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Biomedical subjects

H R Zerkowski

Publications and source records attributed to H R Zerkowski.

At least 19 recordsLinked to original sources
PubMed2000

Deloading of the left ventricle by ventricular assist device normalizes increased expression of endothelin ET(A) receptors but not endothelin-converting enzyme-1 in patients with end-stage heart failure.

BACKGROUND: Ventricular assist devices (VAD) are implanted in patients with end-stage heart failure for bridging the time until heart transplantation, resulting in hemodynamic unloading of the failing heart, improved cardiac contractile and mitochondrial function, and reversal of cardiac hypertrophy. It is unknown whether VAD unloading may affect the cardiac endothelin (ET) system, which has been proposed as one of the putative pathomechanisms of heart failure. METHODS AND RESULTS: With the use of standard-calibrated, competitive reverse-transcription-polymerase chain reaction mRNA expression of components of the ET system was analyzed in left ventricular myocardium from nonfailing donor hearts, from failing hearts without and with ACE inhibitor therapy, and from patients with end-stage heart failure at the time of VAD implantation and 103+/-15 days after VAD implantation during removal with subsequent heart transplantation. ET receptor A (ET(A)) was markedly upregulated in failing human myocardium. This increased ET(A) expression was not affected by ACE inhibitor treatment but was normalized by VAD unloading. ET(A) expression before or after VAD implantation did not correlate with duration of VAD implantation or suppression of Pro-ANP mRNA. ET(B) mRNA expression was unaffected by heart failure or VAD. In contrast, increased ET-converting enzyme-1 mRNA and ET-1 peptide levels in failing myocardium were partially normalized by ACE inhibition but not by VAD unloading. CONCLUSIONS: We conclude that VAD implantation normalizes ET(A) expression in failing human left ventricular myocardium, probably as the result of the beneficial effects of VAD unloading.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Aberrant right pulmonary artery and double outlet ventricle: one-stage repair.

We report a 13-month-old male child with anomalous origin of the right pulmonary artery from the ascending aorta and a double outlet right ventricle. Aortic wall was used for elongation of the pulmonary artery and side-to-end connection to the pulmonary trunk. Special emphasis is made on this particular operative technique for strictly laterally originating right pulmonary artery that requires no prosthetic material, avoids extreme stretching, and may enable normal growth potential.

Aorta↗
PubMed2000

Expression of secreted frizzled related proteins 3 and 4 in human ventricular myocardium correlates with apoptosis related gene expression.

OBJECTIVE: Overload-induced heart failure is associated with myocyte apoptosis induced by unknown mechanisms. Wnt genes encode secreted signaling molecules that bind to frizzled receptors and stabilize cytosolic beta-catenin which is translocated into the nucleus, acts as transcriptional activator and imparts an apoptosis resistant phenotype. This signaling pathway is antagonized by secreted frizzled related proteins (sFRPs) which modulate apoptosis susceptibility in cell culture models. On the basis of these considerations, the present investigation compares myocardial mRNA expression of sFRPs and the level of soluble beta-catenin in tissue samples from nonfailing and failing hearts. METHODS: Nonischemic transmural samples from human failing left ventricles and from nonfailing donor ventricles were used in the present study. The mRNA concentration of the Wnt-antagonists sFRP 1-4 were determined by quantitative reverse transcription polymerase chain reaction (RT-PCR). The myocardial localization of sFRP 3 and 4 expression was investigated using in situ RT-PCR. The pool of soluble beta-catenin was quantified by Western blot analysis of protein extracts. RESULTS: The mRNA levels of proapoptotic sFRPs 3 and 4 but not of sFRP 1 and 2 were elevated in failing ventricles compared to donor hearts. There was no significant difference between patients suffering from a dilated cardiomyopathy or a coronary heart disease. sFRPs 3 and 4 were expressed in cardiomyocytes and their expression correlated with the mRNA expression of the proapoptotic Fas/Fas-antagonist ratio, but inversely with the mRNA levels of the antiapoptotic bcl-xL. The size of the pool of 0.1% Triton soluble beta-catenin tended to decrease in myocardial samples with high sFRP 3 and 4 expression levels. CONCLUSIONS: The results support the hypothesis that in failing human myocardium the Wnt/beta-catenin pathway is attenuated by enhanced expression of two endogenous Wnt-antagonists. This might contribute to an apoptosis susceptible phenotype of overloaded human myocardium.

Apoptosis↗
PubMed2000

Predictive value of S-100beta and neuron-specific enolase serum levels for adverse neurologic outcome after cardiac surgery.

OBJECTIVES: The aim of this study was to evaluate the time course of S-100beta and neuron-specific enolase serum levels after cardiac surgery and their clinical relevance in predicting postoperative adverse neurologic outcomes; the 2 proteins are only released in peripheral blood in association with nervous system lesions. METHODS: We neurologically assessed 190 consecutive patients undergoing elective cardiac operations for coronary artery bypass (n = 147), valve replacement (n = 29), or both (n = 14), before as well as after the operation. Postoperative outcome was classified as type I (uncomplicated), type II (confusion, agitation, disorientation, or epileptic seizures), or type III (stroke, stupor, or coma). Levels of S-100beta and neuron-specific enolase were evaluated in venous blood samples drawn preoperatively and then daily in the first 5 postoperative days. RESULTS: Levels of S-100beta and neuron-specific enolase differed significantly among the 3 groups (type III > type II > type I) throughout the postoperative period and had a diagnostic specificity and specificity of 89% and 79%, respectively, in identifying patients with type III outcome. S-100beta (but not neuron-specific enolase) levels were identified as significant independent predictors for type II and III outcomes (odds ratio 16.2, P <.0004). The same was true for duration of cardiopulmonary bypass (odds ratio 1.02, P <.006). CONCLUSIONS: Serum levels of S-100beta are reliable markers for adverse neurologic outcomes after cardiac surgery.

Biomarkers↗
PubMed2000

Improved outcome of APACHE II score-defined escalating systemic inflammatory response syndrome in patients post cardiac surgery in 1996 compared to 1988-1990: the ESSICS-study pilot project.

OBJECTIVE: Cardiac surgery using extracorporeal circulation leads to the release of cytokines and subsequently to a systemic inflammatory response syndrome, which is thought to be a negative prognostic factor for patients' outcome. A stratification for the risk of an escalating systemic inflammatory response syndrome had been achieved in a monocenter study carried out in 1988-1990, using APACHE II scoring on the morning of the 1st postoperative day. We now re-evaluated this concept prospectively in three independent centers. METHODS: The APACHE II based risk stratification was put to test in three independent heart surgery centers in the period from June to December 1996. Nine hundred and forty-five patients after elective cardiac surgery (excluding heart transplantation) with the assistance of the cardiopulmonary bypass were prospectively monitored. RESULTS: We found an increase in mortality with higher APACHE II score values determined on the 1st postoperative day. The mortality rose to nearly 50% with an APACHE II score of > or = 28. Patients at high risk for the development of a systemic inflammatory response syndrome (APACHE II score > or = 24) significantly differed from patients at lower risk (APACHE II score < 19) in the duration of mechanical ventilation and extracorporeal circulation, age and New York Heart Association (NYHA) classification (P < 0.05). CONCLUSION: The APACHE II score determined on the morning of the 1st postoperative day helps identifying the subgroup of patients with escalating systemic inflammatory response syndrome. Comparison with the data obtained in the years 1988-1990, suggests a better prognosis in the current trial for patients at high risk with a similar degree of escalating systemic inflammatory response syndrome.

APACHE↗
PubMed2000

The mechanism of cryoinjury: In vitro studies on human internal mammary arteries.

The mechanism of cryoinjury was investigated in human internal mammary arteries (IMA) by monitoring contractile responses to ET-1 and KCl. For cryopreservation segments of IMA were equilibrated for 20 min with the cryomedium (RPMI 1640 culture medium containing 1.8 M DMSO and 0.1 M sucrose), frozen at a mean cooling rate of 1.3 degrees C min(-1) to -70 degrees C and stored in liquid nitrogen. Before use, samples were thawed slowly and the cryomedium removed by dilution. Compared to unfrozen controls, ET-1 stimulated frozen/thawed IMA with similar efficacy but at 3 fold lower concentrations (P<0.001). Addition of ET-1 (100 nM) induced maximal contraction of unfrozen IMA within 10 min, declining thereafter to 25% after 90 min. In frozen/thawed IMA the ET-1-induced contraction was sustained but could be reversed if protein kinase C was blocked by staurosporine (100 nM). Responses to ET-1 of cryostored IMA were 5 fold more susceptible to blockade by nifedipine than those of controls. After cryostorage the efficacy of KCl was diminished to 40% (P<0.05) and the KCl curve was shifted to the left (2 fold, P<0. 001). In both unfrozen and cryostored IMA the KCl (60 mM) effect was sustained and equally susceptible to nifedipine. It is suggested that the smooth muscle cell of IMA is receptive to physical forces which occur during cryopreservation. These forces modify transmembrane signal transduction and intracellular pathways, that are common to pharmacological agonists thereby changing vascular responses to several contractile agonists after thawing.

Calcium↗
PubMed2000

Differential pattern of endothelin-1-induced inotropic effects in right atria and left ventricles of the human heart.

In human right atrium, endothelin A (ET(A)) receptors couple to both inositol phosphate formation and inhibition of adenylylcyclase, whereas in human left ventricle, ET(A) receptors couple only to inositol phosphate formation. To find out whether this might be of functional relevance, we studied, in right atria obtained from 32 patients undergoing coronary bypass grafting without apparent heart failure, and in right atria and left ventricles from eight patients with end-stage heart failure (NYHA IV) undergoing heart transplantation, the effects of endothelin-1 (ET-1) on basal force of contraction or on force of contraction increased by 1 microM forskolin. ET-1 (0.1 microM) exerted a positive inotropic effect in atrial and ventricular tissue; this could be antagonized by the ET(A)-receptor antagonist BQ 123, but not by the ET(B)-receptor antagonist BQ 788. In atrial, but not in ventricular tissue, this positive inotropic effect was preceded by a transient negative inotropic effect. This negative inotropic effect was inhibited by BQ 123, but not by BQ 788. It was significantly prolonged in forskolin-prestimulated atria, and was significantly larger in atria from failing hearts. We conclude that, because ET-1 inhibits adenylylcyclase and causes negative inotropic effects in atria but not in ventricles, adenylylcyclase inhibition might be responsible for the transient negative inotropic effect of ET-1.

Analysis of Variance↗
PubMed2000

Late conduction defects following aortic valve replacement.

BACKGROUND AND AIM OF THE STUDY: The study aim was to determine the incidence and clinical significance of late cardiac conduction defects (CD) after aortic valve replacement (AVR). METHODS: An analysis was made of 100 consecutive cases after AVR in a prospective outpatient evaluation program. RESULTS: The perioperative (30-day) mortality rate was 5%, and incidence of perioperative pacemaker implantation 3%. Among patients, 19% had CDs before surgery; a normal ECG was present during all periods in 45% of patients. The most frequent perioperative CD was left anterior hemiblock (LAHB; n = 8), and the most frequent late CD was left bundle branch block (LBBB; n = 8). Overall, 13.7% of operative survivors with normal preoperative and perioperative ECGs developed late CDs; one patient (1%) required pacemaker implantation 82 months after AVR. A further three patients (3%) had worsening of pre-existent CDs. Late CDs occurred over a wide time range (3 to 102 months) after surgery. CONCLUSION: There is an important incidence of CDs that occur late after AVR, even if the perioperative ECGs are normal; however, a need for late pacemaker implantation is rare. As CDs may occur at any time after surgery, regular follow up with precise evaluation of ECGs is called for.

Adult↗
PubMed2000

[Reverse remodeling by surgery--fact or fiction?].

Mortality of chronic heart failure in industrial countries remains unacceptably high despite advances in medical therapy. Heart transplantation, the gold standard in the treatment of end-stage heart failure is reserved for only a few patients because of the shortage of donor hearts. Surgical alternatives to transplantation include dynamic cardiomyoplasty (CMP), mitral valve reconstruction, left ventricular reduction surgery (PLVR) and ventricular assist devices (VAD). Improved survival and objective physiologic improvement have not been documented for CMP in the treatment of dilative cardiomyopathy. Mitral valve reconstruction on the other hand shows promising results. PLVR is an innovative procedure in which the heart is surgically reduced in size and cardiac function is dramatically improved immediately after surgery. The presence of long-term effects is still unknown. VAD have been shown to be extremely effective as a short- and long-term "bridge" to heart transplantation. They are not approved for permanent support. A randomized trial in the U.S. is underway to compare the efficacy of these devices with the efficacy of medical therapy in NYHA functional class IV patients in quality of life, survival and costs.

Cardiomyoplasty↗
PubMed1999

Myocardial gene expression of regulators of myocyte apoptosis and myocyte calcium homeostasis during hemodynamic unloading by ventricular assist devices in patients with end-stage heart failure.

BACKGROUND: In patients with end-stage heart failure, characterized by an increased susceptibility to cardiomyocyte apoptosis and a labile cardiomyocyte calcium homeostasis, a ventricular assist device (VAD) is implanted for bridging to cardiac transplantation and results in myocardial unloading. Although phenotype changes in the failing heart are assumed to result from hemodynamic overload, the reversibility of these changes under unloading is unknown. METHODS AND RESULTS: By use of quantitative reverse-transcription polymerase chain reaction, mRNA expression analyses were performed on left ventricular specimens obtained from 10 nonfailing donor hearts (from 8 patients with dilated cardiomyopathy and 2 patients with coronary heart disease) at the time of VAD implantation and 36 to 169 days later during VAD removal with subsequent cardiac transplantation. In terminally failing hearts before VAD support, left ventricular mRNA analyses revealed increased Pro-ANP, reduced antiapoptotic Bcl-x(L) and antiapoptotic Fas isoform FasExo6Del, and a decreased ratio of sarcoplasmic reticulum Ca(2+)-ATPase per sarcolemmal Na(+)-Ca(2+) exchanger in comparison with nonfailing ventricles. After VAD unloading, ventricular transcription of Pro-ANP was immediately normalized, and apoptotic DNA fragmentation was attenuated. In patients with dilated cardiomyopathy, mRNAs of Bcl-x(L) and FasExo6Del/Fas were enhanced depending on time on VAD. The Bcl-x(L) mRNA level correlated positively with that of the Bcl-x(L) protein. Transcription of sarcoplasmic reticulum Ca(2+)-ATPase/Na(+)-Ca(2+) exchanger demonstrated recovery in only 4 of 10 patients. CONCLUSIONS: Mechanical support of the failing heart induces a time-dependent change in myocardial gene expression compatible with a decreased susceptibility to apoptosis.

Adult↗
PubMed1999

Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein.

BACKGROUND: Oxidatively modified LDL (oxLDL) plays an important role in the development of atherosclerosis. OxLDL effects, eg, foam cell formation, are mediated in part by the classic scavenger receptor, whereas other effects may involve the recently cloned endothelial oxLDL receptor, LOX-1 (lectinlike oxLDL receptor-1), which is distinct from macrophage scavenger receptors. Because the regulation of LOX-1 must still be defined, we investigated whether LOX-1 is regulated by the potentially proatherosclerotic stimulant angiotensin II (Ang II). METHODS AND RESULTS: Using competitive reverse transcription-polymerase chain reaction (RT-PCR), we quantified mRNA expression of LOX-1 in primary cultures of human umbilical vein endothelial cells (HUVECs). After treatment with Ang II for 3 hours (1 nmol/L to 1 micromol/L), LOX-1 mRNA was concentration-dependently induced (from 6.9+/-1.4 to 23.1+/-5.5 relative units [RU] by 1 micromol/L Ang II; P<0.05). The angiotensin II type 1 (AT(1)) receptor antagonist losartan prevented this induction. Incubation of HUVECs with Ang II (100 nmol/L, 3 hours) induced LOX-1 protein expression (212+/-21% of control level; P<0. 01) and uptake of 1,1'-dioctadecyl-3,3,3', 3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled oxLDL (209+/-17% of control level; P<0.05) by an AT(1)-dependent pathway, reaching its maximum after 24 hours (680+/-89%; P<0.05). In internal mammary artery biopsy samples from patients with or without ACE inhibitor treatment before coronary artery bypass surgery, LOX-1 mRNA was downregulated by ACE inhibition (6.4+/-2.0 versus 19.3+/-5. 9 RU; n=12 each; P<0.05). CONCLUSIONS: We conclude that LOX-1 is regulated by Ang II in vitro and in vivo, that induction of LOX-1 is mediated by the AT(1) receptor, and that repression of LOX-1 by long-term ACE inhibitor treatment may contribute to the antiatherosclerotic potential of this therapy.

Angiotensin II↗
PubMed1999

Surgical aspects of resection for suspected invasive pulmonary fungal infection in neutropenic patients.

BACKGROUND: Morbidity and mortality of early resection of invasive pulmonary fungal disease in neutropenic patients are still considered prohibitive for surgical treatment. METHODS: We retrospectively analyzed results of 28 (16 men, 12 women; mean age, 38.9 years) consecutive neutropenic hematologic patients who had lung resections for suspicion of invasive pulmonary fungal disease. RESULTS: We did 28 lung resections (19 lobectomies, one bilobectomy, eight single or multiple wedge resections including three video-assisted wedge resections). The disease was proved histologically in 22 (78.6%) cases. Intraoperative difficulties, such as diffuse oozing or mycotic infiltration, and solid postinflammatory adhesions were encountered in 5 (17.8%) and 6 (21.4%) patients respectively. In one case (3.6%) it lead to a major intraoperative hemorrhage. There were no intraoperative deaths, overall 30-day mortality rate was two of 28 (7.1%), overall 90-day mortality rate was seven of 28 (25%), with one death (3.6%) possibly related to surgery. Minor surgery-related complications were seen in ten (35.7%) cases, major surgery-related complications occurred in three (10.7%) cases. Twelve of 22 patients (54.5%) with proven invasive fungal infection are currently alive (mean follow-up, 32.3 months). CONCLUSIONS: Surgery-related complications and mortality are acceptable for this high risk group of patients. Resection should be carried out early for diagnostic as well as therapeutic reasons.

Adolescent↗
PubMed1999

Altered levels of mRNA of apoptosis-mediating genes after mid-term mechanical ventricular support in dilative cardiomyopathy--first results of the Halle Assist Induced Recovery Study (HAIR).

BACKGROUND: Ventricular assist devices (VADs) lead to an immediate unloading of the failing heart. Although VADs are used as a bridge to transplant, in some cases patients suffering from dilated cardiomyopathy have been weaned from the VAD without transplantation after a recovery process initiated by the cardiac support. Myocardial apoptosis is associated with inadequate myocardium and might be reverted during VAD support of the failing heart. Therefore we measured transcription of apoptosis-associated genes FasExo6 Del, Fas-receptor, and Bcl-xL as markers of a putative recovery. METHODS: Fas-receptor, its soluble isoform FasExo6Del, and Bcl-xL mRNA were quantified by standard calibrated competitive reverse-transcription polymerase chain reaction (PCR) in 6 patients suffering from dilated cardiomyopathy. RNA standards were prepared by introducing 100 bp deletions into the native cDNA, resulting in truncated PCR products with identical primer-binding sites. Standards were transcribed in vitro and the resulting RNA was quantified. RESULTS: Transcription of apoptosis-inhibiting genes FasExo6 Del and Bcl-xL were upregulated in patients supported for more than 6 weeks. Fas receptor mRNA remained unaffected by VAD support. CONCLUSIONS: Transcriptional upregulation of apoptosis-inhibiting genes might be caused by a desensitization to apoptotic stimuli and might indicate a relaxation of the diseased status of the myocardium. These data outline the first biochemical evidence of a remodelling process occurring in supported ventricular myocardium.

Apoptosis↗
PubMed1998

Age-dependent decrease in the negative inotropic effect of carbachol on isolated human right atrium.

On isolated, electrically driven human right atrial strips, carbachol (10(-8)-10(-3) M) concentration-dependently decreased force of contraction prestimulated with 1 microM forskolin; maximal negative inotropic effects of carbachol (10(-6)-3 x 10(-6) M), however, were in atria from patients aged < 25 years (mean age: 16.8 +/- 2.0 years, n = 9) significantly larger than in patients aged 50-69 years (mean age: 62.5 +/- 0.7 years, n = 33) and were further decreased in patients aged > 70 years (mean age: 73.8 +/- 0.6 years, n = 11). We conclude that, in human right atrium, the recently described age-dependent decrease in muscarinic M2 receptor density is accompanied by a decrease in negative inotropic effects.

Adolescent↗
PubMed1998

Endothelin receptors in the failing and nonfailing human heart.

BACKGROUND: In patients with chronic heart failure (CHF), plasma endothelin-1 (ET-1) levels are increased. We studied whether the cardiac ET-receptor system is altered in CHF patients. METHODS AND RESULTS: We assessed ET-evoked inositol phosphate (IP) formation in slices from right atria and left ventricles from 6 potential heart transplant donors (NFH) and 15 patients with end-stage CHF; in membranes from the same tissues, we studied ET-induced inhibition of isoprenaline- and forskolin-stimulated adenylyl cyclase and ET-receptor density. ET (10[-9] to 10[-6] mol/L, ET-1 >>> ET-3) increased IP formation in right atria and left ventricles through ET(A)-receptor stimulation in a concentration-dependent manner; no difference in potency or efficacy between NFH and CHF hearts was observed. ET-1 (10[-10] to 10[-6] mol/L), via ET(A)-receptor stimulation, inhibited isoprenaline- and forskolin-stimulated adenylyl cyclase in right atria but not in left ventricles, whereas carbachol inhibited adenylyl cyclase in both tissues; again, the potency and efficacy of ET- or carbachol-induced adenylyl cyclase inhibition was not different between NFH and CHF hearts. [125I]ET-1 binding revealed the coexistence of ET(A) and ET(B) receptors in both tissues; however, the density of ET(A) receptors was not significantly different between NFH and CHF hearts. Finally, the immunodetectable amount of left ventricular Gq/11 protein did not differ between NFH and CHF hearts. CONCLUSIONS: In the human heart, ET(A) and ET(B) receptors coexist; however, only ET(A) receptors are of functional importance. In right atria, ET(A) receptors couple to IP formation and inhibition of adenylyl cyclase; in left ventricles, they couple only to IP formation. In end-stage CHF, the functional responsiveness of the cardiac ET(A)-receptor system is not altered.

Adenylyl Cyclases↗
PubMed1998

Cardiac muscarinic receptors decrease with age. In vitro and in vivo studies.

The M1 muscarinic receptor antagonist pirenzepine in low doses decreases resting heart rate; this effect declines with age (Poller, U., G. Nedelka, J. Radke, K. Pönicke, and O.-E. Brodde. 1997. J. Am. Coll. Cardiol. 29:187-193). To study possible mechanisms underlying this effect, we assessed (a) in six young (26 yr old) and six older volunteers (61 yr old), pirenzepine effects (0.32 and 0.64 mg intravenous [i.v.] bolus) on isoprenaline-induced heart rate increases; (b) in five heart transplant recipients, pirenzepine effects (0.05-10 mg i.v. bolus) on resting heart rate in the recipient's native and transplanted sinus nodes; and (c) in right atria from 39 patients of different ages (5 d-76 yr) undergoing open heart surgery, M2 muscarinic receptor density (by [3H]N-methyl-scopolamine binding) and adenylyl cyclase activity. (a) Pirenzepine at both doses decreased heart rate in young volunteers significantly more than in older volunteers; (b) pirenzepine (< 1 mg) decreased resting heart rate in the recipient's native but not transplanted sinus node; and (c) M2 receptor density and carbachol-induced inhibition of forskolin-stimulated adenylyl cyclase activity decreased significantly with the age of the patients. We conclude that pirenzepine decreases heart rate via inhibition of presynaptic M1 autoreceptors, thereby releasing endogenous acetylcholine, and that the heart rate-decreasing effect of acetylcholine declines with age because right atrial M2 receptor density and function decrease.

Acetylcholine↗