Unrecognized High Occurrence of Genetically Confirmed Hereditary Carnitine Palmitoyltransferase II Deficiency in an Austrian Family Points to the Ongoing Underdiagnosis of the Disease

Adult muscle carnitine palmitoyltransferase (CPT) II deficiency is a rare autosomal recessive disorder of long-chain fatty acid metabolism. It is typically associated with recurrent episodes of exercise-induced rhabdomyolysis and myoglobinuria, in most cases caused by a c.338C > T mutation in the CPT2 gene. Here we present the pedigree of one of the largest family studies of CPT II deficiency caused by the c.338C > T mutation, documented so far. The pedigree comprises 24 blood relatives of the index patient, a 32 year old female with genetically proven CPT II deficiency. In total, the mutation was detected in 20 family members, among them five homozygotes and 15 heterozygotes. Among all homozygotes, first symptoms of CPT II deficiency occurred during childhood. Additionally, two already deceased relatives of the index patient were carriers of at least one copy of the genetic variant, revealing a remarkably high prevalence of the c.338C > T mutation within the tested family. Beside the index patient, only one individual had been diagnosed with CPT II deficiency prior to this study and three cases of CPT II deficiency were newly detected by this family study, pointing to a general underdiagnosis of the disease. Therefore, this study emphasizes the need to raise awareness of CPT II deficiency for correct diagnosis and accurate management of the disease

Preoperative Factors Associated with Target Lesion Revascularization following Endovascular Therapy of the Superficial Femoral Artery.

Objectives: In patients with symptomatic peripheral arterial occlusive disease (PAOD), endovascular revascularization of the superficial femoral artery (SFA) is the most frequent intervention. A major drawback of endovascular procedures is clinically driven target lesion revascularization (CD-TLR), which may cause recurrence of symptoms, re-hospitalizations, and re-interventions. Outcome studies comparing endovascular modalities are heterogeneous and focus more on intraoperative rather than preoperative aspects. Studies have not examined potential risk factors in patients' phenotype before an intervention to prevent CD-TLR. Design: Monocentric, retrospective cohort study of 781 patients with symptomatic PAOD referred to an endovascular intervention of the SFA between 2000 and 2018. Methods: The study aim was to identify risk factors and phenotypes leading to symptomatic PAOD in patients with de novo lesions of the SFA and ≥1 CD-TLR within 12 months post-index procedure. Two groups were differentiated: patients without CD-TLR and with ≥1 CD-TLR. Patient phenotype was compared for cardiovascular (CV) risk factors, age, gender, and renal function. Results: 662 patients (84.8%) (age 73.5 ± 11.2 years; 243 women (36.7%)) with no CD-TLR were compared to 119 patients (15.2%) with ≥1 CD-TLR (age 70.9 ± 12.4 years; 55 women (46.2%)). Women, as well as subjects with dyslipidemia, had each a 1.8-time higher odds ratio of receiving multiple interventions within one year than men or subjects without dyslipidemia. Older subjects (per decade) had a lower odds ratio (0.7) for multiple interventions. Subjects with an eGFR (estimated glomerular filtration rate) <30 mL/min had 3.8 times higher and subjects with eGFR ≥30 and <60 mL/min had a 2.4 higher odds ratio of receiving multiple interventions than subjects with eGFR values ≥90 mL/min. Conclusion: Our data indicate that younger women, patients with dyslipidemia, or those with renal insufficiency are at risk for recurrent midterm CD-TLR after endovascular therapy of the SFA

False versus True Statin Intolerance in Patients with Peripheral Artery Disease.

BACKGROUND Statin intolerance (SI) is often documented in patients' charts but rarely confirmed by objective methods. OBJECTIVE We aimed to identify the rate of true SI in a large population with peripheral artery disease (PAD) as well as the subsequent use of such drugs and the impact on cardiovascular outcomes. METHODS Patients with PAD and reported SI were retrospectively classified in those with "probable/possible" (pp) and "unlikely" (u) SI, after the application of the "Statin Myalgia Clinical Index Score" (SAMS-CI). Both groups were compared after 62 months (date of observation period?). RESULTS Among the 4,505 included patients, 139 (3%) had been reported as having SI. Of those, 33 (24%) had ppSI, and 106 (76%) had uSI. During the observation period, statin use decreased in patients with both ppSI (from 97% to 21%; p < 0.0001) and uSI (from 87% to 53%; p < 0.0001). At the end of the observation period, patients with ppSI more often received PCSK9 inhibitors (55% vs. 7%; p < 0.0001), had a stronger decrease in LDL-C from baseline to follow-up (1.82 ± 1.69 mmol/L vs. 0.85 ± 1.41 mmol/L; p < 0.01), and a lower rate of mortality (3% vs. 21%; p = 0.04) than those with uSI. CONCLUSIONS SI is low in PAD patients (3.1%), with only one quarter fulfilling the criteria of ppSI. The overdiagnosis of SI is related to an underuse of statins and an increased mortality in a short time period

Bile Acid Metabolites in Serum: Intraindividual Variation and Associations with Coronary Heart Disease, Metabolic Syndrome and Diabetes Mellitus

Bile acids (BAs) regulate glucose and lipid metabolism. In longitudinal and case-control-studies, we investigated the diurnal variation of serum concentrations of the 15 major BAs as well as the biosynthetic precursor 7α-hydroxy-4-cholesten-3-one (C4) and their associations, respectively, with coronary artery disease (CAD), diabetes mellitus type 2 (T2DM), and non-diabetic metabolic syndrome (MetS). In hourly taken blood samples of four healthy probands, the intraindividual 24 h variation of C4, conjugated and unconjugated BAs ranged from 42% to 72%, from 23% to 91%, and from 49% to 90%, respectively. Conjugated BA concentrations mainly increased following food intake. Serum levels of C4 and unconjugated BAs changed with daytime with maxima varying interindividually between 20h00 and 1h00 and between 3h00 and 8h00, respectively. Comparisons of data from 75 CAD patients with 75 CAD-free controls revealed no statistically significant association of CAD with BAs or C4. Comparisons of data from 50 controls free of T2DM or MetS, 50 MetS patients, and 50 T2DM patients revealed significantly increased fasting serum levels of C4 in patients with MetS and T2DM. Multiple regression analysis revealed body mass index (BMI) and plasma levels of triglycerides (TG) as independent determinants of C4 levels. Upon multivariate and principle component analyses the association of C4 with T2DM and/or MetS was not independent of or superior to the canonical MetS components. In conclusion, despite large intra- and interindividual variation, serum levels of C4,are significantly increased in patients with MetS and T2DM but confounded with BMI and TG

Unrecognized High Occurrence of Genetically Confirmed Hereditary Carnitine Palmitoyltransferase II Deficiency in an Austrian Family Points to the Ongoing Underdiagnosis of the Disease.

Adult muscle carnitine palmitoyltransferase (CPT) II deficiency is a rare autosomal recessive disorder of long-chain fatty acid metabolism. It is typically associated with recurrent episodes of exercise-induced rhabdomyolysis and myoglobinuria, in most cases caused by a c.338C > T mutation in the CPT2 gene. Here we present the pedigree of one of the largest family studies of CPT II deficiency caused by the c.338C > T mutation, documented so far. The pedigree comprises 24 blood relatives of the index patient, a 32 year old female with genetically proven CPT II deficiency. In total, the mutation was detected in 20 family members, among them five homozygotes and 15 heterozygotes. Among all homozygotes, first symptoms of CPT II deficiency occurred during childhood. Additionally, two already deceased relatives of the index patient were carriers of at least one copy of the genetic variant, revealing a remarkably high prevalence of the c.338C > T mutation within the tested family. Beside the index patient, only one individual had been diagnosed with CPT II deficiency prior to this study and three cases of CPT II deficiency were newly detected by this family study, pointing to a general underdiagnosis of the disease. Therefore, this study emphasizes the need to raise awareness of CPT II deficiency for correct diagnosis and accurate management of the disease

Spielen CRP-Spiegel neben IL-6 und PCT noch eine Rolle für Patienten auf Intensivstationen? / Are circulating levels of CRP compared to IL-6 and PCT still relevant in intensive care unit patients?

In der Diagnostik von Infektionen und inflammatorischen Prozessen ist das C-reaktive Protein (CRP) einer der meistverwendeten Parameter, unter anderem aufgrund der geringen Kosten und der schnellen Verfügbarkeit. Im Zuge der letzten Jahre gewannen jedoch andere Entzündungsparameter, wie zum Beispiel das Interleukin 6 (IL-6) oder Procalcitonin (PCT), zunehmend an Bedeutung. Obwohl diese Parameter im klinischen Alltag noch nicht überall etabliert sind, besitzen sie doch wesentliche Vorteile in der Diagnostik und im Verlaufsmonitoring von entzündlichen Erkrankungen. Beispielsweise ist die Erkennung entzündlicher Komplikationen auf Intensivstationen durch erhöhte IL-6 Spiegel 24 bis 48 Stunden vor einer Erhöhung des CRP möglich. Die deutliche Überlegenheit von PCT gegenüber CRP in der Diagnostik von bakteriellen Infektionen und Sepsis begründet sich in der höheren Spezifität des PCT für bakterielle Infektionen. Der PCT-Verlauf ermöglicht daher eine bessere Beurteilung des Therapieerfolges und Krankheitsverlaufs des Patienten und liefert Hinweise auf eine gegebenenfalls erforderliche Therapieumstellung. Daraus ergibt sich die Frage, ob die Messung des CRP-Spiegels durch IL-6 und/oder PCT ersetzt werden kann. In dieser Übersichtsarbeit wird die derzeitige Bedeutung von CRP im Verhältnis zu den neueren Entzündungsparametern in der Diagnostik von bakteriellen Infektionen, im therapeutischen Monitoring und in seiner Aussagekraft bezüglich der Prognose des Patienten auf Intensivstationen dargestellt.C-reactive protein (CRP) currently constitutes one of the most widely used parameters for the diagnosis of infections and inflammatory processes, due to simple methods and low costs. However, in recent years, other parameters, such as interleukin 6 (IL-6) and procalcitonin (PCT), have gained in importance. Although these parameters are presently not established everywhere in clinical routine, they provide significant advantages in the diagnosis and monitoring of inflammatory diseases. For instance, in intensive care, the increase in IL-6 levels may indicate inflammatory complications 24 to 48 h prior to the increase in circulating CRP levels. In contrast to CRP, PCT shows a higher specificity for bacterial infections, which facilitates the diagnosis of bacterial infections and sepsis. Therefore, PCT values provide a better evaluation of prognosis and therapeutic success and of a necessary change in therapy. These points raise the question whether CRP levels should at least in part be replaced by PCT and/or IL-6. Thus, this review seeks to examine the value of CRP in relation to PCT and IL-6 in the diagnosis of bacterial infections, in therapeutic monitoring, and regarding prognosis in critical care patients

Prognostic Role of Polyvascular Involvement in Patients with Symptomatic Peripheral Artery Disease.

Background: Statin therapy is recommended for patients with peripheral artery disease (PAD). However, PAD patients with polyvascular (PV) extent remain threatened by an increased residual cardiovascular (CV) risk. Purpose: To investigate the association of prescribed statin therapy and mortality in PAD patients with or without PV extent. Methods: A single-center retrospective longitudinal observational study originating from a consecutive registry with 1380 symptomatic PAD patients over a mean observational time of 60 ± 32 months. The association of atherosclerotic extent and statin use (PAD, plus one additional region (CAD or CeVD, [+1 V]), +2 vascular regions (+CAD and CeVD [+2 V]) with the risk of all-cause mortality was evaluated using Cox proportional hazard models adjusted for potential confounding factors. Results: The mean age of the study's participants was 72.0 ± 11.7 years, with 36% being female. PAD patients with PV extent [+1 V] and [+2 V] were older and suffered from diabetes, hypertension, or dyslipidemia more often; they, too, had more severely impaired kidney function (all p < 0.0001) compared to patients with PAD only. PAD patients with PV [+1 V] and [+2 V] received better statin medication and reached the recommended LDL-C target compared to PAD-only patients (p < 0.001). Despite better statin treatment, the rate of all-cause mortality was higher in PV patients than in PAD-only patients (PAD only: 13%; [+1 V]: 22%; [+2 V]: 35%; p < 0.0001). Conclusion: PV patients receive better statin therapy than PAD-only patients but nevertheless still have higher mortality rates. Future studies are needed to explore whether more aggressive LDL-lowering treatment for PAD patients may be translated into better prognosis

Ezetimibe reduces cholesterol content and NF-kappaB activation in liver but not in intestinal tissue in guinea pigs

Background: Statins (HMG CoA reductase inhibitors), in addition to reducing circulating cholesterol and incidence of coronary heart disease, also have pleiotropic, anti-inflammatory effects. Patients with chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) or hepatitis C are often excluded from statin therapy because of adverse effects in a small cohort of patients despite increased cardiovascular risk cholesterol. Ezetimibe, which inhibits cholesterol absorption by inhibition of Niemann-Pick C1 like 1 (NPC1L1) protein in the brush border of intestinal cells, has been suggested as a new therapeutic option in these patients. Methods: Effects of ezetimibe on lipoprotein metabolism, hepatic and intestinal lipid content in guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans were investigated. In order to investigate a possible effect of ezetimibe on cholesterol induced inflammation NF-kappaB activation as an indicator for inflammatory processes in liver and gut tissue was measured. Results: Lipid enriched diet led to accumulation of lipids in hepatic tissue which caused strong hepatic NF-kappaB activation. Ezetimibe reduced lipid diet induced increase of circulating cholesterol by about 77% and prevent hepatic NF-kappaB activation almost completely. In contrast in intestinal cells Ezetimibe, though lowering diet induced cholesterol accumulation, increased triglyceride content and subsequent NF-kappaB activation. Conclusion: In summary these data show, that ezetimibe effectively reduced diet induced circulating cholesterol levels, hepatic lipid accumulation and inflammatory response in our guinea pig model. However this drug elicited a local inflammatory response in intestinal tissue. Whether these diverse effects of ezetimibe on inflammatory parameters such as NF-kappaB have clinical relevance remains to be determined