Gregory A. Thomas

Skeletal muscle ventricles: Left ventricular apex to aorta configuration

Skeletal muscle ventricles (SMVs) were constructed from the latissimus dorsi muscle in 6 dogs. After 3 weeks of vascular delay followed by 6 weeks of 2-Hz continuous electrical conditioning, a valved conduit was placed between the left ventricular apex and the SMV and a second valved conduit, between the SMV and the aorta. The SMV was stimulated to contract during diastole at a 1:2 ratio with the heart. The SMV pumped 47% of the systemic blood flow initially (0.73 ± 0.23 versus 1.54 ± 0.42 L/min) and 40% after 3 hours. Skeletal muscle ventricle stimulation resulted in a 58% increase in mean diastolic pressure initially (52 ± 9 to 82 ± 11 mm Hg; p < 0.05) and a 73% increase (45 ± 7 to 78 ± 8 mm Hg) after 3 hours of continuous pumping. This was associated with a 68% increase in the endocardial viability ratio initially and a 63% increase at 3 hours. The systolic tension-time index decreased by 26% initially and 25% at 3 hours. This study indicates that the SMV configuration of left ventricular apex to aorta may be particularly suitable for left ventricular assist.

Functional assessment of skeletal muscle ventricles after pumping for up to four years in circulation

BACKGROUND The successful treatment of cardiac failure by heart transplantation is severely limited by the shortage of donor organs, and alternative surgical approaches are needed. An experimental approach that holds considerable promise is the skeletal muscle ventricle (SMV), an auxiliary blood pump formed from a pedicled graft of latissimus dorsi muscle and connected to the circulation in a cardiac assist configuration. Adaptive transformation, or conditioning, by electrical stimulation enables the skeletal muscle to perform a significant proportion of cardiac work indefinitely without fatigue. METHODS In 10 dogs, SMVs were constructed from the latissimus dorsi muscle, lined internally with pericardium, and conditioned by electrical stimulation to induce fatigue resistant properties. The SMVs were connected to the descending thoracic aorta via two 12-mm Gore-Tex conduits and the aorta was ligated between the two grafts. The SMV was stimulated to contract during the diastolic phase of alternate cardiac cycles. The animals were monitored at regular intervals. RESULTS At initial hemodynamic assessment, SMV contraction augmented mean diastolic blood pressure by 24.6% (from 61 +/- 7 to 76 +/- 9 mm Hg). Presystolic pressure was reduced by 15% (from 60 +/- 8 to 51 +/- 7 mm Hg) after an assisted beat. Four animals died early, 1 from a presumed arrhythmia, and 3 during propranolol-induced hypotension. The other 6 animals survived for 273, 596, 672, 779, 969, 1,081, and 1,510 days. Diastolic augmentation was 27.4% at 1 year (93 +/- 9 vs 73 +/- 6 mm Hg; n = 5), 34.7% at 2 years (85 +/- 6 vs 63 +/- 7 mm Hg; n = 3), 21.2% (89 +/- 10 vs 73 +/- 8 mm Hg; n = 2) at 3 years, and 34.5% (78 vs 58 mm Hg; n = 1) after 4 years in circulation. After 4 years, the isolated SMV was able to maintain a pressure of over 80 mm Hg while ejecting fluid at 20 mL/s. No animal showed evidence of SMV rupture or thromboembolism. CONCLUSIONS The SMVs in this study provided effective and stable hemodynamic assistance over an extended period of time. There was no evidence that the working pattern imposed on the muscular wall of the SMV compromised its viability. Areas of fibrofatty degeneration were suggestive of early damage that future protocols should seek to minimize.

Pericardium-lined skeletal muscle ventricles in circulation up to 589 days

Skeletal muscle ventricles (SMVs) were constructed from the latissimus dorsi muscle in 15 beagles. The animals were divided into two groups based on modifications in the SMV construction: group I consisted of 5 animals and group II of 10 animals. After a 3-week vascular delay and 6 to 8 weeks of 2-Hz electrical conditioning, the SMVs were connected to the thoracic aorta. In group I, counterpulsation at 33 Hz resulted in an initial 24.4% augmentation of the mean diastolic pressure, a 27.1% decrease in the presystolic pressure, and a 15.9% increase in the endocardial viability ratio. In group II, the mean diastolic pressure rose by 24.7%, the presystolic pressure decreased by 14.3%, and the endocardial viability ratio increased by 24.5%. During propranolol-induced heart failure, the percentage increase in the mean diastolic pressure was improved (12.9% before propranolol infusion versus 27.6% during propranolol infusion), as was the percentage increase in the endocardial viability ratio (11.2% versus 28.7%). Under low cardiac output conditions, SMV contraction resulted in small but statistically significant increases in the total cardiac output (4.3% at 33 Hz, 7.6% at 85 Hz). One animal in group I survived for 589 days with a functioning SMV before progressive dilation of the SMV (impending rupture) developed. Delayed rupture of the SMV sewing ring anastomosis occurred in 2 dogs. Five animals in group II are all alive, with functioning SMVs in the circulation for 377 to 464 days. No animals in group II had rupture of their SMV or showed evidence of thrombus formation.

Chronic morphologic changes of skeletal muscle ventricles in circulation

Skeletal muscle ventricles (SMVs) were constructed either extrathoracically or intrathoracically in 44 dogs using the left latissimus dorsi muscle. These SMVs functioned as aortic counterpulsators for from several hours to 216 days. In this study, the relationship between the morphologic changes in the SMVs and their time course in the circulation was evaluated retrospectively. The average volume of the SMV chamber after it had been excised and fixed in formalin was 21.3 +/- 11.0 mL (mean +/- the standard deviation) for extrathoracic SMVs and 20.0 +/- 7.5 mL for intrathoracic SMVs. The volume of the SMV chamber did not correlate with the time course in the circulation. The SMV wall was mainly composed of three components: muscular, fibrous, and fatty aspects. The overall thickness of the wall appeared to be preserved over time in the circulation. However, the thickness of the muscular component tended to decrease over time. SMV rupture occurred in 15 dogs between postoperative days 4 and 39. All ruptures occurred at the suture line between the SMV and the vascular conduits. There was some degree of thrombus in 24 SMVs. Before SMVs can be applied clinically for the purpose of cardiac assist, problems with rupture and thrombus formation must be solved. A better understanding of the morphologic changes that take place in the SMV over time also is needed.

Endothelial cell–lined skeletal muscle ventricles in circulation

Skeletal muscle ventricles were constructed from the latissimus dorsi in six dogs by wrapping the muscle around a polypropylene mandrel. Jugular vein endothelial cells were harvested enzymatically and grown in tissue culture. After 3 weeks of vascular delay and 4 weeks of electrical conditioning, five skeletal muscle ventricles were seeded with 5 to 8 x 10(6) autologous endothelial cells by percutaneous injection of a cellular suspension into the lumen of the skeletal muscle ventricle; one skeletal muscle ventricle was injected with culture medium alone as an unseeded control. The autologous endothelial cells were all prelabeled with a lipid-bound cellular marker, PKH-26. After an additional 4 weeks of electrical conditioning, the mandrels were removed and the skeletal muscle ventricles were connected to the descending thoracic aorta and activated to contract during cardiac diastole at a 1:2 ratio with the heart. After 3 hours of continuous pumping, mean diastolic pressure was increased by 35% (58 +/- 7 versus 78 +/- 6 mm Hg, p < 0.05). At this time, the skeletal muscle ventricles were excised for histologic examination. Sections stained with hematoxylin and eosin revealed a continuous cellular layer lining the skeletal muscle ventricle; no cells were present on the lumen of the control skeletal muscle ventricle. All seeded skeletal muscle ventricles exhibited fluorescence as a result of the PKH-26 cellular marker. Immunofluorescent staining with antibodies to von Willebrand factor and ultrastructural analysis with an electron microscope confirmed the endothelial character of these cells lining the lumen of the skeletal muscle ventricles. The ability to create endothelial cell-lined muscular pumping chambers holds important implications for the resolution of thrombotic events in cardiac assist devices as well as toward the clinical application of skeletal muscle ventricles.

Pericardium-Lined Skeletal Muscle Ventricles: Up to Two Years' In-Circulation Experience1

BACKGROUND Skeletal muscle ventricles (SMVs) are autologous pumping chambers constructed from skeletal muscle. Skeletal muscle ventricular rupture and thromboembolism have complicated chronic models of this method of skeletal muscle cardiac assist. METHODS The SMVs were constructed from the latissimus dorsi muscle in 10 dogs. The inner surface of each SMV was lined with autologous pericardium harvested at the time of SMV construction. After a 3-week period of vascular delay and 6 weeks of electrical conditioning to convert the muscle to a fatigue-resistant state, SMVs were connected to the descending thoracic aorta and stimulated to contract during cardiac diastole. RESULTS Initial hemodynamics revealed that SMV contraction at 33 Hz increased diastolic pressure 24.7% (60.8 +/- 7.3 mm Hg versus 80.3 +/- 8.8 mm Hg). Skeletal muscle ventricle relaxation decreased presystolic pressure 14.4% (59.9 +/- 7.7 mm Hg versus 51.3 +/- 7.5 mm Hg) and decreased peak systolic pressure 4.1% (90.2 +/- 7.3 mm Hg versus 86.5 +/- 5.8 mm Hg). Hemodynamics were assessed at 1 to 2 weeks, then at 1, 2, 3, and 6 months, and at 6-month intervals thereafter. Hemodynamic performance remained stable for the duration of this study. After 2 years of pumping continuously in circulation, SMV contraction resulted in a 34.8% augmentation of diastolic pressure (63.6 +/- 6.6 mm Hg versus 85.3 +/- 6.4 mm Hg), a 17.2% decrease in presystolic pressure (54.7 +/- 3.73 mm Hg versus 45.3 +/- 4.1 mm Hg), and a 4.2% decrease in peak systolic pressure (95.3 +/- 10.4 mm Hg versus 91.3 +/- 12.3 mm Hg). Three dogs survived to 2 years with the SMVs in circulation. No animal showed evidence of thromboembolism during serial echocardiography or at autopsy and no SMVs ruptured. CONCLUSIONS These data demonstrate that SMVs can provide effective hemodynamic assist over an extended period without specific complications related to the SMVs.

Skeletal muscle ventricles seeded with autogenous endothelium.

&NA; Skeletal muscle ventricles (SMVs) are muscular pumping chambers constructed from skeletal muscle. Previously, SMVs were connected to the systemic circulation with vascular conduits and used to assist the heart. In this study, SMVs were constructed from the latissimus dorsi muscle in eight dogs. The SMVs were seeded with autologous endothelial cells, but not connected to the circulation. Endothelial cells were harvested enzymatically from autogenous external jugular vein and grown in tissue culture. After 9 weeks, 6 electrically conditioned SMVs were seeded with endothelial cells by injecting 4‐5 ml of culture medium containing 5‐8 × 106 autogenous endothelial cells into each SMV lumen adjacent to the mandrel. Conditioning was stopped at the time of endothelial seeding. One week after seeding, electrical conditioning was resumed. Two weeks after seeding, the animals were killed and the SMVs excised. Histologic examination confirmed the presence of a confluent monolayer of cells covering 80‐100% of the luminal surface in each seeded SMV. The endothelial nature of the cells lining the SMV lumen was established by fluorescent microscopy. Endothelial cells were pre labeled with the cellular marker PKH before seeding; the SMVs were also incubated with the endothelial marker dil‐acetylated LDL. Endothelial cells also were identified by staining with fluorescently labeled antibodies to von Willebrand factor. Based upon these data, electrically conditioned SMVs can be seeded successfully with a near‐complete, autologous endothelial monolayer. Additionally, this endothelial monolayer can be maintained on the luminal surface of a contracting SMV. In‐circulation studies will determine whether endothelial cell seeding of SMVs can decrease or eliminate the incidence of thromboembolism. ASAIO Journal 1995; 41:204‐211.

Power output of pericardium-lined skeletal muscle ventricles, left ventricular apex to aorta configuration: Up to eight months in circulation

OBJECTIVE The purpose of this experiment was to evaluate the potential for a skeletal muscle ventricle connected to the circulation between the left ventricle and the aorta to provide effective, long-term cardiac assist. METHODS Skeletal muscle ventricles were constructed from the latissimus muscle in 10 dogs. After conditioning, the skeletal muscle ventricles were connected to the left ventricle and the aorta with 2 valved conduits. The skeletal muscle ventricle was programmed to contract during diastole. RESULTS At time of implantation, skeletal muscle ventricles stimulated at 33 Hz and in a 1:2 ratio with the heart significantly decreased left ventricular work by 56% (P <.01) and at 50 Hz by 65% (P <.01). At a 1:2 ratio, the power output of the skeletal muscle ventricles was 59% of left ventricular power output at 33 Hz (P <. 01) and 93% at 50 Hz (P <.01). Animals survived 7, 11, 16, 17, 72, 99, 115, 214, and 249 days. Three deaths were directly related to the skeletal muscle ventricle. One animal is alive at 228 days. In the animal that survived 249 days, skeletal muscle ventricle power output at 8 months with a 33 Hz stimulation frequency and a 1:2 contraction ratio was 57% of left ventricular power output and 82% at 50 Hz. At a 1:1 ratio, skeletal muscle ventricle power output was 97% and 173% of the left ventricle at 33 and 50 Hz, respectively. CONCLUSIONS Left ventricular assist with a skeletal muscle ventricle connected between the left ventricle and the aorta is the most hemodynamically effective configuration we have tested and can maintain significant power output up to 8 months.

Skeletal muscle ventricles in circulation: Decreased incidence of rupture

BACKGROUND Skeletal muscle ventricles (SMVs) are muscular pumping chambers constructed for cardiac assist. Skeletal muscle ventricles can be connected to the circulation in a variety of configurations for both left and right heart assist; when connected to the aorta and stimulated to contract during diastole, they function in a similar fashion as an intraaortic balloon pump. METHODS Skeletal muscle ventricles were constructed in 18 dogs using the left latissimus dorsi muscle. In 10 of these dogs (group 1), the inner surface of the SMV was lined with autogenous pericardium obtained at the time of construction of the SMV. For the remaining 8, the SMVs were lined by fibrous tissue that forms in reaction to the synthetic mandrel around which the latissimus muscle is wrapped. After the muscles were electrically conditioned to a fatigue-resistant state, the mandrels were removed from the SMVs and the SMVs were connected to the descending thoracic aorta with a specially constructed base cap and two polytetrafluoroethylene conduits. RESULTS Initial hemodynamic recordings revealed that the mean diastolic blood pressure increased by 24.7% in group 1 and by 29.8% in group 2. Diastolic augmentation was well maintained over time; augmentation in surviving group 1 animals was 30.0% after 18 months of pumping continuously in circulation. Long-term survival was greater in the dogs whose SMVs were constructed using an inner pericardial lining. At 90 days in circulation, 60% of the dogs in group 1 were alive with functioning SMVs, whereas only 13% of the dogs in group 2 were alive. The incidence of SMV rupture in the fibrouslined SMVs was 63%, whereas the incidence in the pericardial-lined SMVs was 0%. No evidence of thromboembolism occurred in either group. CONCLUSIONS Lining the inner surface of an SMV with pericardium appears to provide structural integrity, which helps to prevent the complication of SMV rupture in this model of cardiac assist.

Double cardiomyoplasty: Acute versus chronic results☆☆☆

We previously found that double cardiomyoplasty using both acutely raised, unconditioned latissimus dorsi muscles increased cardiac output by 9.6% (1,547 +/- 154 versus 1,695 +/- 166 mL/min), stroke volume by 18.2% (12.1 +/- 0.6 versus 14.3 +/- 0.7 mL), peak left ventricular pressure by 18.4% (98 +/- 3 versus 116 +/- 5 mm Hg), and peak right ventricular pressure by 62.5% (24 +/- 2 versus 39 +/- 4 mm Hg) (p < 0.05 for all differences). In this study 10 dogs underwent double cardiomyoplasty: 3 died perioperatively, and 7 underwent 8 weeks of muscle conditioning. After the conditioning period, the muscle flaps did not contract in 2 of the 7 dogs. Hemodynamics were measured in the remaining 5 dogs. Using fatigue-resistant muscle, cardiac output decreased by 3.7% (1,279 +/- 262 versus 1,233 +/- 274 mL/min), stroke volume decreased by 9.0% (9.5 +/- 1.2 versus 8.8 +/- 1.2 mL), and peak left ventricular pressure increased by 10.6% (82.1 +/- 6.5 versus 90.8 +/- 3.2 mm Hg), but not significantly. Peak right ventricular pressure increased significantly by 31.3% (24.3 +/- 2.1 versus 31.9 +/- 3.6 mm Hg; p < 0.05). Hemodynamic effects of individual left or right muscle contractions versus bilateral muscle stimulation were not significantly different except for a greater percentage increase in peak right ventricular pressure (right, 24.9 +/- 2.1 mm Hg unstimulated versus 28.0 +/- 2.1 stimulated; left, 26.3 +/- 0.9 mm Hg unstimulated versus 30.7 +/- 2.4 mm Hg stimulated; bilateral, 24.3 +/- 2.1 mm Hg unstimulated versus 31.9 +/- 3.4 mm Hg stimulated; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)