Ingeborg Friehs

Fluid dynamic comparison of intra-atrial and extracardiac total cavopulmonary connections

OBJECTIVE Extracardiac total cavopulmonary connection has recently been introduced as an alternative to intra-atrial procedures. The purpose of this study was to compare the hydrodynamic efficiency of extracardiac and intra-atrial lateral tunnel procedures in total cavopulmonary connections. METHODS Intra-atrial lateral tunnel, extracardiac tunnel, and extracardiac conduit with and without caval vein offset were performed on explanted sheep heart preparations and studied in an in vitro flow loop. A rate of fluid-energy dissipation analysis was performed for each model using simultaneous measurement of pressure and flow at each inlet and outlet of the right side of the heart. Preparations were perfused by using a steady flow blood pump at 4 flow indices (1-6 L/min/m 2) with the inferior vena cava carrying 65% of the total venous return. RESULTS Fluid-power losses were consistently lower for the extracardiac conduit procedure compared with the two tunnel configurations (P <.01). A further reduction in energy dissipation of up to 36% was noted in the extracardiac procedure, with 5 mm offset of the extracardiac conduit toward the distal right pulmonary. The intra-atrial and extracardiac tunnel procedures were least efficient, with losses 73% greater than the optimal extracardiac conduit procedure. CONCLUSIONS The extracardiac conduit procedure provides superior hemodynamics compared with the intra-atrial lateral tunnel and extracardiac tunnel techniques. This hydrodynamic advantage is markedly enhanced by the use of conduit-superior vena cava offset, particularly at high physiologic flows that are representative of exercise. These data suggest additional rationale for the use of extracardiac conduit procedures for final-stage completion of the Fontan circulation.

Improving results of the modified Fontan operation in patients with heterotaxy syndrome

BACKGROUND Historically the Fontan operation in patients with single ventricle heterotaxy syndrome and atrial isomerism has been associated with high mortality. We studied whether recent modifications of the surgical technique have improved outcome. METHODS A retrospective review of 135 patients with heterotaxy syndrome who underwent a Fontan operation between 1981 and 2000 was performed. RESULTS There were 93 patients with right isomerism and 42 with left isomerism. Anomalies of venous return included 25 patients with extracardiac pulmonary venous connection (19%) and 37 patients with an interrupted inferior vena cava (27%). Thirty-six patients (27%) had at least moderate atrioventricular valve regurgitation. The type of Fontan procedure included 17 patients with an atriopulmonary Fontan connection, 67 with a lateral tunnel modification, 19 with an intraatrial tube graft, 25 with an extracardiac tubegraft, and 7 with an intra-extra atrial tube graft. A fenestration was placed in 93 patients (78%). Early mortality was 19% before 1991, 3% since 1991, and no patient has died early since 1993. Ten-year survivals were 70% for Fontan operations before 1990 and 93% for Fontan operations after 1990. Thirty-two patients (23%) had prolonged pleural effusions. Risk factors for death included anomalous pulmonary venous connection (p = 0.02) and higher preoperative pulmonary vascular resistance (p = 0.002). Sixty-two patients (47%) had some form of early postoperative arrhythmia. At 10 years, freedom from late bradyarrhythmia and late tachyarrhythmia were 78% and 70%, respectively. Preoperative arrhythmias, older age at operation, and anatomic features were each independent predictors of late arrhythmia. CONCLUSIONS The Fontan operation can now be performed in patients with heterotaxy syndrome with excellent survival. However, morbidity in terms of postoperative arrhythmias and prolonged pleural effusions remains significant. Fontan staging, appropriate choice of Fontan modification, aggressive treatment of concomitant malformations, and use of a baffle fenestration contribute to improved outcome.

Forty-one years of surgical experience with congenital supravalvular aortic stenosis.

OBJECTIVE Several techniques for symmetric reconstruction of the aortic root in congenital supravalvular aortic stenosis have been developed, but it remains unclear whether these prove superior to patch enlargement of the noncoronary sinus alone. We reviewed our experience with surgical treatment of supravalvular aortic stenosis and investigated the impact of the surgical technique on long-term results. METHODS AND RESULTS Seventy-five patients underwent operations to treat congenital supravalvular aortic stenosis at our institution between 1957 and 1998. Surgical procedures included patch enlargement of the noncoronary sinus only (n = 34), inverted bifurcated patch plasty (n = 35), and 3-sinus reconstruction of the aortic root (n = 6). There were 7 early deaths. Among those who survived the operation, 100% were alive at 5 years, 96% were alive at 10 years, and 77% were alive at 20 years. According to time-related analysis diffuse stenosis of the ascending aorta proved a risk factor for both survival and reoperation (P <.01 for each). Patients with multiple-sinus reconstructions of the aortic root accounted for only 2 of the 14 reoperations and none of the late deaths (both P <.001). Residual gradients were lower after multiple-sinus reconstruction of the aortic root (median 10 mm Hg vs 20 mm Hg for patch enlargement of the noncoronary sinus only, P =. 008), as was the prevalence of moderate aortic regurgitation at follow-up (3% vs 22%, P =.05). CONCLUSIONS Results of operations for supravalvular aortic stenosis improved greatly after the introduction of more symmetric reconstructions of the aortic root. Multiple-sinus reconstructions (inverted bifurcated patch plasty and 3-sinus reconstruction) resulted in superior hemodynamics and were associated with reductions in both mortality rate and need for reoperation.

A Blood-Resistant Surgical Glue for Minimally Invasive Repair of Vessels and Heart Defects

A light-activated, biodegradable adhesive seals cardiovascular defects in the presence of blood flow and could be useful during minimally invasive surgery. Light-Activated Adhesive Seals Tissues An easy way to repair vessels or attach devices to tissues would be welcomed by surgeons. An adhesive, for instance, can reconnect tissue and interface prosthetics, but currently available materials have limitations such as low strength, high toxicity, and most do not function well in wet environments. In response, Lang and colleagues developed a new biomaterial glue that is biocompatible, biodegradable, and easily manipulated. This material, called poly(glycerol sebacate acrylate) (PGSA), when combined with a photoinitiator, creates a solution that the authors called HLAA: hydrophobic light-activated adhesive. The HLAA is a thick gel that can be slathered on a tissue and then cross-linked within seconds by ultraviolet light, which is a unique feature that avoids stitches. The resulting bond is water-tight yet flexible and stays intact in the face of high pressure and flowing blood. The authors first tested their material in rats, showing that the HLAA could be used to attach a polymer patch to the heart and that the HLAA alone could seal up defects in the heart wall, performing as well as sutures. Lang et al. then moved into pigs, whose hearts beat at similar rates to humans (by contrast, rats have much higher heart rates). Lang et al. showed that the light-activated adhesive could attach a patch to the interventricular septum of a pig’s beating heart and that this patch remained in place even under higher than normal heart rates (induced by adrenaline). Additionally, the HLAA alone was able to immediately close up defects in the pig carotid artery without any bleeding complications. The light-responsive adhesive performed well in several different in vivo scenarios, suggesting its broad applicability in the clinic, at least for cardiovascular surgeries and defects. As an added bonus, components of PGSA—namely, glycerol and sebacic acid—exist in the body and are readily metabolized. It is expected that this material could be translated soon to use in people. Currently, there are no clinically approved surgical glues that are nontoxic, bind strongly to tissue, and work well within wet and highly dynamic environments within the body. This is especially relevant to minimally invasive surgery that is increasingly performed to reduce postoperative complications, recovery times, and patient discomfort. We describe the engineering of a bioinspired elastic and biocompatible hydrophobic light-activated adhesive (HLAA) that achieves a strong level of adhesion to wet tissue and is not compromised by preexposure to blood. The HLAA provided an on-demand hemostatic seal, within seconds of light application, when applied to high-pressure large blood vessels and cardiac wall defects in pigs. HLAA-coated patches attached to the interventricular septum in a beating porcine heart and resisted supraphysiologic pressures by remaining attached for 24 hours, which is relevant to intracardiac interventions in humans. The HLAA could be used for many cardiovascular and surgical applications, with immediate application in repair of vascular defects and surgical hemostasis.

Increased susceptibility of hypertrophied hearts to ischemic injury

Cardiac hypertrophy is an adaptive response that compensates for increased workload by normalizing wall stress and preserving cardiac contractile function. In advanced stages, however, clinical and experimental studies have shown that when the high workload is maintained, hypertrophy progresses to ventricular dilatation, contractile dysfunction, and decreased tolerance to ischemia/reperfusion. Development of hypertrophy is accompanied by distinct qualitative and quantitative changes in contractile protein expression and isoform switching, cytosolic calcium regulation, and substrate delivery and use. We have focused our investigations on changes in substrate delivery and capillary density in pressure overload hypertrophy and on the effects that these changes have on tolerance to ischemia/reperfusion. This report summarizes our work in this area using a model of aortic banding in 10-day-old rabbits, which exhibits the same pattern of concentric hypertrophy early, followed by ventricular dilatation and contractile dysfunction that is clinically apparent.

Vascular Endothelial Growth Factor Prevents Apoptosis and Preserves Contractile Function in Hypertrophied Infant Heart

Background— Cardiac hypertrophy is an adaptive response to increased workload that, if unrelieved, leads to heart failure. It has been reported that cardiomyocyte apoptosis contributes to failure, and that vascular endothelial growth factor (VEGF) treatment of hypertrophied myocardium increases capillary density and improves myocardial perfusion. In this study we hypothesized that VEGF treatment reduces cardiomyocyte apoptosis and thereby preserves myocardial contractile function. Methods and Results— Newborn rabbits underwent aortic banding. At 4 and 6 weeks of age, hypertrophied animals were treated with intrapericardial administration of recombinant VEGF protein. Three groups of animals were investigated: age-matched controls (C), untreated hypertrophied (H), and VEGF-treated hypertrophied hearts (T). Cardiomyocyte apoptosis was determined by TUNEL staining and PARP cleavage (immunoblotting of nuclear extracts) and cardiac function by transthoracic echocardiography. Death attributable to severe heart failure occurred in 14 of 43 untreated and 2 of 29 VEGF-treated animals (P<0.01). TUNEL-positive cardiomyocyte nuclei (n/1000 nuclei) were significantly increased in untreated hearts at 5 weeks (H: 10±1.8 versus T: 3±0.7) and at 7 weeks (H: 13±3.6 versus T: 5±1.5; P<0.05). Increased apoptosis in untreated hypertrophy was also confirmed by the presence of PARP cleavage (H: 74±7 versus T: 41±4 arbitrary densitometry units; P<0.05). VEGF treatment preserved left ventricular mass, prevented dilation (T: 1.01±0.06 versus H: 0.77±0.07; P<0.05), and preserved contractility indices compared with untreated hearts. Conclusions— Lack of adaptive capillary growth impairs myocardial perfusion and substrate delivery in hypertrophying myocardium. VEGF treatment reduces myocardial apoptosis and prolongs survival in a model of severe progressive left ventricular hypertrophy. Promoting capillary growth with VEGF reduces apoptosis, preserves myocardial contractile function, and delays the onset of failure in pressure-loaded infant myocardium.

A Highly Tunable Biocompatible and Multifunctional Biodegradable Elastomer

Biodegradable elastomers have emerged as promising materials for their potential to mimic the viscoelastic properties of several tissues and exhibit compliance with dynamic environments without damaging the surrounding tissue.[1, 2] Several elastomers have been recently proposed;[3–8] however, the development of highly tunable biodegradable elastomers that can effectively and controllably present biological and physical signals and withstand repeated cycles of physiologic loads, has remained elusive. Such materials should be useful for a broad range of clinically-relevant applications, such as cardiac therapy. For example, following myocardial infarction, the local controlled delivery of bioactive cues[9] or the physical support of the left ventricle wall[10] have been shown to improve cardiac function. The synergistic therapeutic effect of biochemical and biophysical cues has not yet been explored using degradable materials given the absence of materials that can simultaneously deliver bioactive cues and maintain mechanical integrity in a dynamic environment such as the beating heart. Here, we describe a novel biocompatible and mechanically tunable elastomer, poly(glycerol sebacate urethane) (PGSU), suitable for efficient encapsulation and controlled delivery of bioactive macromolecules and with the potential to be applied to cardiac drug delivery.

Inhaled Nitric Oxide versus Inhaled Prostacyclin and Intravenous versus Inhaled Prostacyclin in Acute Respiratory Failure with Pulmonary Hypertension in Piglets

ABSTRACT: This study was a prospective, randomized design to compare oxygenation and pulmonary hemodynamics between inhaled nitric oxide (NO) and inhaled prostacylcin (PGI2), and between inhaled and i.v. PGI2 in acute respiratory failure with pulmonary hypertension. Acute respiratory failure with pulmonary hypertension was induced in 12 piglets weighing 9–12 kg by repeated lung lavages and a continuous infusion of the stable endoperoxane analogue of thromboxane. Thereafter the animals were randomly assigned either for NO or PGI2 application. All animals were treated with different concentrations of NO or different doses of PGI2 applied i.v. and inhaled in random order. Continuous monitoring included ECG, central venous pressure (CVP), mean pulmonary artery pressure (MPAP), mean arterial pressure (MAP), artertial oxygen saturation (SaO2), and mixed venous oxygen saturation (SvO2) measurements. NO inhalation of 10 ppm resulted in a significant increase in Pao2/fraction of inspired oxygen (FiO2) from 7.8 ± 1.34 kPa to 46.1 ± 9.7 kPa. MPAP decreased significantly from 5.1 ± 0.26 kPa to 3.7 ± 0.26 kPa during inhaled NO of 40 ppm; i.v. infusion of PGI2 slightly increased oxygenation parameters. A significant increase in Pao2/FiO2 up to 32.4 ± 3.1kPa was observed during PGI2 aerosol delivery (p < 0.01); i.v. PGI2 decreased MAP from 11.5 ± 0.39 kPa to 9.8 ± 0.66 kPa (p < 0.05) and MPAP from 5.8 ± 0.53 kPa to 4.5 ± 0.66 kPa, respectively (p < 0.05). PGI2 aerosol delivery significantly decreased the MPAP to 3.7 ± 0.53 kPa (p < 0.05) without influencing the MAP. It was concluded that inhaled NO and inhaled PGI2 act as selective pulmonary vasodilators in acute respiratory failure with pulmonary hypertension resulting in improved oxygenation mainly due to improved mismatch of pulmonary perfusion and ventilation. Intravenous PGI2 improves oxygenation and pulmonary hemodynamics to a lesser extent than aerosolized PGI2 and has the risk of systemic hypotension at a higher dose.

Vascular endothelial growth factor delays onset of failure in pressure-overload hypertrophy through matrix metalloproteinase activation and angiogenesis.

AbstractObjectivePressure–overload hypertrophy is associated with decreased capillary density in myocardium resulting in impaired substrate delivery. Treatment of hypertrophied hearts with vascular endothelial growth factor (VEGF) induces angiogenesis. Since angiogenesis is associated with extracellular matrix degradation, we sought to determine whether VEGF induced angiogenesis in hypertrophy required matrix metalloproteinases (MMP) activation.MethodsNewborn rabbits underwent aortic banding. Progression of hypertrophy (mass–to–volume (M/V) ratio) and mid–wall contractility index was monitored by echocardiography. At 4 and 6 weeks, VEGF (2 µg/kg), vehicle or VEGF combined with GM6001 (5 mg/kg), a MMP inhibitor, was administered intrapericardially. CD–31 (indicator of angiogenesis), MMP–2, MT1–MMP and TIMPs (endogenous MMP inhibitors) expression were measured by immunoblotting. MMP–2 activity was determined by gelatin zymography.ResultsUntreated hypertrophied hearts progressed to ventricular dilatation at 7 wks (M/V ratio: 0.75 ± 0.07), but compensatory hypertrophy was maintained with VEGF (0.91 ± 0.07; p < 0.05). LV contractility declined in untreated hearts from –0.41 ± 0.9 (5 wks) to –0.73 ± 0.5 (7 wks; p < 0.05) but remained normal with VEGF (+1.61 ± 0.6 vs. +0.47 ± 0.2). MMP–2 expression and activity were significantly elevated in VEGF treated hypertrophied hearts (p < 0.05) and were blocked by concomitant administration of GM6001. VEGF induced neovascularization was inhibited by addition of GM6001. MT1–MMP showed a trend to higher levels in VEGF treated hearts. TIMPs were unchanged in all three groups.ConclusionsExogenous VEGF and resultant MMP–2 activation leads to increased capillary formation in severe hypertrophy, preventing progression to ventricular dilation and dysfunction. VEGF and the associated MMP–2 activation play an important and potentially therapeutic role in vascular remodeling of hypertrophied hearts.

Endocardial Fibroelastosis is Caused by Aberrant Endothelial to Mesenchymal Transition

RATIONALE Endocardial fibroelastosis (EFE) is a unique form of fibrosis, which forms a de novo subendocardial tissue layer encapsulating the myocardium and stunting its growth, and which is typically associated with congenital heart diseases of heterogeneous origin, such as hypoplastic left heart syndrome. Relevance of EFE was only recently highlighted through the establishment of staged biventricular repair surgery in infant patients with hypoplastic left heart syndrome, where surgical removal of EFE tissue has resulted in improvement in the restrictive physiology leading to the growth of the left ventricle in parallel with somatic growth. However, pathomechanisms underlying EFE formation are still scarce, and specific therapeutic targets are not yet known. OBJECTIVE Here, we aimed to investigate the cellular origins of EFE tissue and to gain insights into the underlying molecular mechanisms to ultimately develop novel therapeutic strategies. METHODS AND RESULTS By utilizing a novel EFE model of heterotopic transplantation of hearts from newborn reporter mice and by analyzing human EFE tissue, we demonstrate for the first time that fibrogenic cells within EFE tissue originate from endocardial endothelial cells via aberrant endothelial to mesenchymal transition. We further demonstrate that such aberrant endothelial to mesenchymal transition involving endocardial endothelial cells is caused by dysregulated transforming growth factor beta/bone morphogenetic proteins signaling and that this imbalance is at least in part caused by aberrant promoter methylation and subsequent transcriptional suppression of bone morphogenetic proteins 5 and 7. Finally, we provide evidence that supplementation of exogenous recombinant bone morphogenetic proteins 7 effectively ameliorates endothelial to mesenchymal transition and experimental EFE in rats. CONCLUSIONS In summary, our data point to aberrant endothelial to mesenchymal transition as a common denominator of infant EFE development in heterogeneous, congenital heart diseases, and to bone morphogenetic proteins 7 as an effective treatment for EFE and its restriction of heart growth.