How to optimize lipoprotein apheresis treatment--a second look.

BACKGROUND: Lipoprotein apheresis (LA) is used in hypercholesterolemic patients suffering from cardiovascular disease (CHD) if a modified diet and lipid-lowering drug regimens had failed. During the first LA treatments LDL-cholesterol (LDL-C) and lipoprotein (a) (Lp(a)) can be decreased very effectively when using generally accepted formulas for calculating plasma (PV) (e.g. Pearson) or blood volumes (BV) as a basis for calculating treatment volume (e.g. Nadler). With respect to LDL-C and Lp(a) levels after LA treatment not all treated patients on steady state with apheresis treatment procedures may achieve the desired target concentrations for LDL-C (<70 mg/dl) and Lp(a) (<30 mg/dl). Are there further ways to increase the effectiveness of LA? METHODS: Over months or years of LA the treated volumes were stepwise increased in patients to achieve target cholesterol concentrations but not sufficiently in all cases. Therefore the patients' actual LA treatment volumes were compared to the calculated PV or BV. To possibly optimize the treatment capacity of LA procedures independent of calculated PV or BV the capacity threshold was determined in addition. During LA procedures every 20 min cholesterol, triglycerides, LDL-C, HDL-C and Lp(a) concentrations were determined and related to the hematocrit to exclude dilution effects. RESULTS: In patients undergoing regular LA treated volumes vs. calculated volumes were different: for PV 28 ± 18% (n = 7); for BV 28 ± 20% (n = 6). The mean treated volumes were 1.3 fold larger than the calculated volumes to achieve cholesterol target levels in most LA treatments. With respect to the capacity threshold we observed in only 1 of 13 patients an ineffective long treatment time. No LA procedure failed due to exhausted capacity. CONCLUSIONS: Lipoprotein apheresis treatment is a very effective treatment procedure in lowering LDL-C and Lp(a). However, not in all procedures the optimal treatment volume for LA patients may be calculated. However calculations of PV and BV are more or less error-prone. An increase of 1.3 fold in the calculated volumes may be the first step in optimizing individual LA treatment options. In addition, to exclude an exhaustion of LA procedures the determination of the individual capacity threshold in every LA patient may be further helpful to adjust treatment volumes. To substantiate our demand on changed treatment volumes further data are necessary.

Current view: indications for extracorporeal lipid apheresis treatment.

BACKGROUND: One of the first investigations concerning extracorporeal treatment of hypercholesterolemia was performed in 1967 by plasma exchange in patients with homozygous or severe heterozygous familial hypercholesterolemia (FH). In the following decades, several specific lipid apheresis systems were developed to efficiently eliminate low-density lipoprotein (LDL) cholesterol and Lp(a) cholesterol in hypercholesterolemic patients. In the early 1980s, the main clinical indication has been homozygous FH including mainly children and pregnant women. In consideration of the current development of lipid-lowering regimens and scientific knowledge of preventing progression of cardiovascular diseases, the spectrum of indications to initiate lipid apheresis was extended due to still insufficient lipid-lowering therapy in some clinical cases. However, a generally accepted indication for lipid apheresis treatment is still under discussion. In Germany, the target-oriented distribution of increasingly limited healthcare resources demand data which support the benefit of established treatment procedures such as lipid apheresis. In recent years, the Federal Joint Committee (G-BA), a paramount decision-making body of the German Healthcare System, issued to reassess the approval of chronic lipid apheresis therapy for regular reimbursement. Therefore, in 2005, an interdisciplinary German Apheresis Working Group has been established by members of both the German societies of nephrology. One of the first goals of this working group was a revision of the indications for lipid apheresis corresponding to current guidelines and recommendations for the treatment of lipid disorders. In addition, recently new pathophysiological perceptions of the impact of lipoproteins on atherogenesis and thrombosis were also considered. METHODS AND RESULTS: Since 2005, the working group met on a regular basis to substantiate the first defined goals. The indications for lipid apheresis were critically revised with respect to actual results from clinical investigations, cardiovascular guidelines, and scientific knowledge and were accepted by the members of the apheresis working group. CONCLUSIONS: There is consensus between the medical societies and health insurance funds regarding the need for general accepted guidelines for lipid apheresis. Recommendations for the indications of lipid apheresis were developed, but additionally these results should be confirmed by medical societies to transform them to guidelines. However, due to limited data showing that lipid apheresis has effects on the progression of cardiovascular diseases all members of the apheresis working group support a project for creating a lipid apheresis registry. This apheresis registry has been developed and recently started. The primary goal is to substantiate prospective long-term data on clinical outcome of chronic lipid apheresis treatment and to support additional clinical research activities in this field. In addition, this registry should comply with the actual requests of the Federal Joint Committee (G-BA).

An erythropoietin gene polymorphism in the hypoxia-responsive element at position 3434 is possibly associated with hypertension.

BACKGROUND/AIMS: Several polymorphisms of vasoactive hormones have been implicated in hypertension. Erythropoietin (EPO) interacts with vasoactive substances, such as angiotensin II. Previously detected single nucleotide polymorphisms in the hypoxia-responsive element of EPO might be associated with hypertension and hypertensive end organ damages. METHODS: 400 hypertensive patients and 200 age- and gender-matched normotensive controls were genotyped for an EPO polymorphism [cytosine (C)/thymine (T) single nucleotide polymorphism] at position 3434. Patients were grouped according to their genotype into the CC group (CC genotype) and the CT/TT group (CT and TT genotype). BP was measured by ambulatory BP monitoring. RESULTS: The CC genotype was present in 87% of hypertensive patients and in 78.5% of controls (p = 0.007). In addition, patients with the CC genotype had higher BP levels compared with CT/TT genotypes (BPsys 143.7 ± 20.4 vs. 136.1 ± 13.5 mm Hg, p = 0.01, and BPdias 85.8 ± 11.6 vs. 82.4 ± 8.9, p = 0.043) despite a nearly identical number of antihypertensive drugs (2.3 ± 1.5 vs. 2.3 ± 1.6; p = 0.257). 100% of the small number of patients with end-stage renal disease (n = 15) had the CC genotype. CONCLUSION: The CC genotype of the EPO gene at position 3434 is more frequently found in patients with hypertension and is associated with higher BP levels.

Serial NT-proBNP measurements for risk stratification of patients with decompensated heart failure.

PURPOSE: NT-proBNP is an important prognostic predictor in patients with heart failure. However, it is unknown whether a change of NT-proBNP plasma levels in the early phase of decompensation might be of additional prognostic value in patients with acute decompensation of heart failure. METHODS AND RESULTS: NT-proBNP plasma levels of 116 patients with decompensated heart failure from ischemic/non-ischemic origin were measured at baseline and at 12, 24 and 48 h after hospital admission. Baseline levels and changes of plasma levels within the first 48 h were correlated with 30-day mortality. In all patients, NT-proBNP 12 h after admission was highest and superior with respect to the prediction of 30-day mortality compared to plasma levels on admission. In total, 38 patients died within the first 30 days. In these patients absolute NT-proBNP plasma levels were significantly higher and the increase within 12 h after admission was more pronounced compared to survivors (p<0.001). NT-proBNP at 12 h after admission also had the highest predictive value for the 30-day mortality rate in patients with acute myocardial infarction. The increase of NT-proBNP plasma levels within 12 h after admission had the highest predictive value in patients suffering from decompensated heart failure. CONCLUSIONS: NT-proBNP is a powerful marker of 30-day mortality in patients with decompensated heart failure of ischemic and non-ischemic origin. Compared with single baseline measurements, serial measurements of NT-proBNP plasma levels within 12 h after hospital admission may be used to increase the predictive value of NT-proBNP with regard to the early identification of patients who are at high risk of mortality.

[Sepsis-like disease in an immunocompromised patient with a travel history to Mallorca]. / Sepsisähnliches Krankheitsbild bei Immunsuppression nach früherem Mallorcaurlaub.

In immunosuppressed patients, a high rate of complications due to opportunistic infection is known. We report the case of a 36 year old patient with ulcerative colitis and a septic complication with ongoing pancytopenia. Due to colonic perforation, colectomy had to be performed. Despite this intervention, the septic constellation persisted. The pancytopenia in peripheral blood counts also persisted with the necessity of repetitive transfusions. A bone marrow biopsy showed an infiltration with Leishmania bodies in macrophages. Tissue culture allowed for typing of the parasites as belonging to the L. donovani/infantum complex, DNA sequencing confirmed infection with L. infantum. This infection must have been contracted during a vacation on Mallorca about 1.5 years earlier. Administration of liposomal amphotericin B cured the patient. Surprisingly, histological examination of the resected colon reveiled the presence of an immunoblastic B-cell lymphoma. In this case, immunosuppression was a prerequisite for the manifestation of leishmaniosis.

99mTC-labelled antigranulocyte monoclonal antibody FAB' fragments versus echocardiography in the diagnosis of subacute infective endocarditis.

OBJECTIVE: We performed this pilot study to gain first clinical data of immunoscintigraphy with 99mTc-labelled anti-NCA-90 antigranulocyte antibody Fab' fragments (99mTc-Fab' (LeukoScan((R)))) in endocarditis. PATIENTS AND METHODS: 99mTc-Fab' and echocardiography were used in 24 consecutive patients with suspected endocarditis. Nuclear medicine imaging was performed after i.v. injection of 925 MBq 99mTc-Fab' fragments and evaluation was done by region of interest (ROI) technique and visually. RESULTS: Seven patients were found to have endocarditis on the basis of the revised Duke criteria, which served as gold standard. Initial scintigraphy was true positive in five patients and false positive in one. In the five true positives, T/B ratios in projection to the heart valve plane (with T/B>/=1.3+/-0.072) were highly suspicious for florid endocarditis. TTE and TEE were true positive in two and in six patients, whereas false positives were seen in two and in four patients. Scintigraphy was positive in four of the five patients with the false negative TTE and negative in the three false positive TEE. Vice versa, TEE was positive in the two patients with false negative scintigraphy. CONCLUSIONS: Immunoscintigraphy with 99mTc-Fab' fragments in combination with TEE improves diagnostic accuracy compared with TTE/TEE in patients with subacute infective endocarditis.

Endothelin-1 plasma levels are not elevated in patients with obstructive sleep apnoea.

Endothelin-1 (ET-1), a potent vasoconstrictor, is released mainly by vascular endothelial cells under the influence of hypoxia and other stimuli. ET-1 is related to endothelial dysfunction, as well as arterial and pulmonary hypertension, all of which are thought to be associated with obstructive sleep apnoea (OSA). This study evaluated venous plasma concentrations of ET-1 and noradrenaline and 24-h systemic blood pressure in 29 patients with OSA (age=56.9+/-1.6 yrs; body mass index=29.5+/-0.7 kg x m2 (mean+/-SEM)). Blood samples were taken in the morning, evening and during sleep. In the same way, the patients were assessed during a night of continuous positive airway pressure (CPAP) and after 13.9+/-1.4 months while still on CPAP. ET-1 levels were compared to those of control subjects, who were selected from in- and outpatients and were matched to patients for age, sex, presence of arterial hypertension and coronary artery disease. ET-1 plasma levels were not elevated in the patients compared to the controls (41.6+/-2.2 and 44.9+/-1.3 pg x mL(-1), respectively, p=0.20). The ET-1 concentration did not change significantly, neither during sleep nor in the first night on CPAP therapy, nor under long-term treatment with CPAP. ET-1 neither correlated to the severity of OSA nor to that of systemic hypertension. The results suggest that endothelin-1 does not play a crucial role in the pathophysiology of obstructive sleep apnoea.

Treatment of Cheyne-Stokes respiration with nasal oxygen and carbon dioxide.

Cheyne-Stokes respiration (CSR) is common in patients with congestive heart failure (CHF) and is associated with significant nocturnal O2 desaturation, arousals and sympathetic activation. Nocturnal O2 reduces CSR by only about 50%. More complete suppression of CSR may be achieved by adding CO2 to O2. This study therefore aimed to evaluate the effects of nocturnal O2 plus CO2 on CSR, sleep and sympathetic activation. Nine patients with CHF (age 59+/-5 yrs; left ventricular ejection fraction 17.8+/-1.2% (mean+/-SEM) were studied in a cross-over, single-blind, placebo-controlled trial. After an accommodation night the patients were randomly assigned to one night each of O2 plus CO2 as well as air applied by nasal prongs. Nocturnal O2 plus CO2 reduced the duration of CSR as percentage of total sleep time (48.0+/-10 versus 7.4+/-2.0%; p=0.008) and increased arterial oxygen saturation (Sa,O2) as well as mean transcutaneous carbon dioxide tension (Ptc,CO2) (5.2+/-0.3 kPa (39+/-2 mmHg) versus 5.7+/-0.3 kPa (43+/-2 mmHg) p=0.011). Sleep did not improve and arousals were not reduced. Plasma noradrenaline was higher on the treatment night (486+/-116 versus 669+/-163 ng x L(-1); p=0.035). In conclusion, nocturnal O2 plus CO2 improves Cheyne-Stokes respiration in patients with congestive heart failure but has adverse effects on the sequel of Cheyne-Stokes respiration, namely sympathetic activation.

Cheyne-Stokes respiration and prognosis in congestive heart failure.

Patients with congestive heart failure (CHF) frequently demonstrate Cheyne-Stokes respiration (CSR) with repetitive arousals and oxygen desaturations during sleep. Although it was evident from early publications that CSR during the daytime is a poor prognostic indicator in patients with CHF, it was speculated recently that CSR occurring during sleep could impede left ventricular function and even survival. We therefore followed up 36 patients with CHF and a left ventricular ejection fraction < or = 40% who underwent a sleep study at our institution. The patients showed a reduced ejection fraction (20 +/- 8%) and CSR with a median of 19% of total sleep time (lower and upper quartiles 9% and 56%). In 12 +/- 9% of their time in bed, the arterial oxygen saturation was <90%. No patient was lost to follow-up, which lasted for 32 +/- 15 months (range 11 to 53). One-year survival was 86 +/- 6%, and 2-year survival was 66 +/- 8%. Univariate comparisons for survival between groups stratified by the amount of CSR revealed no significant difference (log rank test, p = 0.84). However, the 20 patients with a left ventricular ejection fraction <20% had a shorter mean survival time than patients with an ejection fraction >20% (9.5 vs 28.3 months; log rank test, p = 0.013). Two patients with CSR during the daytime died within 1 month. No other patient had CSR during the daytime, and only 1 patient without daytime CSR died within 1 month (chi-square test, p <0.001). Higher age, reduced carbon dioxide end-tidal partial pressure, and increased transit time were found to be significantly related to the amount of nocturnal CSR. In conclusion, CSR occurring during sleep has no important prognostic impact in patients with CHF, but CSR present during the daytime suggests a high likelihood of dying within a few months.

[Nocturnal oxygen administration and cardiac arrhythmias during Cheyne-Stokes respiration in patients with heart failure]. / Nächtliche Sauerstoffgabe und Herzrhythmusstörungen während Cheyne-Stokes-Atmung bei Patienten mit Herzinsuffizienz.

Cheyne-Stokes respiration (CSR) is common during sleep in patients with severe congestive heart failure. It is not clear, if there is a relation between CSR and arrhythmias. Therefore in this study the impact of the nocturnal CSR on ventricular arrhythmias and the heart rate, as well as the influence of nasal nocturnal oxygen on CSR and sleep was studied. In a randomized, double-blind, crossover study 22 patients were assigned to 1 week each of oxygen and room air. The age of the patients was 57 +/- 10 years. Their mean left ventricular ejection fraction was 18.9 +/- 6.4%. Breathing oxygen significantly reduced the duration of CSR by over 50% (162 +/- 142 vs 88 +/- 106 min, p < 0.05). Sleep did improve as evidenced mainly by less arousals (21 +/- 13 vs 15 +/- 9/h total sleep time; p < 0.05) and stage 1 sleep as well as more stage 2 and slow wave sleep. Nocturnal oxygen resulted in a reduction of ventricular arrhythmias for ventricular ectopic beats (53.1 +/- 157.7 vs 44.7 +/- 97.1/h), couplets (9.0 +/- 38.3 vs 3.7 +/- 14.3/h) and tachycardias (1.8 +/- 7.2 vs 0.4 +/- 0.8/h). Due to the high day-today variability these differences were not significant, but the decrease of average nocturnal heart rate with oxygen was (71 +/- 14 vs 68 +/- 14/min; p < 0.05). In conclusion, nocturnal oxygen causes a reduction of CSR, an improvement of sleep and a decrease of arousals. A significant reduction of arrhythmias by nocturnal oxygen could not be proved.