.7 +/- 0.5 gm-m/m2 (p less than 0.05). These data demonstrate that the diastolic compliance of the right ventricular free wall decreases significantly after right ventricular isolation. However, there were no changes in regional right ventricular systolic or regional left ventricular function. The isolated right ventricular free wall contributes significantly to postoperative cardiac performance.     

Regional myocardial dimensions following coronary artery bypass grafting in patients. Relationship of functional deterioration to graft occlusion.

The direct relationship between graft flow and regional midwall myocardial function has not been documented in patients. Therefore, the present study was designed to quantitate the effects of coronary artery bypass grafting on regional myocardial mechanics distal to a coronary artery obstruction. Twenty-one patients with subtotal or total occlusion of the left anterior descending (LAD) coronary artery underwent coronary artery bypass grafting. Following completion of the aortic and coronary anastomoses, two miniature ultrasonic dimension transducers (2.5 mm. diameter) were positioned within the minor axis of the anterior left ventricular free wall and were allowed complete freedom of movement. The transducers were placed at midwall depth, and areas of clinically apparent myocardial fibrosis were not utilized as sites of implantation. During control, 30 minutes following the termination of cardiopulmonary bypass, regional myocardial dimensions, pulmonary artery diastolic pressure, arterial pressure, and heart rate were recorded with all saphenous vein grafts open and after 30 seconds of single vein graft occlusion. These measurements were repeated during atrial pacing at a rate of 128 +/- 4 beats per minute. Data are mean +/- the standard error of the mean. During control, graft occlusion resulted in a regional decrease in systolic excursion from 1.3 +/- 0.1 to 1.0 +/- 0.2 mm. (p less than 0.01), as well as a decrease in the rate of shortening from 8.7 +/- 0.2 to 6.2 +/- 1.1 mm. per second (p less than 0.05); heart rate, mean arterial pressure, and diastolic pulmonary artery pressure remained unchanged. Graft occlusion with atrial pacing resulted in an exaggerated decrease in both regional systolic excursion, from 1.2 +/- 0.2 to 0.6 +/- 0.2 mm. (p less than 0.01), and rate of shortening, from 9.4 +/- 1.5 to 4.4 +/- 0.2 mm. per second (p less than 0.01). For the group of patients studied, end-diastolic lengths were unchanged with graft occlusion during control and atrial pacing. Moreover, with graft occlusion, isolated patients demonstrated regional dyskinesia as evidenced by holosystolic bulging. These studies in patients have documented for the first time that, despite a constant preload, afterload, and heart rate, regional myocardial function following coronary artery bypass grafting is dependent upon adequate graft flow, especially during stress.     

Use of candesartan cilexetil decreases proteinuria in renal transplant patients with chronic allograft dysfunction

BACKGROUND: Posttransplant proteinuria and hypertension are difficult to treat after renal transplantation. Therefore, we examined whether candesartan cilexetil is effective in reducing urinary protein excretion or in controlling hypertension in patients with renal allograft dysfunction. METHODS: Sixty-two renal transplant recipients with proteinuria were enrolled in this study. They underwent kidney transplantation under cyclosporine or tacrolimus immunosuppression between February 1983 and December 1998. Causes of proteinuria were chronic rejection in 28, glomerulonephritis in 16, cyclosporine or tacrolimus nephrotoxicity in 9, and unknown in 9 recipients. The dose of candesartan cilexetil ranged from 4 to 12 mg/day. Eleven patients with proteinuria who had not been treated with candesartan cilexetil constituted a matched control population. RESULTS: Hypertension was well controlled by administration of candesartan cilexetil. Both systolic blood pressure and diastolic blood pressure significantly decreased from 141.7+/-14.8 mm Hg to 118.7+/-11.9 mm Hg and 121.2+/-11.6 mm Hg, and from 89.0+/-13.0 mm Hg to 72.0+/-10.4 mm Hg and 74.9+/-9.4 mm Hg, at 2 months and 1 year after administration, respectively. Urinary protein excretion was reduced from 0.93+/-1.2 g/day to 0.34+/-0.7 g/day and 0.43+/-1.2 g/day at 2 months and 1 year after administration, respectively. The levels of creatinine clearance were 55.7+/-28.9 mL/min before treatment, 50.9+/-24.8 mL/min at 2 months, and 52.6+/-24.8 mL/min at 1 year after treatment, respectively. There was no clinically significant difference between them. Regarding the calcineurin inhibitor levels, there was no significant difference between the levels before and 1 year after treatment. There was a significant difference in all examinations (systolic blood pressure, diastolic blood pressure, proteinuria, and renal function) between the patients with and without candesartan at 1 year after treatment. No significant adverse effects occurred. CONCLUSIONS: Candesartan cilexetil can effectively control hypertension and proteinuria without deterioration in renal allograft function. These data suggest that treatment with candesartan cilexetil may be useful for maintaining long-term renal allograft function.     

Cardiovascular effects of successful renal transplantation: a 30-month study on left ventricular morphology, systolic and diastolic functions

The purpose of this study was to determine the effects of a successful renal transplantation on left ventricular (LV) morphology, systolic and diastolic function. Forty-three renal transplant patients prospectively studied by echocardiography (30 months follow-up) were divided into two groups. The first echocardiographic examination was performed 3.0 +/- 2.8 months after renal transplantation in group I (11 men, 12 women); and 34.4 +/- 29.1 months after transplant in group two (9 men, 11 women). We noticed the following changes in blood pressure (BP): group 1 systolic BP reduction (from 140.5 +/- 23.6 to 126 +/- 6.8 mmHg; P < .01), and pulse pressure reduction (from 59.5 +/- 14.9 to 47.5 +/- 9.8 P < .05); group 2, diastolic BP acceleration (from 78.4 +/- 8.7 to 84 +/- 6.9 mmHg, P < .05). LV mass index decreased in group 1 (from 126.4 +/- 18.0 g/m2 to 104.6 +/- 15.9 g/m2, P < .05). The incidence of LV hypertrophy (LVH) decreased in group 1 from 70% to 40% (P < .05). Only one parameter of systolic function-end systolic stress-significantly decreased in both groups: group 1 from 78 +/- 11 to 61 +/- 12 g/cm2; group 2 from 63.8 +/- 9.0 to 55.1 +/- 9.0 g/cm2, P < .05). The pattern of mitral inflow changed: in group 1, the normal pattern decreased from 30% to 20% and the restrictive pattern increased from 0% to 10%; in group 2, the normal mitral inflow pattern decreased from 60% to 20% and abnormal relaxation type increased from 40% to 80%. Regression of LVH after renal transplant improved LV geometry and systolic function. Despite better systolic function a progression of LV diastolic dysfunction was noticed, which might be explained by cyclosporine treatment. Renal transplantation exerted a beneficial impact on cardiomyopathy manifested by LVH and systolic dysfunction.     

Comparison of benefits on myocardial performance of cellular cardiomyoplasty with skeletal myoblasts and fibroblasts

Cellular cardiomyoplasty (CCM), or introduction of immature cells into terminally injured heart, can mediate repair of chronically injured myocardium. Several different cell types, ranging from embryonic stem cells to autologous skeletal myoblasts, have been successfully propagated within damaged heart and shown to improve myocardial performance. However, it is unclear if the functional advantages associated with CCM depend upon the use of myogenic cells or if similar results can be seen with other cell types. Thus, we compared indices of regional contractile (systolic) and diastolic myocardial performance following transplantation of either autologous skeletal myoblasts (Mb) or dermal fibroblasts (Fb) into chronically injured rabbit heart. In vivo left ventricular (LV) pressure (P) and regional segment length (SL) were determined in 15 rabbits by micromanometry and sonomicrometry 1 week following LV cryoinjury (CRYO) and again 3 weeks after autologous skeletal Mb or dermal Fb transplantation. Quantification of systolic performance was based on the linear regression of regional stroke work and end-diastolic (ED) SL. Regional diastolic properties were assessed using the curvilinear relationships between LVEDP and strain (epsilon) as well as LVEDP and EDSL. At study termination, cellular engraftment was characterized histologically in a blinded fashion. Indices of diastolic performance were improved following CCM with either Mb or Fb. However, only Mb transplantation improved systolic performance; Fb transfer actually resulted in a significant decline in systolic performance. These data suggest that both contractile and noncontractile cells can improve regional material properties or structural integrity of terminally injured heart, as reflected by improvements in diastolic performance. However, only Mb improved systolic performance in the damaged region, supporting the role of myogenic cells in augmenting contraction. Further studies are needed to define the mechanism by which these effects occur and to evaluate the long-term safety and efficacy of CCM with any cell type.     

Local myocardial overexpression of growth hormone attenuates postinfarction remodeling and preserves cardiac function

BACKGROUND: Ventricular remodeling with chamber dilation and wall thinning is seen in postinfarction heart failure. Growth hormone induces myocardial hypertrophy when oversecreted. We hypothesized that localized myocardial hypertrophy induced by gene transfer of growth hormone could inhibit remodeling and preserve cardiac function after myocardial infarction. METHODS: Rats underwent direct intramyocardial injection of adenovirus encoding either human growth hormone (n = 9) or empty null vector as control (n = 9) 3 weeks after ligation of the left anterior descending coronary artery. Analysis of the following was performed 3 weeks after delivery: hemodynamics, ventricular geometry, cardiomyocyte fiber size, and serum growth hormone levels. RESULTS: The growth hormone group had significantly better systolic cardiac function as measured by maximum left ventricular pressure (73.6 +/- 6.9 mm Hg versus control 63.7 +/- 7.8 mm Hg, p < 0.05) and maximum dP/dt (2845 +/- 453 mm Hg/s versus 1949 +/- 605 mm Hg/s, p < 0.005), and diastolic function as measured by minimum dP/dt (-2520 +/- 402 mm Hg/s versus -1500 +/- 774 mm Hg/s, p < 0.01). Ventricular geometry was preserved in the growth hormone group (ventricular diameter 12.2 +/- 0.7 mm versus control 13.1 +/- 0.4 mm, p < 0.05; borderzone wall thickness 2.0 +/- 0.2 mm versus 1.5 +/- 0.1 mm, p < 0.001), and was associated with cardiomyocyte hypertrophy (6.09 +/- 0.63 microm versus 4.66 +/- 0.55 microm, p < 0.005). Local myocardial expression of growth hormone was confirmed, whereas serum levels were undetectable after 3 weeks. CONCLUSIONS: Local myocardial overexpression of growth hormone after myocardial infarction resulted in cardiomyocyte hypertrophy, attenuated ventricular remodeling, and improved systolic and diastolic cardiac function. The induction of localized myocardial hypertrophy presents a novel therapeutic approach for the treatment of ischemic heart failure.     

Early mechanical function in the heterotopic heart transplant

The characteristics of left ventricular (LV) function in the nonimmunosuppressed heterotopic heart transplant (TX) with less than 3 hr of cold preservation, were studied in 12 awake chronically instrumented dogs prior to TX (control), 1-12 hr post TX (P1), 12-24 hr post TX (P2), and 24-48 hr post TX (P3). Micromanometers measured LV transmural pressure and ultrasonic transducers measured ventricular dimension in order to allow calculations of myocardial mechanical properties. Immediately after transplant (P1) there was significant (P less than 0.05) depression noted in both diastolic function and systolic function (peak LV pressure, 137 +/- 5 vs 80 +/- 10 mm Hg; dp/dtmax, 2642 +/- 170 vs 1038 +/- 98 mm Hg/sec; maximum velocity of minor axis shortening, 4.46 +/- 0.50 vs 2.41 +/- 0.56; and Emax, 6.5 +/- 1.2 vs 2.0 +/- 1.4 mm Hg/ml). However, the contractility reserve (studied in six dogs) as estimated by postextrasystolic potentiation ratio was maintained (1.41 +/- 0.07 vs 1.37 +/- 0.15), suggesting reversibility of the depressed function. Over the next 2 days the diastolic function and the systolic function (at P3: 109 +/- 6 mm Hg, 1842 +/- 450 mm Hg/sec, 5.54 +/- 0.77 cm/sec, and 4.5 +/- 1.3 mm Hg/ml, respectively) gradually improved toward control. Microscopic examination of the autopsied hearts did not show significant evidence of rejection. Thus, the early depression of function in the heart TX appeared to be the result of ischemia from preservation and surgical trauma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Administration of a tumor necrosis factor inhibitor at the time of myocardial infarction attenuates subsequent ventricular remodeling.

BACKGROUND: Tumor necrosis factor (TNF) causes myocardial extracellular matrix remodeling and fibrosis in myocardial infarction and chronic heart failure models. Pre-clinical and clinical trials of TNF inhibition in chronic heart failure have shown conflicting results. This study examined the effects of the administration of a TNF inhibitor immediately after myocardial infarction on the development of heart failure. METHODS: Lewis rats underwent coronary artery ligation and then received either intravenous etanercept (n = 14), a soluble dimerized TNF receptor that inhibits TNF, or saline as control (n = 13). Leukocyte infiltration into the infarct borderzone was evaluated 4 days post-ligation in 7 animals (etanercept = 4, control = 3). After 6 weeks, the following parameters were evaluated in the remaining animals: cardiac function with a pressure-volume conductance catheter, left ventricular (LV) geometry, and borderzone collagenase activity. RESULTS: Etanercept rats had significantly less borderzone leukocyte infiltration 4 days post-infarction than controls (10.7 +/- 0.5 vs 18.0, +/-2.0 cells/high power field; p < 0.05). At 6 weeks, TNF inhibition resulted in significantly reduced borderzone collagenase activity (110 +/- 30 vs 470 +/- 140 activity units; p < 0.05) and increased LV wall thickness (2.1 +/- 0.1 vs 1.8 +/- 0.1 mm, p < 0.05). Etanercept rats had better systolic function as measured by maximum LV pressure (84 +/- 3 mm Hg vs 68 +/- 5 mm Hg, p < 0.05) and the maximum change in left ventricular pressure over time (maximum dP/dt) (3,110 +/- 230 vs 2,260 +/- 190 mm Hg/sec, p < 0.05), and better diastolic function as measured by minimum dP/dt (-3,060 +/- 240 vs -1,860 +/- 230 mm Hg/sec; p < 0.05) and the relaxation time constant (14.6 +/- 0.6 vs 17.9 +/- 1.2 msec; p < 0.05). CONCLUSIONS: TNF inhibition after infarction reduced leukocyte infiltration and extracellular matrix turnover and preserved cardiac function.     

A clinical study of annular geometry and dynamics in patients with ischemic mitral regurgitation: new insights into asymmetrical ring annuloplasty.

OBJECTIVE: Recent studies in animals showed that regional annulus distortion is a major determinant of ischemic mitral regurgitation (IMR) and accordingly suggested new surgical approaches with asymmetrical annuloplasty rings. As accurate measurement of annulus in patients is still a challenge, we performed this study to analyze the changes in three-dimensional annular geometry in patients with IMR compared to primary valvular lesions. METHODS: We studied 110 patients divided into three groups: (1) 30 with coronary artery disease without IMR, (2) 38 with chronic IMR, and (3) 42 with MR due to primary valvular lesions. Longitudinal and septal-lateral annulus diameters; global diastolic and systolic annular area and its percentual shortening, diastolic and systolic areas of six regions corresponding to the segmental Carpentier classification were measured by 3D-echocardiography. The degree of MR was assessed by three-dimensional color Doppler. Global and regional left ventricular geometry were assessed by sphericity index and by measuring anterior and posterior tethering of papillary muscles. RESULTS: Patients with significant IMR (group 2) showed larger longitudinal (52.7+/-3.9 mm vs 41.8+/-2.9 mm; p<0.01) and antero-lateral (31.8+/-3.5mm vs 26.7+/-2.8mm; p<0.01) annular diameters than the patients with MR due to primary valvular lesions (group 3). Diastolic (997.8+/-64.9 mm(2) vs 700.7+/-46.8mm(2); p<0.01) and systolic (894.9+/-57.3mm(2) vs 547.3+/-35.0mm(2); p<0.01) annular areas were larger in group 2 than in group 3. Annular area change was significantly lower in the group with ischemic mitral regurgitation than in the group with primary valvular lesions (10.3+/-1.1% vs 21.9+/-1.6%; p<0.01). Regional annular areas of the six sectors were homogeneously larger in group 2 than in group 3. The sector P3 did not show larger area than the other ones. The degree of MR, as assessed by the volumes of regurgitant jets, was higher in the group with primary valvular lesions than in the patients with IMR (32.6+/-13.4 cm(3) vs 23.1+/-11.1cm(3); p<0.01). CONCLUSIONS: This study showed that annular enlargement in patients with IMR affects the different annular regions to the same extent. An ideal surgical repair of IMR should be individually tailored after quantitative assessment measurement of geometry and function of each single component of the mitral valve complex.     

Abnormal diastolic left ventricular filling by pulsed Doppler echocardiography in patients on continuous ambulatory peritoneal dialysis.

To determine characteristics of diastolic left ventricular (LV) function in patients on continuous ambulatory peritoneal dialysis (CAPD), two groups of CAPD patients without (n = 23; group 1) vs with (n = 25; group 2) LV hypertrophy (greater than 13 mm) were compared with a group of untreated non-renal hypertensive patients with LV hypertrophy (n = 11; group 3) using Doppler-echocardiography. Age and body surface area were comparable in all three groups, mean CAPD-duration (32 +/- 28 vs 26 +/- 23 months; p = NS) was comparable in renal patients. LV systolic function in echocardiography (LVEF: 62 vs 64 vs 63%) and systolic time intervals were normal and comparable in all three groups. Atrial maximum filling velocities (96 +/- 25 vs 91 +/- 25 vs 67 +/- 8 cm/s) were comparably increased, the ratio of maximal early/atrial filling velocities was comparably decreased (0.73 +/- 0.25 vs 0.77 +/- 0.21 vs 0.99 +/- 0.05) in both groups of renal patients as compared to group 3 (p less than 0.05-0.01). Atrial filling fractions were increased in all three groups, more pronounced in group 1 than in group 3 (50 +/- 11 vs 40 +/- 7%; p less than 0.05). The normal correlation of Doppler parameters with age and with LV radius/thickness ratio was altered in renal patients such that high patient age tended to have an additional negative influence on LV diastolic function of hypertrophied, but not of normal myocardium. Isovolumic relaxation time was prolonged in all three groups (134 +/- 38 vs 131 +/- 34 vs 116 +/- 17 ms; p = NS). We conclude that in patients on CAPD, diastolic LV filling is impaired both in normal and hypertrophied myocardium. High age is a factor that further attributes to diastolic dysfunction of hypertrophied myocardium in CAPD.     

Cardiac functional and morphologic changes of renal allograft recipients in the early posttransplant period

After renal transplantation there is a substantial alteration in cardiac morphology and functions. This prospective study was undertaken to observe changes in different cardiac parameters in early months after transplantation. PATIENTS AND METHODS: Twenty-two allograft recipients (primary disease glomerulonephritis) were evaluated in the immediate pretransplant period (0 month) and 1 and 3 months after transplantation by clinical and echocardiographic (M mode, 2D) evaluations. RESULTS: Pretransplant echocardiogram showed left ventricular hypertrophy (LVH) in 100% subjects, LV dilation in 52%, and systolic dysfunction in 18%. By the third month, significant differences in systolic blood pressure (SBP-161 +/- 16 to 133 +/- 26 mm Hg, P < .002); diastolic BP (DBP-101 +/- 9 to 86 +/- 11 mm Hg, P < .006), and hemoglobin level (Hgb-7.3 +/- 1.6 to 11.2 +/- 3.9 g/dL, P < .006) were evident. Echocardiography showed decreased left atrial diameter (LADd-41 +/- 5 to 35 +/- 3 mm, P < .001); left ventricular internal diameter (LVIDd-54 +/- 6 to 47 +/- 6 mm, P < .02); left ventricular muscle mass index (LVMI-379 +/- 114 to 248 +/- 58 g/m(2), P < .001); and left ventricular end diastolic volume index (LVEDVI-96 +/- 28 to 64 +/- 17 ml/m2, P < .002). Bivariate correlations showed positive associations of mean blood pressure (MBP) and serum creatinine with LVMI, LVEDVI, and negative association of hemoglobin with MBP, serum creatinine, LVMI, and LVEDVI. CONCLUSION: From these observations, we concluded that cardiac morphological parameters start improving in the early posttransplant period. Improvements in renal function, anemia status, and lower blood pressure showed strong associations with these changes.     

Left ventricular function and chronotropic responses after normothermic cardiopulmonary bypass with intermittent antegrade warm blood cardioplegia in patients undergoing coronary artery bypass grafting.

OBJECTIVE: Recent studies indicate that normothermic cardiopulmonary bypass (CPB) with intermittent antegrade warm blood cardioplegia (IAWBC) may have metabolic and clinical advantages, but limited data exist on its effects on myocardial function. Therefore, we investigated the acute effects of this approach on systolic and diastolic left ventricular function and on chronotropic responses. METHODS: In 10 patients undergoing isolated CABG we obtained on-line left ventricular pressure-volume loops using the conductance catheter before and after normothermic CPB with IAWBC. Steady state and load-independent indices of left ventricular function derived from pressure-volume relations were obtained during right atrial pacing (80-100-120 beats/min) to determine baseline systolic and diastolic function and chronotropic responses. RESULTS: The mean time of CPB was 105+/-36 min (median 103, range 60-167 min) with a mean aortic cross-clamp time of 75+/-27 min (median 69, range 43-129 min). Baseline (80 beats/min) end-systolic elastance (E(ES)) did not change after CPB (1.22+/-0.53 to 1.12+/-0.28 mm Hg/ml, P>0.2), while the diastolic chamber stiffness constant (k(ED)) significantly increased (0.014+/-0.005 to 0.040+/-0.007 ml-1, P=0.018) and relaxation time constant (tau) significantly decreased (61+/-3 to 49+/-2 ms, P=0.004). Before CPB, incremental atrial pacing had no significant effects on E(ES) and tau but significant negative effects on kED (0.014+/-0.005 to 0.045+/-0.012 ml-1, P=0.013). After CPB, atrial pacing had significant positive effects on E(ES), tau and kED (E(ES): 1.12+/-0.28 to 2.60+/-1.54 mm Hg/ml, P=0.021; tau: 49+/-2 to 45+/-2 ms, P=0.009; kED: 0.040+/-0.007 to 0.026+/-0.005 mm Hg, P=0.010), indicating improved systolic and diastolic chronotropic responses. CONCLUSION: On-pump normothermic CABG with IAWBC preserved systolic function, increased diastolic stiffness, and improved systolic and diastolic chronotropic responses. Normalization of the chronotropic responses post-CPB is likely due to effects of successful revascularization and subsequent relief of ischemia.     

Reduction of systolic and diastolic dysfunction by retrograde coronary sinus perfusion during off-pump coronary surgery

OBJECTIVES: We evaluated the protective effects of retrograde coronary sinus perfusion to offset potential systolic and diastolic dysfunction (myocardial stunning) after temporary regional ischemia needed for off-pump coronary artery bypass grafting. METHODS: Twenty Yorkshire-Duroc pigs (31.8 +/- 3.9 kg) underwent 15 minutes of mid-left anterior descending coronary artery ischemia in the beating heart. In 8 pigs, no protective measures were used. In 12 pigs, an aorta-coronary sinus shunt (with conventional cannulas) allowed retrograde perfusion during temporary ischemia; in 6 of these pigs, no leakage to the right atrium was ensured. Regional endocardial contraction was measured with sonomicrometer crystals. Systolic dysfunction (impaired regional shortening), diastolic dysfunction (contraction extending into early diastole), and coronary sinus nitric oxide and endothelin-1 levels were recorded. RESULTS: Before ischemia, contraction did not extend into the diastolic interval. During ischemia, paradoxic bulging occurred in all hearts except in the occlusive coronary sinus shunt group (16% +/- 6% of baseline, P <.01). Sixty minutes after ischemia, systolic segment shortening recovered 36% +/- 24% without retrograde perfusion versus 56% +/- 20% and 61% +/- 14% with coronary sinus shunting (P <.05). Diastolic dysfunction (as percentage of diastolic time in contraction) was 38% +/- 16% in the nontreated group versus 22% +/- 22% and 9% +/- 9% (P <.05) after shunting and occlusive shunting, respectively. This correlated with a left ventricular end-diastolic pressure increase of 4 mm Hg in the ischemic group versus no change in the retrograde perfusion groups. Nitric oxide decreased 15% without shunting and increased 8% after occlusive coronary sinus shunting (P <.05). CONCLUSIONS: Retrograde coronary sinus perfusion during simulated off-pump coronary revascularization diminishes systolic and diastolic dysfunction. An aortic-coronary sinus shunt is a rapid, recognized approach that can improve myocardial muscle and endothelial safety during off-pump coronary artery bypass grafting.     

Regional myocardial blood flow in left ventricular hypertrophy. An experimental investigation in Newfoundland dogs with congenital subaortic stenosis

To test the hypothesis that left ventricular hypertrophy (LVH) may predispose the subendocardium to ischemia, we studied regional myocardial blood flow in dogs with the fibrous ring form of subvalvular aortic stenosis and concentric LVH. Radioactive microspheres, 9 +/- 1 mu in diameter, were used. Eleven dogs with LVH (left ventricular body weight ratio of 6.35 +/- 0.46 gm/kg [mean +/- SEM] and peak left ventricular outflow gradient of 51 +/- 7 mm Hg) were compared to 12 normal dogs (left ventricular/body weight ratio of 3.41 +/- 0.12 gm/kg and peak left ventricular outflow gradient of 6 +/- 3 mm Hg). The two groups of dogs were subjected to comparable experimental interventions including (1) tachycardia produced by atrial pacing (221 +/- 4 beats/min), (2) ascending aortic constriction producing systolic hypertension (212 +/- 5 mm Hg), and (3) creation of an aortic-right atrial fistula lowering diastolic blood pressure (38 +/- 3 mm Hg). Basal regional myocardial blood flow was distributed similarly for LVH and normal dogs (endocardial/epicardial ratio = 0.90 +/- 0.05 and 0.94 +/- 0.03, respectively). During experimental interventions, regional blood flow remained equal to all myocardial layers in normal dogs; however, the endocardial/epicardial ratio diminished in LVH dogs during atrial tachycardia to 0.61 +/- 0.08, during systolic hypertension to 0.68 +/- 0.06, and during diastolic hypotension to 0.50 +/- 0.09. When the diastolic/systolic pressure time index ratio (DPTI/SPTI) was less than 0.8, subendocardial ischemia occurred in dogs with LVH (endocardial/epicardial ratio = 0.66 +/- 0.04) but not in normal dogs (endocardial/epicardial ratio = 0.92 +/- 0.03) (p less than 0.0001). Animals with infracoronary obstruction and LVH demonstrate greater susceptibility to development of subendocardial ischemia for identical hemodynamic interventions than do normal animals.     

Reversibility of pulmonary artery hypertension in aortic stenosis after aortic valve replacement

Fifty-two surgical patients with isolated aortic valve stenosis were studied preoperatively and postoperatively to determine the incidence of pulmonary hypertension and its response to surgical intervention. Pulmonary artery systolic hypertension was classified as absent (group 1, less than 30 mm Hg), mild (group 2, 30 to 39 mm Hg), moderate (group 3, 40 to 59 mm Hg), and severe (group 4, greater than 60 mm Hg). Thirty-seven of our patients (71%) had preoperative pulmonary hypertension. There was a positive correlation between left ventricular end-diastolic pressure and both systolic and diastolic pulmonary artery pressures preoperatively (p less than 0.001). After operation we found a decrease in mean systolic pulmonary pressure in group 4, from 85.8 +/- 23 mm Hg to 41.2 +/- 10.4 mm Hg (a 52% decrease, p less than 0.001), and in group 3, from 48.9 +/- 5.9 mm Hg to 32.1 +/- 7.1 mm Hg (a 34% decrease, p less than 0.001). A significant decrease in the mean diastolic pressure was found only in group 4, in which the pressure decreased from 33.7 +/- 8.7 mm Hg to 26.0 +/- 7.6 mm Hg (p less than 0.05). The operative mortality was 1.9%. Our data indicate that pulmonary artery hypertension in aortic stenosis is common, is related to end-diastolic pressure, and can be expected to improve in the early postoperative period.     

Start with a subjective assessment of skin temperature to identify hypoperfusion in intensive care unit patients

OBJECTIVE: To determine whether physical examination alone or in combination with biochemical markers can accurately diagnose hypoperfusion. METHODS: Data from 264 consecutive surgical intensive care unit patients were collected by two intensivists and included extremity temperature, vital signs, arterial lactate, arterial blood gases, hemoglobin, and pulmonary artery catheter values with derived indices. Days of data were divided into data collected from patients with cool extremities (cool skin temperature [CST] group) versus warm extremities (warm skin temperature [WST] group). Values are means +/- SD. Comparisons between groups were made by two-tailed unpaired t test; significance was assumed for p < or = 0.05. RESULTS: There were 328 days of observations in the CST group versus 439 in the WST group. There were no differences (p > 0.05) between CST and WST data with regard to heart rate (107 +/- 14 vs. 99 +/- 19 beats/min), systolic blood pressure (118 +/- 24 vs. 127 +/- 28 mm Hg), diastolic blood pressure (57 +/- 14 vs. 62 +/- 15 mm Hg), pulmonary artery occlusion pressure (14 +/- 6 vs. 16 +/- 5 mm Hg), Fio2 (0.48 +/- 0.7 vs. 0.45 +/- 0.2), hemoglobin (8.8 +/- 1.6 vs. 9.3 +/- 1.3 g/dL), Pco2 (44.3 +/- 11.8 vs. 40.7 +/- 9.2 mm Hg), or Po2 (96.4 +/- 12.6 vs. 103.8 +/- 22.2 mm Hg). However, cardiac output (5.3 +/- 2.2 vs. 8.2 +/- 2.6 L/min), cardiac index (2.9 +/- 1.2 vs. 4.3 +/- 1.2 L/min/m2), pH (7.32 +/- 0.2 vs. 7.39 +/- 0.07), TCO2 (19.5 +/- 3.1 vs. 25.1 +/- 4.8 mEq/L), and Svo2 (60.2 +/- 4.4% vs. 68.2 +/- 7.8%) were all significantly lower (p < 0.05) in CST patients compared with WST patients. By comparison, lactate (4.7 +/- 1.5 vs. 2.2 +/- 1.6 mmol/L, p < 0.05) was significantly elevated in patients with cool extremities. CONCLUSION: Combining physical examination with serum bicarbonate and arterial lactate identifies patients with hypoperfusion as defined by low Svo2 and cardiac index. Hypoperfusion may occur despite supranormal cardiac indices. Patients with cool extremities and elevated lactate levels may benefit from a pulmonary artery catheter to guide but not initiate therapy.