Erwin P. Bauer

Progression From Compensated Hypertrophy to Failure in the Pressure-Overloaded Human Heart Structural Deterioration and Compensatory Mechanisms

Background—The progression of compensated hypertrophy to heart failure (HF) is still debated. We investigated patients with isolated valvular aortic stenosis and differing degrees of left ventricular (LV) systolic dysfunction to test the hypothesis that structural remodeling, as well as cell death, contributes to the transition to HF. Methods and Results—Structural alterations were studied in LV myectomies from 3 groups of patients (group 1: ejection fraction [EF] >50%, n=12; group 2: EF 30% to 50%, n=12; group 3: EF <30%, n=10) undergoing aortic valve replacement. Control patients were patients with mitral valve stenosis but normal LV (n=6). Myocyte hypertrophy was accompanied by increased nuclear DNA and Sc-35 (splicing factor) content. ACE and TGF-&bgr;1 were upregulated correlating with fibrosis, which increased 2.3-, 2.2-, and 3.2-fold over control in the 3 groups. Myocyte degeneration increased 10, 22, and 32 times over control. A significant correlation exists between EF and myocyte degeneration or fibrosis. Ubiquitin-related autophagic cell death was 0.5‰ in control and group 1, 1.05 in group 2, and 6.05‰ in group 3. Death by oncosis was 0‰ in control, 3‰ in group 1, and increased to 5‰ (groups 2 and 3). Apoptosis was not detectable in control and group 3, but it was present at 0.02‰ in group 1 and 0.01‰ in group 2. Cardiomyocyte mitosis was never observed. Conclusions—These structure-function correlations confirm the hypothesis that transition to HF occurs by fibrosis and myocyte degeneration partially compensated by hypertrophy involving DNA synthesis and transcription. Cell loss, mainly by autophagy and oncosis, contributes significantly to the progression of LV systolic dysfunction.

Increased Expression of Cytoskeletal, Linkage, and Extracellular Proteins in Failing Human Myocardium

Experimental studies have shown that in hypertrophy and heart failure, accumulation of microtubules occurs that impedes sarcomere motion and contributes to decreased ventricular compliance. We tested the hypothesis that these changes are present in the failing human heart and that an entire complex of structural components, including cytoskeletal, linkage, and extracellular proteins, are involved in causing functional deterioration. In explanted human hearts failing because of dilated cardiomyopathy (ejection fraction </=20%), expression of alpha- and beta-tubulin, desmin, vinculin, fibronectin, and vimentin was determined by Northern and Western blot analysis and compared with normal myocardium from explants not used for transplantation. The mRNA for alpha- and beta-tubulin was increased to 2.4-fold (P<0.01) and 1.25-fold (NS), respectively; for desmin, 1.2-fold (P<0.05); for fibronectin, 5-fold (P<0.001); and for vimentin, 1.7-fold (P<0.05). Protein levels for alpha-tubulin increased 2.6-fold (P<0.02); for beta-tubulin, 1.2-fold (P<0.005); for desmin, 2.1-fold (P<0.001); for vinculin, 1.2-fold (P<0.005); for fibronectin, 2.9-fold (P<0.001); and for vimentin, 1.5-fold (P<0. 005). Confocal microscopy showed augmentation and disorganization of all proteins studied. In combination with the loss of myofilaments and sarcomeric skeleton previously reported, these changes suggest cardiomyocyte remodeling. Increased fibronectin and elevated interstitial cellularity (vimentin labeling) indicate progressive fibrosis. The present results suggest a causative role of cytoskeletal abnormalities and myofilament loss for intrinsic contractile and diastolic dysfunction in failing hearts.

Spatiotemporal Development and Distribution of Intercellular Junctions in Adult Rat Cardiomyocytes in Culture

The mode of development of the intercalated disk (ID) is largely unknown, and the hypothesis was tested that the assembly of cell adhesion junctions may precede the formation of gap junctions (GJ) in developing ID in adult rat cardiomyocyte (ARC) in long-term culture. Immunostaining for connexin 43 (Cx43) and for cell adhesion junction proteins (N-cadherin, catenins, and desmoplakin) in single- and double-label techniques was analyzed and quantified by confocal and electron microscopy. All proteins investigated disappeared 48 hours after ARC isolation and reappeared parallel to redifferentiation of ARC. The newly formed ID, observed after 5 days, showed the presence of N-cadherin, catenins, and desmoplakin, low levels of Cx43, and absence of ultrastructurally discernible gap junctions. A progressive incorporation of Cx43 within ID was observed after 6 days, when cell adhesion junction proteins were already organized as zipper-like structures. Quantitative confocal analysis revealed a progressive augmentation of the fluorescence intensity of Cx43, associated with an increase in both the number and size of GJ, resulting in a substantial increase in the percentage of total GJ length per reassembled ID from 1.67% (day 6) to 15.58% (day 12). In the present study, we show that (1) the formation of the ID can be followed in ARC in culture and (2) the assembly of the adhering type of junction is the prerequisite for subsequent GJ formation within the ID. These findings may have clinical relevance in elaborating strategies for using myocardial grafts and for the potential restoration of GJ communication in cardiac diseases.

Upregulated and Downregulated Transcription of Myocardial Genes After Pulmonary Artery Banding in Pigs

BACKGROUND Acute or chronic pressure overload may occur during or after cardiac surgical procedures. Typical examples are aortic cross-clamping and pulmonary artery banding. It is well known that mechanical stress induces transcription of different myocardial genes. However, these results were mainly obtained from in vitro studies and experiments with rodents. This experiment was carried out to investigate molecular alterations after pressure overload in porcine hearts. METHODS The study was performed with 35 Landrace pigs with a mean weight of 32+/-1.2 kg. The five groups consisted of 7 pigs each, 3 sham-operated pigs and 4 banded pigs. The hearts were exised after different time intervals. We investigated messenger RNA expression of sarcoplasmic reticulum adenosine triphosphatase, phospholamban, alpha-/beta-myosin heavy chain, and atrial natriuretic factor by Northern blot analysis. RESULTS The ratio of right ventricular weight to body weight increased significantly after 7 and 24 days in banded pigs (p < 0.05). Atrial natriuretic factor messenger RNA was significantly upregulated in banded pigs versus sham-operated pigs after 1 day (240%+/-7% versus 100%+/-6%; p < 0.01) and 3 days (520%+/-8% versus 100%+/-8%; p < 0.01). There was insignificant downregulation of sarcoplasmic reticulum adenosine triphosphatase and phospholamban after 1, 3, and 7 days. Myosin heavy chain messenger RNA expression remained unchanged. CONCLUSIONS Pulmonary artery banding results in hypertrophic response of the porcine right ventricle; however, the weight increase is not the result of myosin heavy chain messenger RNA upregulation. Atrial natriuretic factor messenger RNA is locally expressed in mechanically stressed myocytes. Furthermore, pressure overload downregulates transcription of calcium-binding proteins that can influence ventricular contractility. These results may have an impact on cardiac surgical procedures.

Cardioscopy: potential applications and benefit in cardiac surgery

OBJECTIVE Cardioscopy in open heart surgery is still not routine in most units. However, since our first report in 1996 we use this device more frequently, because we think that safety and accuracy of different surgical procedures is increased. METHODS Between 1/96 and 12/97 we performed cardioscopy in 100 patients. Indications (IND) for cardioscopy were as follows: IND (1) resection of hypertrophied septum (N = 15); IND (2) evaluation of aortic valve with low grade stenosis or insufficiency (N = 12); IND (3) removal of intracardiac foreign bodies/tumors (N = 13); IND (4) inspection of VSD prior and after repair (N = 8); IND (5) identification of paravalvular leakage (N = 8); IND (6) diagnostic purposes (N = 4); IND (7) education of surgeons and operating room staff (N = 40). During cardioplegic arrest the 5 mm rigid or flexible cardioscope (Storz, Tuttlingen, Germany) was inserted through ascending aorta, aortic valve or tricuspid valve depending on indication. RESULTS No complication occurred during cardioscopy. IND (1): there was an excellent view of all intracardiac structures. Thorough resection of hypertrophied septum was possible and there was no injury of adjacent structures or aortic valve. IND (2): all valves were inspected through a 1 cm aortic incision and the pathology of the valves was documented. In case of severe calcification, the valve was replaced although transvalvular gradient was less than 50 mm Hg. IND (3): intraventricular foreign bodies, such as felt pledges (N = 2), debris (N = 5), thrombi (N = 4) and tumors (N = 2) were entirely removed through the aortic valve with a special forceps. IND (4): anatomy of VSD was documented in all cases. It was possible to test accuracy of all patch-sutures. IND (5): all paravalvular leakages were identified even though there was heavy immobility of the mechanical valve. IND (6): a papillary muscle (N = 2) and a thrombus formation (N = 2) were diagnosed. IND (7): the surgeons and operating room staff could follow the entire procedure in all cases. CONCLUSIONS Cardioscopy is a supporting technique to clearly identify intracardiac structures, to control several surgical procedures, to document valve pathology, and to educate surgeons and operating room staff. Handling is easy and does not increase operative risk. Some procedures will be performed with minimal invasivity in future.

Increased growth factor transcription after pulmonary artery banding

OBJECTIVE Several mechanisms are known to produce mechanical stress during and after cardiac surgery, e.g. aortic cross-clamping and pulmonary artery banding (PAB). However, little is known about the transcription of myocardial genes which are changed during mechanical overload. This study was performed to investigate growth factor mRNA expression after PAB in porcine hearts. METHODS The experiment was performed in 35 pigs (five groups). Each group consisted of three sham-pigs (S-pigs) and four banding-pigs (B-pigs). The mean transbanding gradient in B-pigs was 29 +/- 2.5 mm Hg. The hearts were excised after different time intervals. The probes were snap-frozen in liquid nitrogen and stored at -80 degrees C. Analysis was performed by Northern blot. RESULTS Right ventricular weight increased significantly after 7 and 24 days (P < 0.05). There was an upregulation of transcriptional and growth factors in B-pigs: c-jun mRNA: 412 +/- 12.1% after 2 h (P < 0.001); c-fos mRNA: 303 +/- 18.5% after 2 h (P < 0.001); vascular endothelial growth factor (VEGF) mRNA: 203 +/- 18.2% after 2 h (P < 0.001); Flk-1 mRNA: 156 +/- 16% after 2 h (P < 0.05), 253 +/- 5% after 24 h (P < 0.01) and 184 +/- 12% after 3 days (P < 0.01); transforming growth factor-beta1 (TGF-beta1) mRNA: 255 +/- 21.5% after 24 h (P < 0.002). Fibroblast growth factors 1 and 2 (FGF-1 and FGF-2) were constitutively expressed in B- and S-pigs and did not change their expression. CONCLUSIONS Pulmonary artery banding results in significant right ventricular hypertrophy and upregulation of different growth factors. However, growth factors known to induce hypertrophy in vitro, like the FGFs, showed unchanged expression. We think that myocardial growth factors may have trophic functions in the heart which may be useful for cardiac surgery in future.

Video-Assisted Resection of Hypertrophied and Fibrous Intraventricular Tissue

There is increasing interest in endoscopic techniques in cardiac surgery. However, use of the endoscope during open heart operations is still not routine. Cardioscopy has been used in patients with hypertrophied obstructive cardiomyopathy, asymmetric septal hypertrophy, or membranous subaortic stenosis. We demonstrate the resection of this pathologic tissue under direct visualization. With this technique we could increase the safety and accuracy of this surgical procedure. Beside this advantage, the entire operating room staff could follow the surgical intervention, which increases its educational side-effect.

Diagnostic Transaortic Cardioscopy of the Left Ventricle

Preoperative diagnosis of pathologic intracardiac structures by noninvasive techniques is sometimes difficult or even impossible. In these cases a heart operation is required with opening of one or more cardiac chambers. We demonstrate direct visualization of the left ventricular cavity by transaortic cardioscopy in a patient with a pathologic intraventricular structure. With this technique we could avoid ventriculotomy.

Valve surgery combined with coronary artery operation: is the use of internal mammary artery a predictor for early complications?

The internal mammary artery (IMA) provides better early and long-term patency than venous grafts do. Although IMA is the conduit of choice in isolated coronary artery bypass grafting (CABG), its use in combined procedures is not routine in some cardiovascular units. During a 16-month period, 188 patients underwent valve surgery combined with CABG. Internal mammary grafts were used in 68/188 (36%) patients (group 1) and vein grafts without arterial grafts (group 2) in 120/188 (64%). Left IMA was implanted in 67/68 (99%) and right IMA in 1/68 1%) cases. Surgeon A used IMA in 28/44 (64%), surgeon B in 20/32 (63%), surgeon C in 18/44 (41%), surgeon D in 1/4 (25%) and surgeon E in 1/63 (2%) patients. The final decision to use IMA in a combined procedure was left up to the surgeon. Statistically, the preoperative- and perioperative data were identical in the two groups, although the frequency of IMA grafting in patients with double valve replacement and reoperation was lower (1/68 vs 11/120, ns, and 3/68 vs 9/120, ns). Ten of 188 (5.3%) patients died within 30 days after operation. Longer cross-clamp time (P = 0.008) and mitral valve replacement (P = 0.05) were independent risk factors for early death. The use of IMA did not increase the risk of early mortality. The postoperative variables were similar in the IMA and vein groups, in particular data suggesting perioperative myocardial infarction (CK-MB, catecholamine support). Postoperative mechanical ventilation was longer in the IMA group, although not significantly (P = 0.06). Early mortality and morbidity were identical in the two groups in combined procedures. We did not find any hints for an increased risk of using IMA in this type of surgery. Internal mammary artery implantation is safe in selected patients undergoing combined valve and CABG surgery. Beside the better long-term patency of IMA, its use may have several technical advantages.

Thrombotic formations within the aortic arch as source of embolization in patients with coagulopathia

Thrombotic formations on atherosclerotic lesions of the thoracic aorta are potential sources of cerebral and systemic embolization. Especially younger patients without calcifications of atherosclerotic plaques or coagulation disorders have a higher risk for embolization. Magnetic resonance imaging and transesophageal echocardiography are the diagnostic methods of choice. As an alternative to anticoagulation surgical therapy is indicated to prevent severe brain damage or multiorgan failure in patients with mobile thrombotic formations. Herein we describe two patients in whom successful surgical treatment was performed in deep hypothermic circulatory arrest by excision of the aortic arch atheroma.