Survival after radical resection of cardiac sarcomas.
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Heart Neoplasms↗
Biomedical subjects
Stefan Klotz
Publications and source records attributed to Stefan Klotz.
Development of heart failure in chronic hypertensive Dahl rats: focus on heart failure with preserved ejection fraction.
The impact of hypertension on left ventricular (LV) structure, pump function, and heart failure in Dahl salt-sensitive rats is poorly characterized but hypothesized to yield insights into the pathophysiology of heart failure with normal or preserved ejection fraction. Eighty Dahl salt-sensitive rats were fed either a high-salt (HS) or low-salt (LS, controls) diet starting at age 7 weeks. Ventricular properties were measured by echocardiography, hemodynamics and end-systolic and end-diastolic pressure-volume relationships (ESPVR and EDPVR, respectively). Compared with LS controls, HS rats developed severe hypertension and LV hypertrophy. At week 12, HS rats developed passive diastolic dysfunction (leftward/upward shifted EDPVR, increased chamber stiffness) with reductions in end-diastolic volume. However, the ESPVR also shifted upward (enhanced end-systolic function) so that overall pump function was enhanced compared with LS, and there was no change in end-diastolic pressure (EDP). At 16 and 20 weeks, HS hearts enlarged so that end-diastolic volumes and EDPVRs became similar to the respective age-matched LS controls. Concomitantly, the ESPVRs and overall pump function curves also moved toward controls, and ejection fraction declined. Despite normal or enhanced overall pump function at these times, EDP and wet lung weight increased, indicative of development of heart failure. In the Dahl salt-sensitive rat, which pathophysiologically retains salt and water, the development of heart failure (increased EDP and wet lung weight) is dissociated from changes in passive diastolic and active systolic properties. These observations suggest that a volume overload sate plays an important pathophysiological role in development of heart failure despite preserved overall ventricular pump function in this model of chronic hypertension.
Animals↗
Structural properties of the amorphous ices: an analysis in terms of distance-ranked neighbors and angular correlations.
In this work we study through computer simulations the three known forms of amorphous ice, namely, the low density (LDA), the high density (HDA), and the very high density (VHDA) amorphous ices, at various pressures and temperatures. Adopting the TIP4P model, we are able to reproduce these three forms by following experiment-like procedures. Those systems are characterized from thermodynamic and structural points of view, in particular through an insightful analysis of the behavior of the second-shell neighbors in the various stages of the simulations. The distance-ranked neighbors are found to be the relevant markers of the differentiation mechanisms of the three forms, since their response to pressure induces specific distortions of the orientational correlations. We show that LDA, HDA, and VHDA are disordered forms whose local structures tend to a single tetrahedral network, to an ice-VII-like arrangement, and to a random-close-packed simple liquid-like structure, respectively. Despite the major structural deformations induced by pressure, the hydrogen bonds are still present in each of those forms, even though deformations of the tetrahedral angles are necessary to adapt to the denser structures.
Journal Article↗
Single-beat estimation of end-diastolic pressure-volume relationship: a novel method with potential for noninvasive application.
Whereas end-systolic and end-diastolic pressure-volume relations (ESPVR, EDPVR) characterize left ventricular (LV) pump properties, clinical utility of these relations has been hampered by the need for invasive measurements over a range of pressure and volumes. We propose a single-beat approach to estimate the whole EDPVR from one measured volume-pressure (Vm and Pm) point. Ex vivo EDPVRs were measured from 80 human hearts of different etiologies (normal, congestive heart failure, left ventricular assist device support). Independent of etiology, when EDPVRs were normalized (EDPVRn) by appropriate scaling of LV volumes, EDPVRns were nearly identical and were optimally described by the relation EDP = An.EDV (Bn), with An = 28.2 mmHg and Bn = 2.79. V0 (the volume at the pressure of approximately 0 mmHg) was predicted by using the relation V0 = Vm.(0.6 - 0.006.Pm) and V30 by V30 = V0 + (Vm,n - V0)/(Pm/An) (1/Bn). The entire EDPVR of an individual heart was then predicted by forcing the curve through Vm, Pm, and the predicted V0 and V30. This technique was applied prospectively to the ex vivo human EDPVRs not used in determining optimal An and Bn values and to 36 in vivo human, 12 acute and 14 chronic canine, and 80 in vivo and ex vivo rat studies. The root-mean-square error (RMSE) in pressure between measured and predicted EDPVRs over the range of 0-40 mmHg was < 3 mmHg of measured EDPVR in all settings, indicating a good predictive value of this approach. Volume-normalized EDPVRs have a common shape, despite different etiology and species. This allows the entire curve to be predicted by a new method with a potential for noninvasive application. The results are most accurate when applied to groups of hearts rather than to individual hearts.
Algorithms↗
beta(2)-Adrenergic stimulation attenuates left ventricular remodeling, decreases apoptosis, and improves calcium homeostasis in a rodent model of ischemic cardiomyopathy.
The benefit of the beta(2)-adrenergic agonist, clenbuterol, in left ventricular assist device patients with dilated cardiomyopathy has been reported, but its effect on ischemic heart failure (HF) is unknown. We investigated whether clenbuterol improves left ventricular remodeling, myocardial apoptosis and has synergy with a beta(1) antagonist, metoprolol, in a model of ischemic HF. Rats were randomized to: 1) HF only; 2) HF + clenbuterol; 3) HF + metoprolol; 4) HF + clenbuterol + metoprolol; and 5) rats with sham surgery. HF was induced by left anterior descending artery (LAD) artery ligation and confirmed by decreased left ventricular fractional shortening, decreased maximum left ventricular dP/dt (dP/dt(max)), and elevated left ventricular end-diastolic pressure (LVEDP) compared with sham rats (p < 0.01). After 9 weeks of oral therapy, echocardiographic, hemodynamic, and ex vivo end-diastolic pressure-volume relationship (EDPVR) measurements were obtained. Immunohistochemistry was performed for myocardial apoptosis and DNA damage markers. Levels of calcium-handling proteins were assessed by Western blot analysis. Clenbuterol-treated HF rats had increased weight gain and heart weights versus HF rats (p < 0.05). EDPVR curves revealed a leftward shift in clenbuterol rats versus metoprolol and HF rats (p < 0.05). The metoprolol-treated group had a lower LVEDP and higher dP/dt(max) versus the HF group (p < 0.05). Clenbuterol and metoprolol groups had decreased myocardial apoptosis and DNA damage markers and increased DNA repair markers versus HF rats (all p < 0.01). Protein levels of the ryanodine receptor and sarcoplasmic reticulum calcium-ATPase were improved in clenbuterol-, metoprolol-, and clenbuterol+metoprolol-treated groups versus HF rats. However, as a combination therapy, there were no synergistic effects of clenbuterol+metoprolol treatment. We conclude that clenbuterol ameliorates EDPVR, apoptosis, and calcium homeostasis but does not have synergy with metoprolol in our model of ischemic HF.
Adrenergic beta-Agonists↗
[Surgical therapy of end-stage heart failure. State of the art 2006].
Cardiac transplantation still remains the gold standard despite recent success in organ-preserving therapy. However, organ shortage forces to process alternative therapies. Cardiac resynchronization therapy and cardiac contractility modulation are new and promising therapies, which are able either to delay or even prevent the need for cardiac transplantation. High-risk cardiac revascularization and valve replacement is another important therapy in especially evaluated patients. With newer organ-protective procedures and novel treatment options like the off-pump bypass surgery, end-stage heart failure could be treated successfully. The volume reduction surgery, the so-called Batista procedure, has its indication only in special selected patients with dilated cardiomyopathy. A modified procedure, the surgical ventricular restoration (SVR) therapy, however, has a definitive potential and is evaluated in a multicenter trial (RESTORE). Mechanical cardiac assist devices have still a high impact in the therapy of acute or chronic end-stage heart failure. By means of smaller devices with axial rotary blades, the high rates of thromboembolic events, infections and mechanical device complications were significantly reduced. Survival to transplant with mechanical assist device support is nowadays around 80%. New centrifugal pumps are tested in clinical trials right now. Passive cardiac support devices and the total artificial heart are limited to special indications. The organ shortage could be overcome with the xenotransplantation. However, the problem of hyperacute rejection and the risk of transfection of animal diseases limit the clinical use considerably. The cell therapy has probably the highest potential for the future. Still unsolved are problems with the potential trigger of arrhythmias and ethical preconceptions regarding embryonic stem cells. In summary, cardiac transplantation still remains the gold standard in the therapy of end-stage heart failure with 10-year survival rates of 50%. With increasing donor shortage a potential combination therapy of organ-preserving cardiac surgery and cell transplantation might be the future for the 21st century.
Cardiac Volume↗
Does continuous flow left ventricular assist device technology have a positive impact on outcome pretransplant and posttransplant?
BACKGROUND: Left ventricular assist devices (LVADs) with continuous flow properties are increasingly used to bridge heart failure patients to cardiac transplantation. Advantages in comparison with the pulsatile LVADs are smaller size, better endurance, and lower thromboembolic events. However, whether these new pumps have similar pre- and posttransplant outcomes is not clear. METHODS: Fifty patients with a continuous flow device (Micromed DeBakey, Houston, TX or InCor BerlinHeart, Berlin, Germany) were compared with an age-, disease-, and LVAD duration-matched control group (n = 80) supported with a pulsatile device (Novacor, WorldHeart, Oakland, CA or HeartMate, Thoratec Corp, Pleasanton, CA). RESULTS: Age (44.3 +/- 13.4 vs 46.1 +/- 11.1 years), disease (idiopathic dilated cardiomyopathy, 58% vs 65%), and LVAD duration (138 +/- 131 vs 128 +/- 106 days) were comparable in both groups. Successful bridging to transplantation was similar with continuous flow in comparison with pulsatile device support (52% vs 56%, p = not significant [NS]). Thirty-day mortality after cardiac transplantation in patients with continuous flow LVAD support was 21.7% vs 22.2% with pulsatile LVADs (p = NS). Reasons for death were similar among the different LVAD groups. Long-term survival was similar in both LVAD groups compared with patients without previous LVAD support. Interestingly, severe rejections were significantly more frequent in patients with a continuous flow LVAD (p < 0.001). CONCLUSIONS: The new generation of cardiac assist devices with continuous flow pattern has a similar rate of pre- and posttransplant mortality in comparison with pulsatile LVADs. However, the rate and severity of posttransplant rejection was significantly higher in the group with continuous flow devices. Further studies are warranted to explain the higher rate of severe rejections.
Adult↗
Reversible pulmonary hypertension in heart transplant candidates: to transplant or not to transplant.
BACKGROUND: Pulmonary hypertension (PHT), defined as a pulmonary vascular resistance (PVR) greater than 2.5 Wood units [WU] and(or) transpulmonary gradient (TPG) greater than 12 mm Hg, is a risk factor for mortality in cardiac transplantation due to elevated postoperative right heart failure. Orthotopic heart transplantation is possible if PVR could be reversed below 2.5 WU and TPG below 12 mm Hg. We show the Muenster experience from the last 10 years. METHODS: From April 1996 to December 2005 all cardiac transplant recipients separated into patients with and without PHT were included. All patients with PHT had successful reduction (PVR < or = 2.5 WU and TPG < or = 12 mm Hg) using prostaglandin I2 or E1. Posttransplant early and late mortality and incidence of right heart failure were studied. RESULTS: Two hundred seventeen patients were included in this study. Of these, 168 had normal pulmonary pressures (non-PHT group), 49 (22.6%) had reversible PHT (rev-PHT group). Mean PVR was 1.6 +/- 1.1 WU vs 2.1 +/- 1.1 WU (p < 0.01; non-PHT vs rev-PHT) and mean TPG 8.0 +/- 1.9 mm Hg vs 10.6 +/- 4.1 mm Hg (p = not significant [NS]). Thirty-day survival after orthotopic cardiac transplantation was 85% vs 78% (p = 0.150) and 10 year survival 63% vs 61% (p = NS). Right heart failure during the first 30 days after transplantation occurred in 27% in the non-PHT group and in 64% in the rev-PHT group (p = 0.035). However, in patients transplanted after 2001 it did not appear. CONCLUSIONS: Cardiac transplant candidates with reversible PHT have still significantly elevated pulmonary pressures compared with patients without PHT. Despite a significantly higher risk of right heart failure, long-term survival after orthotopic cardiac transplantation was not affected.
Adult↗
LVAD-induced reverse remodeling: basic and clinical implications for myocardial recovery.
BACKGROUND: With improved technology, increasing clinical experience, and expanding indications for use, left ventricular assist devices (LVADs) are assuming a greater role in the care of patients with end-stage heart failure. Early in the course of LVAD use as a bridge to transplant, it became evident that some patients exhibit substantial recovery of ventricular function, which led to the concept of reverse remodeling. METHODS AND RESULTS: Herein we summarize and integrate insights derived from a multitude of studies that have investigated how LVAD support influences ventricular structural, cellular, extracellular matrix, molecular, biochemical, and metabolic characteristics of the end-stage failing heart. The focus includes a review of the extent and sustainability of reverse remodeling, the important advances in understanding of the pathophysiology of heart failure derived from these studies and the implications of these findings for development of new therapeutic strategies. CONCLUSION: In brief, studies of LVAD-heart interactions have led to the understanding that although we once considered the end-stage failing heart of patients near death to be irreversibly diseased, when given sufficient mechanical unloading and restoration of more normal neurohormonal milieu, a relatively large degree of myocardial recovery is possible. Comparison of effects on right and left ventricles have provided mechanistic insights by implicating hemodynamic unloading as primarily regulating certain aspects of reverse remodeling, neurohormonal factors as regulating other aspects, and joint regulation of still other aspects. As such these observations have driven a shift of thinking of chronic heart failure as a progressive irreversible disease process to a potentially treatable entity.
Heart↗
Ventricular lateral wall rupture after myocardial infarction detected by means of multislice computed tomography.
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Fatal Outcome↗
Relating geographical variation in pollination types to environmental and spatial factors using novel statistical methods.
The relative frequencies of functional traits of plant species show notable spatial variation, which is often related to environmental factors. Pollination type (insect-, wind- or self-pollination) is a critical trait for plant reproduction and provision of ecosystem services. Here, we mapped the distribution of pollination types across Germany by combining databases on plant distribution and plant pollination types. Applying a new method, we modelled the composition of pollination types using a set of 12 environmental variables as predictors within a Bayesian framework which allows for the analysis of compositional data in the presence of spatial autocorrelation. A clear biogeographical pattern in the distribution of pollination types was revealed which was adequately captured by our model. The most striking relationship was a relative increase in insect-pollination and a corresponding decrease of selfing with increasing altitude. Further important factors were wind speed, geology and land use. We present a powerful tool to analyse the distribution patterns of plant functional types such as pollination types and their relationship with environmental parameters in a spatially explicit framework.
Demography↗
Cardiomyopathic etiology and SERCA2a reverse remodeling during mechanical support of the failing human heart.
Many hearts in end-stage, chronic failure (CHF) retain the capacity to reverse abnormal expression of genes regulating myocyte calcium cycling when supported with a left ventricular assist device (LVAD). In the present study, we determined whether LVAD-induced upregulation of the gene encoding for the key calcium cycling protein sarcoplasmic endoreticular calcium adenosine triphosphatase subtype 2a (SERCA2a) is influenced by the nature of underlying disease broadly characterized as ischemic (ICM) or idiopathic dilated (DCM) cardiomyopathy. Data from Northern blot analysis of SERCA2a messenger (m)RNA within 84 heart samples (50 CHF [23 DCM and 27 ICM] and 34 CHF+LVAD [18 DCM and 16 ICM]) were used for characterizing gene expression. In addition, measurements of the force-frequency relationship (FFR), a reflection of in vivo SERCA2a function, were obtained in myocardial trabeculae isolated from 75 hearts (51 CHF [29 DCM and 22 ICM] and 24 CHF+LVAD [10 DCM and 14 ICM]). SERCA2a mRNA demonstrated upregulation after LVAD that was not influenced by ICM or DCM. However, only in DCM hearts was the proportion of trabeculae exhibiting a normal FFR increased after LVAD. Thus, although upregulated SERCA2a gene expression after LVAD support is independent of myopathic origin, normalization of myocardial FFR, an index of SERCA2a function, is not. These data provide new insight into the process of cardiac "reverse molecular remodeling," and underscore potential differences in the impact of disease processes on posttranscriptional events.
Adult↗
Direct left ventricle-to-coronary artery stent restores perfusion to chronic ischemic swine myocardium.
BACKGROUND: Direct left ventricle (LV)-to-coronary artery shunts (VSTENT) have been proposed as an alternative means of myocardial revascularization. The goal of this study was to examine quantitative changes in myocardial perfusion and possible mechanisms of revascularization with an LV-to-coronary shunt. METHODS: Ameroid occluders were implanted on the proximal left anterior descending coronary artery (LAD) of 6 pigs to create chronic ischemia. Four weeks later, a VSTENT was placed to directly connect the distal LAD with the LV chamber. Animals survived for an additional 3 weeks and received periodic bromodeoxyuridine (BrdU) injections to identify dividing cells to identify and quantify angiogenesis. Regional myocardial perfusion (RMP) was measured with color microspheres under adenosine vasodilatory stress before and 3 weeks after VSTENT implantation. Vascularity was assessed histologically by an overall vascularity index and a growth index reflecting the density of BrdU-positive vascular cells. RESULTS: Three weeks after VSTENT placement, RMP improved from 38.4% +/- 19.6% of non-ischemic flow to 86.8% +/- 13.7% in treated animals (P < .05). This benefit was accompanied by histological evidence of increased vascularity and vascular proliferation. Four of 5 animals had patent and functional devices at the end of the study. CONCLUSION: Chronic VSTENT placement improves RMP and may promote arterial remodeling in chronically ischemic porcine myocardium.
Animals↗
Isobaric annealing of high-density amorphous ice between 0.3 and 1.9 GPa: in situ density values and structural changes.
We report in situ density values of amorphous ice obtained between 0.3 and 1.9 GPa and 144 to 183 K. Starting from high-density amorphous ice made by pressure-amorphizing hexagonal ice at 77 K, samples were heated at a constant pressure until crystallization to high-pressure ices occurred. Densities of amorphous ice were calculated from those of high-pressure ice mixtures and the volume change on crystallization. In the density versus pressure plot a pronounced change of slope occurs at approximately 0.8 GPa, with a slope of 0.21 g cm(-3) GPa(-1) below 0.8 GPa and a slope of 0.10 g cm(-3) GPa(-1) above 0.8 GPa. Both X-ray diffractograms and Raman spectra of recovered samples show that major structural changes occur up to approximately 0.8 GPa, developing towards those of very high-density amorphous ice reported by (T. Loerting, C. Salzmann, I. Kohl, E. Mayer and A. Hallbrucker, Phys. Chem. Chem. Phys., 2001, 3, 5355) and that further increase of pressure has only a minor effect. In addition, the effect of annealing temperature (T(A)) at a given pressure on the structural changes was studied by Raman spectra of recovered samples in the coupled O-H and decoupled O-D stretching band region: at 0.5 GPa structural changes are observed between approximately 100-116 K, at 1.17 GPa between approximately 121-130 K. Further increase of T(A) or of annealing time has no effect, thus indicating that the samples are fully relaxed. We conclude that mainly irreversible structural changes between 0.3 to approximately 0.8 GPa lead to the pronounced increase in density, whereas above approximately 0.8 GPa the density increase is dominated to a large extent by reversible elastic compression. These results seem consistent with simulation studies by (R. Martonàk, D. Donadio and M. Parrinello, J. Chem. Phys., 2005, 122, 134501) where substantial reconstruction of the topology of the hydrogen bonded network and changes in the ring statistics from e.g. mainly six-membered to mainly nine-membered rings were observed on pressure increase up to 0.9 GPa and further pressure increase had little effect.
Algorithms↗
Hemodynamic response during non-pulsatile vs pulsatile left ventricular assist device support.
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Cardiac Catheterization↗
Mechanical unloading during left ventricular assist device support increases left ventricular collagen cross-linking and myocardial stiffness.
BACKGROUND: Left ventricular assist devices (LVADs) induce reverse remodeling of the failing heart except for the extracellular matrix, which exhibits additional pathophysiological changes, although their mechanisms and functional consequences are unknown. METHODS AND RESULTS: Hearts were obtained at transplant from patients with idiopathic dilated cardiomyopathy (DCM) not requiring LVAD support (n=30), patients requiring LVAD support (n=16; LVAD duration, 145+/-33 days), and 5 nonfailing hearts. Left (LV) and right ventricular (RV) ex vivo pressure-volume relationships were measured, and chamber and myocardial stiffness constants were determined. Myocardial tissue content of total and cross-linked collagen, collagen types I and III, MMP-1, MMP-9, TIMP-1, and angiotensin (Ang) I and II were measured. LV size, mass, and myocyte diameter decreased after LVAD compared with DCM without LVAD (P<0.05). Total and cross-linked collagen and ratio of type I to III collagen increased in DCM compared with nonfailing hearts and increased further after LVAD (P<0.05 versus DCM and nonfailing). Concomitantly, chamber and myocardial stiffness increased with LVAD. The ratio of MMP-1 to TIMP-1 increased in DCM and almost normalized after LVAD, favoring decreased collagen degradation. Tissue Ang I and II also increased during LVAD. There was no significant change in the RV of LVAD-supported heart compared with DCM. CONCLUSIONS: LVAD support increases LV collagen cross-linking and the ratio of collagen type I to III, which is associated with increased myocardial stiffness. Decreased tissue MMP-1-to-TIMP-1 ratio (decreased degradation) and increased Ang levels (stimulants of synthesis) are likely mechanisms for these changes. Lack of significant effects on the RV suggest that hemodynamic unloading of the LV (not provided to the RV) might be the primary factor that regulates these extracellular matrix changes.
Adult↗
Reversible pulmonary hypertension in heart transplant candidates does not obligatorily predict worse outcome post-transplantation.
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Comorbidity↗
Left ventricular assist device support normalizes left and right ventricular beta-adrenergic pathway properties.
OBJECTIVES: We hypothesized that some aspects of left ventricular assist device (LVAD) reverse remodeling could be independent of hemodynamic factors and would primarily depend upon normalization of neurohormonal milieu. BACKGROUND: The relative contributions of LVAD-induced hemodynamic unloading (provided to the left ventricle [LV]) and normalized neurohormonal milieu (provided to LV and right ventricle [RV]) to reverse remodeling are not understood. METHODS: Structural and functional characteristics were measured from hearts of 65 medically managed transplant patients (MED), 30 patients supported with an LVAD, and 5 nonfailing donor hearts not suitable for transplantation. RESULTS: Compared with MED patients, diastolic pulmonary pressures trended lower (p < 0.01) and cardiac output higher (p < 0.001) in LVAD patients; V(30) (ex vivo ventricular volume yielding 30 mm Hg, an index of ventricular size) in LVAD patients was decreased in the LV (p < 0.05) but did not change significantly in RV. The LVAD support improved force generation in response to beta-adrenergic stimulation in isolated LV (increase in developed force from 6.3 +/- 0.6 to 18.5 +/- 4.4 mN/m(2), p < 0.01) and RV (increase in developed force, from 10.9 +/- 2.0 to 20.5 +/- 3.1 mN/m(2), p < 0.05) trabeculae. The LVAD patients had higher myocardial beta-adrenergic receptor density in LV (p < 0.01) and RV (p < 0.01). Protein kinase A (PKA) hyperphosphorylation of the ryanodine receptor 2 (RyR2)/calcium release channel was significantly reduced by LVAD in both RV and LV (p < 0.01). CONCLUSIONS: Improved beta-adrenergic responsiveness, normalization of the RyR2 PKA phosphorylation, and increased beta-adrenergic receptor density in LV and RV after LVAD support suggest a primary role of neurohormonal environment in determining reverse remodeling of the beta-adrenergic pathway.
Adult↗