Thomas Andersen Schmidt

Percutaneous Implantation of the CoreValve Self-Expanding Valve Prosthesis in High-Risk Patients With Aortic Valve Disease The Siegburg First-in-Man Study

Background— The morbidity and mortality of surgical aortic valve replacement are increased in elderly patients with multiple high-risk comorbid conditions. Therefore, a prospective, single-center, nonrandomized study was performed in high-risk patients with aortic valve disease to evaluate the feasibility and safety of percutaneous implantation of a novel self-expanding aortic valve bioprosthesis (CoreValve). Methods and Results— Symptomatic high-risk patients with an aortic valve area <1 cm2 were considered for enrollment. CoreValve implantation was performed under general anesthesia with extracorporeal support using the retrograde approach. Clinical follow-up and transthoracic echocardiography were performed after the procedure and at days 15 and 30 after device implantation to evaluate short-term patient and device outcomes. A total of 25 patients with symptomatic aortic valve stenosis (mean gradient before implantation, 44.2±10.8 mm Hg) and multiple comorbidities (median logistic EuroScore, 11.0%) were enrolled. Device success and procedural success were achieved in 22 (88%) and 21 (84%) patients, respectively. Successful device implantation resulted in a marked reduction in the aortic valve gradients (mean gradient after implantation, 12.4±3.0 mm Hg; P<0.0001). The mean aortic regurgitation grade was unchanged. Major in-hospital cardiovascular and cerebral events occurred in 8 patients (32%), including mortality in 5 patients (20%). Among 18 patients with device success surviving to discharge, no adverse events occurred within 30 days after leaving the hospital. Conclusions— Percutaneous implantation of the self-expanding CoreValve aortic valve prosthesis in high-risk patients with aortic stenosis with or without aortic regurgitation is feasible and, when successful, results in marked hemodynamic and clinical improvement.

No adaptation to digitalization as evaluated by digitalis receptor (Na,K-ATPase) quantification in explanted hearts from donors without heart disease and from digitalized recipients with end-stage heart failure.

Speculations about development of tolerance to the inotropic effect of digitalis have been engendered since studies in various in vitro systems and tissues not representative of the heart have shown up-regulation of sodium potassium adenosine triphosphatase (Na,K-ATPase) when exposed to digitalis. Moreover the digitalis receptor (i.e., Na,K-ATPase) concentration in the normal, vital human left ventricle has not been previously determined. On this basis, digitalis receptor concentration was quantified in the left ventricle of explanted hearts from subjects without heart disease and from patients with end-stage heart failure who had received digitalis therapy. This was performed using vanadate-facilitated 3H-ouabain binding to intact tissue samples giving values of 728 +/- 58 (n = 5) and 467 +/- 55 pmol/g wet weight (n = 6) (mean +/- SEM) (p < 0.005), respectively. However, some of the digitalis receptors may have retained digoxin before 3H-ouabain binding and thus may have escaped detection. To eliminate this effect of retained digoxin, samples were exposed to prolonged washing in buffer containing excess digoxin antibody, a method recently shown to clear digoxin from receptors and allow subsequent complete digitalis receptor quantification by 3H-ouabain binding. After washing in digoxin specific antibody, specific digitalis receptor concentration was 760 +/- 58 pmol/g (n = 5) and 614 +/- 47 pmol/g (n = 6) wet weight in samples of the normal and failing hearts, respectively (p < 0.08). Thus, digitalization was associated with occupancy of digitalis receptors in the failing human heart of 24% (p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Digoxin affects potassium homeostasis during exercise in patients with heart failure

OBJECTIVE The aim was to evaluate whether digitalisation of heart failure patients affects extrarenal potassium handling during and following exercise, and to assess digoxin receptor occupancy in human skeletal muscle in vivo. METHODS In a paired study of before versus after digitalisation, 10 patients with congestive heart failure underwent identical exercise sessions consisting of three bouts of increasing work rates, 41-93 W, on a cycle ergometer. The final bouts were followed by exercise to exhaustion. The femoral vessels and brachial artery were catheterised. Arterial blood pressure, heart rate, leg blood flow, cardiac output, plasma potassium, haemoglobin, pH, and skeletal muscle receptor occupancy with digoxin in biopsies were determined. RESULTS Occupancy of skeletal muscle Na/K-ATPase with digoxin was 9% (P < 0.05). Following digitalisation femoral venous plasma potassium increased by 0.2-0.3 mmol.litre-1 (P < 0.05) at work rates of 69 W, 93 W, and at exhaustion, as well as during the first 3 min of recovery. Following digitalisation the femoral venoarterial difference in plasma potassium increased by 50-100% (P < 0.05) during exercise, and decreased by 66-75% (P < 0.05) during early recovery. Total loss of potassium from the leg increased by 138%. The effects of digitalisation on plasma potassium were not the outcome of changes in haemodynamics, because cardiac output and leg blood flow increased by up to 13% and 19% (P < 0.05), nor was it the outcome of changes in haemoconcentration or pH. CONCLUSIONS Extrarenal potassium handling is altered as a result of digoxin treatment. This is likely to reflect a reduced capacity of skeletal muscle Na/K-ATPase for active potassium uptake because of inhibition by digoxin, adding to the reduction of skeletal muscle Na/K-ATPase concentration induced by heart failure per se. In heart failure patients, improved haemodynamics induced by digoxin may, however, increase the capacity for physical conditioning. Thus the impairment of extrarenal potassium homeostasis by heart failure and digoxin treatment may be counterbalanced by training.

Quantification of Rat Cerebral Cortex Na+,K+‐ATPase: Effect of Age and Potassium Depletion

Abstract: Na+,K+‐ATPase concentration in rat cerebral cortex was studied by vanadate‐facilitated [3H]ouabain binding to intact samples and by K+‐dependent 3‐O‐methylfluorescein phosphatase activity determinations in crude homogenates. Methodological errors of both methods were evaluated. [3H]Ouabain binding to cerebral cortex obtained from 12‐week‐old rats measured incubating samples in buffer containing [3H]ouabain, and ouabain at a final concentration of 1 × 10–6 mol/L gave a value of 11,351 ± 177 (n = 5) pmol/g wet weight (mean ± SEM) without any significant variation between the lobes. Evaluation of affinity for ouabain was in agreement with a heterogeneous population of [3H]ouabain binding sites. K+‐dependent 3‐O‐methylfluorescein phosphatase activity in crude cerebral homogenates of age‐matched rats was 7.24 ± 0.14 (n = 5) μmol/min/g wet weight, corresponding to a Na+,K+‐ATPase concentration of 12,209 ± 236 pmol/g wet weight. It was concluded that the present methods were suitable for quantitative studies of cerebral cortex Na+,K+‐ATPase. The concentration of rat cerebral cortex Na+,K+‐ATPase showed ∼10‐fold increase within the first 4 weeks of life to reach a plateau of ∼11,000–12,000 pmol/g wet weight, indicating a larger synthesis of Na+,K+ pumps than tissue mass in rat cerebral cortex during the first 4 weeks of development. K+ depletion induced by K+‐deficient fodder for 2 weeks resulted in a slight tendency toward a reduction in K+ content (6%, p > 0.5) and Na+,K+‐ATPase concentration (3%, p > 0.4) in cerebral cortex, whereas soleus muscle K+ content and Na+,K+‐ATPase concentration were decreased by 30 (p < 0.02) and 32% (p < 0.001), respectively. Hence, during K+ depletion, cerebral cortex can maintain almost normal K+ homeostasis, whereas K+ as well as Na+,K+ pumps are lost from skeletal muscles.

Quantification of the total Na,K-ATPase concentration in atria and ventricles from mammalian species by measuring 3H-ouabain binding to intact myocardial samples. Stability to short term ischemia reperfusion

SummaryNa,K-ATPase concentration was measured by vanadata facilitated3H-ouabain binding to intact samples taken from various parts of porcine and canine myocardium. In porcine and canine heart3H-ouabain binding site concentration in ventricles was 1.4–2.5 times larger than in atria. Evaluation of3H-ouabain binding kinetics revealed no major difference between atria and ventricles: Equilibrium was obtained after the same incubation time in right atrium (RA) as in left ventricle (LV), both in porcine and canine heart. Unspecific uptake and retention of3H-ouabain was for porcine heart RA and LV 1.5 and 1.4, respectively, and for canine heart RA and LV, both 1.2% filling (i.c., volume (ml) of incubation medium3H-radioactivity taken up per mass unit (g wet wt.) of tissue multiplied by 100). The apparent dissociation constant (Kd) was 1.4×10−8 and 1.9×10−8 in porcine RA and LV and 2.6×10−8 and 6.1×10−8 mol/l in canine RA and LV. Loss of specifically bound3H-ouabain during the washout procedure occurred with a half-life time (T1/2) of 16.7 in RA and LV of porcine heart and 91.2 and 151.6h in RA and LV of canine heart. Duly corrected for these errors of the method-factor 1.16 and 1.13, respectively, for porcine RA and LV, and factor 1.11 and 1.13 for canine RA and LV, total3H-ouabain binding site concentration was found to be 553±74 and 1037±45 pmol/g wet wt. (means±SEM, n=5) in porcine RA and LV, and 569±37 and 1410±40 pmol/g wet wt. (means ±SEM, n=5) in the canine RA and LV. These values were confirmed by measurements of3H-digoxin binding to the porcine heart. The present quantification of myocardial Na, K-ATPase gives values up to 154 times higher than measurements based upon Na,K-ATPase activities in membrane fractions where the recovery of Na,KK-ATPase may be less than 1% due to loss during purification. A higher Na,K-ATPase concentration is found in small animals than in large animals. A relationship between higher concentration of Na, K-ATPase and larger pressure work in ventricles compared to atria is suggested. Myocardial3H-ouabain binding sites were found to be stable for 20 min of ischemia, followed by 1h of reperfusion, supporting the concept that myocyte injury induced by short term ischemia may be reversible and that reperfusion may result in normalization.

Human skeletal muscle digitalis glycoside receptors (Na,K-ATPase)—Importance during digitalization

SummaryThe aims of the present study were to evaluate in humans the putative importance of skeletal muscle digitalis glycoside receptors (Na,K-ATPase) in the volume of distribution of digoxin and to assess whether therapeutic digoxin exposure might cause digitalis receptor upregulation in skeletal muscle. Samples of the vastus lateralis were obtained postmortem from 11 long-term (9 months to 9 years) digitalized (125–187.5 µg daily) and eight undigitalized subjects. In intact samples from digitalized patients, vanadate-facilitated3H-ouabain binding increased 15% (p<0.02) from 150±18 to 173±13 pmol/g wet wt. (mean ± SEM) after clearing receptors of bound digoxin by washing samples in excess specific digoxin antibody fragments.3H-ouabain binding in the untreated group was 257±28 and 274±26 pmol/g wet wt. (7%, p>0.30) before and after washing in specific dogoxin antibody fragments, respectively. Thus, the present study indicates a ~13% occupancy of skeletal muscle digitalis glycoside receptors with digoxin during digitalization. In light of the large skeletal muscle contribution to body mass, this indicates that the skeletal muscle Na,K-ATPase pool constitutes a major volume of distribution for digoxin during digitalization. The results gave no indication of skeletal muscle digitalis glycoside receptor upregulation in response to digoxin treatment. On the contrary, there was evidence of significantly lower (37%, p<0.005) digitalis glycoside receptor concentration in the vastus lateralis of the digitalized patients, which may be of importance for skeletal muscle incapacity in heart failure.

Human myocardial Na,K-ATPase — quantification, regulation and relation to Ca

Time for primary review 26 days. The Na,K-ATPase (sodium, potassium adenosine triphosphatase) or the Na,K-pump is an ubiquitous enzyme which performs the active transport of Na and K across the cell membrane [1]. Thus, by hydrolysing ATP the Na,K-ATPase pumps 3 Na ions out of the cell and 2 K ions into the cell. Hence, Na,K-ATPase is of importance for the characteristic distribution of these cations across the cell membrane and for generation of the membrane potential; thus optimum Na,K-ATPase function is required to ensure excitability and conduction. By generating the Na gradient across the sarcolemma, Na,K-ATPase creates a driving force for active Ca extrusion via the Na — Ca exchanger embedded in the membrane. Together with the Ca-ATPase located in the sarcolemma and in the membrane of the sarcoplasmic reticulum, the Na-Ca exchanger is of importance for maintaining low diastolic Ca concentration [2]. When muscular cells are depolarized intracellular Ca rises as much as 10 fold to around 1 μmol×litre−1 [3]. Subsequently Ca binds to troponin C triggering the force generating interaction between actin and myosin. Thus, Na,K-ATPase has the capacity for influencing muscular force generation. It might be noted that whereas the Na,K-pump utilizes around 4% of myocardial energy expenditure to maintain Na,K gradients, as much as 30% is used to fuel the Ca-ATPase [4]. Cardiac glycosides bind to the Na,K-ATPase in a 1: 1 ratio [5], and myocardial Na,K-ATPase is generally accepted to be the target for its positive inotropic action eliciting an increase in the availability of Ca to the contractile proteins in heart cells [6]. Cardiac glycosides bind with high affinity and specificity to an inhibitory site on the α subunit of Na,K-ATPase facing the outside of the cell, resulting in the complete inhibition of Na and K … * Corresponding author. Tel. (+45) 3545 2871; Fax: (+45) 3138 3186.

Reduced3H-ouabain binding site (Na,K-ATPase) concentration in ventricular myocardium of dogs with tachycardia induced heart failure

SummaryThe present study evaluates3H-ouabain binding site (Na,K-ATPase) concentration in left ventricular myocardium of dogs with heart failure induced by tachycardia as a result of ventricular pacing. Samples of left ventricle were obtained from 10 dogs exposed to pacing of 240 beats/min for 3 to 4 weeks and eight sham-operated controls. Na,K-ATPase was quantified using vanadate facilitated3H-ouabain binding to intact samples. At time of sacrifice paced dogs showed clinical signs of heart failure, a significant 257% increase in left ventricular end diastolic pressure and a significant 46% decrease in left ventricular dP/dt compared with control. There was no significant change in left ventricular mass.3H-ouabain binding concentration was significantly reduced by 16%. Evaluation of3H-ouabain binding kinetics revealed no significant difference between myocardium from paced and control dogs: Equilibrium binding conditions were at the various concentrations used obtained after similar incubation time; nonspecific uptake and retention of3H-ouabain was 0.9–0.8% of total uptake and retention obtained in the standard assay; apparent dissociation constant (KD) was 6.5×10−8–6.6×10−8mol/l; loss of specifically bound3H-ouabain during washout at 0°C occurred with a half-life time (T3/2) of 120 and 121h. Hence, total3H-ouabain binding site concentration in left ventricular myocardium was (mean±SEM) 1110±56 and 1317±68 pmol/g wet weight, 8.54±0.43 and 10.05±0.52 pmol/mg protein, and the total amount of3H-ouabain binding sites in the entire left ventricle 121±6 and 162±8 nmol in paced (n=10) and control (n=8) dogs (p<0.05), respectively. In conclusion, the present study reports a significant reduction in left ventricular myocardium3H-ouabain binding site concentration in tachycardia induced heart failure. This observation supports the concept of a relationship between Na,K-ATPase concentration and contractile capacity and may be of pathophysiological importance in tachycardia and heart failure.

Minimally invasive aortic valve replacement reduces atelectasis in cardiac intensive care.

Objective: Respiratory failure is a major complication after cardiac surgery. The purpose was to evaluate the impact of minimally invasive aortic valve replacement (mini AVR) on the occurrence of left lower lobe atelectasis (LLLA) in the cardiac intensive care unit (ICU). Patients and Methods: 98 patients were scheduled to undergo mini AVR. 14 of these patients were converted to a full sternotomy due to technical problems. These patients were compared to a group of 50 patients having planned AVR through a full sternotomy. The incidence of LLLA was evaluated on the first postoperative chest X-ray in the cardiac ICU. Results: In the group having completed mini AVR 20/84 (24%) had a partial LLLA while in the group having extension to a full sternotomy 9/14 (64%) had LLLA lobe (P<0.005). In the group of 50 patients who had AVR through a full sternotomy, 27 patients (54%) had LLLA in the ICU which is also significantly higher (P<0.008) than the percentage of atelectasis in the mini AVR group. Conclusions: Patients who had mini AVR had a significantly lower incidence of LLLA in the cardiac ICU than patients who had AVR through a full sternotomy.

Advantages and Limitations of Ribosomal RNA PCR and DNA Sequencing for Identification of Bacteria in Cardiac Valves of Danish Patients

Studies on the value of culture-independent molecular identification of bacteria in cardiac valves are mostly restricted to comparing agreement of identification to what is obtained by culture to the number of identified bacteria in culture-negative cases. However, evaluation of the usefulness of direct molecular identification should also address weaknesses, their relevance in the given setting, and possible improvements. In this study cardiac valves from 56 Danish patients referred for surgery for infective endocarditis were analysed by microscopy and culture as well as by PCR targeting part of the bacterial 16S rRNA gene followed by DNA sequencing of the PCR product. PCR and DNA sequencing identified significant bacteria in 49 samples from 43 patients, including five out of 13 culture-negative cases. No rare, exotic, or intracellular bacteria were identified. There was a general agreement between bacterial identity obtained by ribosomal PCR and DNA sequencing from the valves and bacterial isolates from blood culture. However, DNA sequencing of the 16S rRNA gene did not discriminate well among non-haemolytic streptococci, especially within the Streptococcus mitis group. Ribosomal PCR with subsequent DNA sequencing is an efficient and reliable method of identifying the cause of IE, but exact species identification of some of the most common causes, i.e. non-haemolytic streptococci, may be improved with other molecular methods.