Dataset Information

Relationship between plasma, atrial and ventricular perhexiline concentrations in humans: insights into factors affecting myocardial uptake.

ABSTRACT: AIM:Little is known regarding the steady-state uptake of drugs into the human myocardium. Perhexiline is a prophylactic anti-anginal drug which is increasingly also used in the treatment of heart failure and hypertrophic cardiomyopathy. We explored the relationship between plasma perhexiline concentrations and its uptake into the myocardium. METHODS:Blood, right atrium ± left ventricle biopsies were obtained from patients treated with perhexiline for a median of 8.5 days before undergoing coronary surgery in the perhexiline arm of a randomized controlled trial. Perhexiline concentrations in plasma and heart tissue were determined by HPLC. RESULTS:Atrial biopsies were obtained from 94 patients and ventricular biopsies from 28 patients. The median plasma perhexiline concentration was within the therapeutic range at 0.24 mg?l?¹ (IQR 0.12-0.44), the median atrial concentration was 6.02 ?mg?kg?¹ (IQR 2.70-9.06) and median ventricular concentration was 10.0 mg?kg?¹ (IQR 5.76-13.1). Atrial (r² = 0.76) and ventricular (r² = 0.73) perhexiline concentrations were closely and directly correlated with plasma concentrations (both P < 0.001). The median atrial?:?plasma ratio was 21.5 (IQR 18.1-27.1), ventricular?:?plasma ratio was 34.9 (IQR 24.5-55.2) and ventricular?:?atrial ratio was 1.67 (IQR 1.39-2.22). Using multiple regression, the best model for predicting steady-state atrial concentration included plasma perhexiline, heart rate and age (r² = 0.83). Ventricular concentrations were directly correlated with plasma perhexiline concentration and length of therapy (r² = 0.84). CONCLUSIONS:This study demonstrates that plasma perhexiline concentrations are predictive of myocardial drug concentrations, a major determinant of drug effect. However, net myocardial perhexiline uptake is significantly modulated by patient age, potentially via alteration of myocardial:extracardiac drug uptake.

SUBMITTER: Drury NE

PROVIDER: S-EPMC4004399 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Relationship between plasma, atrial and ventricular perhexiline concentrations in humans: insights into factors affecting myocardial uptake.

Drury Nigel E NE Licari Giovanni G Chong Cher-Rin CR Howell Neil J NJ Frenneaux Michael P MP Horowitz John D JD Pagano Domenico D Sallustio Benedetta C BC

British journal of clinical pharmacology 20140501 5

<h4>Aim</h4>Little is known regarding the steady-state uptake of drugs into the human myocardium. Perhexiline is a prophylactic anti-anginal drug which is increasingly also used in the treatment of heart failure and hypertrophic cardiomyopathy. We explored the relationship between plasma perhexiline concentrations and its uptake into the myocardium.<h4>Methods</h4>Blood, right atrium ± left ventricle biopsies were obtained from patients treated with perhexiline for a median of 8.5 days before un ...[more]

PMID: 24117487

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Project description:Background: Lamins A/C (encoded by the LMNA gene) can lead to dilated cardiomyopathy (DCM). Objectives: This study sought to undertake proteomic analysis of myocardial tissue to explore the postgenomic phenotype of end-stage lamin heart disease. Methods: Consecutive patients with end-stage lamin heart disease (LMNA-group, n=7) and ischaemic DCM (ICM-group, n=7) undergoing heart transplantation were enrolled. Samples were obtained from left atrium(LA), left ventricle(LV), right atrium(RA), right ventricle(RV) and interventricular septum(IVS). Liquid chromatography combined with mass-spectrometry was used for protein quantification. We compared protein concentrations in cardiac samples between LMNA and ICM groups. Proteins were considered differentially abundant if the quantitative difference was 1.5-fold and corrected p-value <0.05 at a false discovery rate of 0.01. Gene ontology(GO) enrichment analysis explored the related biological processes. Results: 4,247 proteins were identified in LMNA and ICM samples, of which 633 were differentially abundant in LA, 39 in LV, 181 in RA, 52 in RV, and 85 in IVS. Abundance of lamin A/C was reduced but lamin B (LMNB) increased in LMNA LA/RA tissue compared to ICM, but not in LV/RV. Transthyretin was more abundant in the LV/RV of LMNA compared to ICM while sarcomeric proteins such as titin and cardiac myosin heavy chain were generally reduced in RA/LA of LMNA. Protein expression profiling and GO enrichment analysis revealed sarcopenia, extracellular matrix(ECM) remodeling, deficient myocardial energetics, redox imbalances, and abnormal calcium handling in LMNA samples. Conclusion: Lamin heart disease is a biventricular and biatrial disease, characterized by sarcopenia, aberrant metabolism, and ECM remodeling. LMNB and transthyretin were unexpectedly abundant in the atria and ventricles respectively of patients with end-stage lamin heart disease potentially hinting to the possibility of compensatory responses.

Project description:PurposeCardiac 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography (FDG PET) is widely used to assess myocardial viability in patients with ischemic heart disease. While sufficient glucose uptake is a prerequisite for accurate interpretation of cardiac viability, there are a lack of data on which clinical variables have the most significant impact on myocardial glucose metabolism. Therefore, this study was designed to evaluate several clinical variables that could affect myocardial glucose metabolism.MethodsA total of 214 consecutive cases were retrospectively enrolled in this study. All subjects received 250 mg of acipimox and underwent glucose loading as preparation for cardiac FDG PET/CT. Three-dimensional regions of interest (ROIs) were drawn on PET/CT fusion images. Myocardial glucose uptake ratio (MGUR = SUVmax of LV myocardium/SUVmean of liver) was then calculated. Multiple clinical variables including body mass index (BMI), blood glucose levels at different times, administered insulin dosage, lipid profiles, and ejection fraction were measured and analyzed for correlation with myocardial glucose uptake. After dichotomizing the subjects based on a BMI of 25, each group's MGUR was compared.ResultsMyocardial uptake showed significant correlations with BMI (r = -0.162, p = 0.018), HbA1c (r = -0.150, p = 0.030), and triglyceride levels (r = -0.137, p = 0.046). No other clinical variables showed a significant correlation with myocardial glucose uptake. After multiple linear regression analysis, BMI (p = 0.032) and HbA1c (p = 0.050) showed a correlation with MGUR. In group analysis, after dividing patients based on BMI, the obese group showed significantly lower myocardial uptake than the non-obese group (3.8 ± 1.9 vs. 4.4 ± 2.1, p = 0.031).ConclusionsAmong several clinical variables, BMI and HbA1c levels were related to myocardial glucose uptake. A prospective study would be needed to examine whether a protocol that additionally considers BMI and HbA1c levels is necessary for the current cardiac FDG PET protocol.

Dataset Information

Relationship between plasma, atrial and ventricular perhexiline concentrations in humans: insights into factors affecting myocardial uptake.

Publications

Relationship between plasma, atrial and ventricular perhexiline concentrations in humans: insights into factors affecting myocardial uptake.

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