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Background: Medication nonadherence presents one of the greatest challenges to hypertension management. Previous studies from our group have shown therapeutic drug monitoring (TDM), biochemical monitoring of drug levels, is more accurate than self-report, detailed questionnaires, or prescription fill rate in detecting nonadherence. Prior studies have also shown a prevalence of nonadherence from 45% to 80% among insured patients with uncontrolled hypertension despite having been prescribed a multi-drug regimen. Previous studies have not assessed adherence to antihypertensive drugs in a safety net population by TDM. Methods: We performed a cross-sectional study in patients with uncontrolled hypertension in the primary care Internal Medicine and Cardiology Clinics at Parkland Health& Hospital System (PHHS). Patients with BP of 130/80 mmHg, prescribed ≥2 antihypertensive medications, and self-reporting medication adherence were enrolled after informed consent. Plasma samples were obtained for measurement of 44 cardiovascular drugs using liquid chromatography mass spectrometry. Results: Among 77 patients with uncontrolled hypertension (57% female, 65% Black, 12% Hispanic), 13 (17%) were nonadherent to at least one anti-hypertensive drug by TDM. There was no difference in baseline characteristics between the two groups. The adherent and nonadherent groups had similar systolic (146±13 vs 148±18, p=0.67) and diastolic (83±9 vs 88±10 mmHg, p=0.13) BP. All patients had either medical insurance or some form of prescription financial assistance. 15 patients had prescription financial assistance, while 62 patients had medical insurance. Nonadherence rates for patients on financial assistance programs did not significantly differ from patients with medical insurance (13% vs 18%, p>0.999). Conclusions: We found a surprisingly low prevalence of anti-hypertensive medication nonadherence in this uncontrolled hypertension population despite many barriers to treatment. Our study suggests a lesser role of medication nonadherence in uncontrolled hypertension in the safety net population.

This study examines the concordance of jugular venous pressure assessments taken at the bedside vs remotely and compares these with invasively measured right atrial pressure.

Objective: Therapeutic drug monitoring (TDM) is the assessment of medication adherence by detection of a drug or its metabolites in blood or urine samples. TDM-guided feedback has been shown to improve medication adherence and subsequent blood pressure (BP) control in patients with resistant hypertension. Herein, we sought to evaluate the attitudes of patients with uncontrolled hypertension as well as their providers towards incorporating TDM in clinical practice. Methods: We conducted a qualitative study consisting of in-depth, cognitive interviews in 10 patients seen in Parkland General Cardiology and Internal Medicine Clinics with uncontrolled hypertension. The patients were asked a series of 9 standardized questions to elicit their attitudes towards TDM use in the management of hypertension after informed consent. In addition, 10 providers, including faculty, trainees, and pharmacists, were also interviewed, using the same questionnaire to evaluate their attitudes of incorporating TDM in hypertension management. Results: Of the patients interviewed, 90% (9 of 10) were supportive of TDM use in clinical practice. Similarly, 100% (10 of 10) of providers thought TDM was a good idea and should be used regularly. On subsequent questioning, 78% (7 of 9) of patients who felt TDM was a good idea expressed reservation that TDM could negatively impact the physician-patient relationship. Nonetheless, 86% (6 of 7) of these patients felt TDM could be a useful tool to identifying and solving non-adherence of antihypertensive drugs, if providers are mindful of patients’ unique circumstances. Amongst providers, 90% (9 of 10) felt TDM may negatively impact the physician-patient relationship, yet felt TDM could still be useful in addressing non-adherence. Conclusion: TDM was found to be well accepted amongst patients and providers, though between 80-90% of patients and providers still had concerns that TDM could negatively impact the physician-patient relationship. However, the majority of patients and providers believed that TDM could be an effective tool in identifying and solving barriers to adherence, if the providers are sensitive to the patients’ specific needs. Our survey suggested feasibility of adopting TDM in improving medication adherence.

Pharmacy refill data are frequently used to screen for medication non-adherence in clinical practice but its accuracy has not been validated against therapeutic drug monitoring (TDM) in patients with uncontrolled hypertension. Accordingly, we evaluated the accuracy of proportions of days covered (PDC) and medication possession ratio (MPR) in assessing non-adherence to cardiovascular medications against therapeutic drug monitoring (TDM) in patients with uncontrolled hypertension at outpatient clinics of Parkland Memorial Hospital. Patients who had blood pressure of >130/80 mmHg, were on ≥2 antihypertensive medications, and verbally reported full medication compliance were enrolled in the study after an informed consent. Plasma samples were obtained for measurement of 36 cardiovascular drugs including statins, using liquid chromatography mass spectrometry assay. Among 38 patients enrolled in our study, 21% (8/38 patients) were non-adherent to at least 1 antihypertensive medication, while 39% (12/31 patients) were non-adherent to statin drugs. The non-adherent patients were younger than the adherent patients (57.2±12.0 vs. 62.9±7.8, p=0.08), and were less likely to be African Americans (7/17 vs. 16/21, p2 =0.15, p=0.11 for PDC; r 2 =0.15, p=0.16 for MPR). Using a threshold of < 80%, low PDC has a sensitivity of 100% and a specificity of 63% in detecting medication non-adherence when compared to TDM. Similar results were obtained for MPR: sensitivity of 100% and specificity of 65%. While medication refill data may be a sensitive screening tool for medication non-adherence, it has limited specificity and availability when compared to TDM. Thus, TDM constitutes a more efficient and reliable way to assess medication non-adherence, which is crucial in optimizing cardiovascular risk factors in this indigent population.

Background Increased blood pressure ( BP ) variability and nondipping status seen on 24‐hour ambulatory BP monitoring are often observed in autonomic failure ( ATF ). Methods and Results We assessed BP variability and nocturnal BP dipping in 273 patients undergoing ambulatory BP monitoring at Southwestern Medical Center between 2010 and 2017. SD , average real variability, and variation independent of mean were calculated from ambulatory BP monitoring. Patients were divided into a discovery cohort (n=201) and a validation cohort (n=72). ATF was confirmed by formal autonomic function test. In the discovery cohort, 24‐hour and nighttime average real variability, SD , and variation independent of mean did not differ significantly between ATF (n=25) and controls (n=176, all P >0.05). However, daytime SD, daytime coefficient of variation, and daytime variation independent of mean of systolic BP ( SBP ) were all significantly higher in patients with ATF than in controls in both discovery and validation cohorts. Nocturnal BP dipping was more blunted in ATF patients than controls in both cohorts (both P SBP yielded a sensitivity of 77% and specificity of 82% in detecting ATF in the validation cohort, whereas nondipping status had a sensitivity of 80% and specificity of 44%. The area under the receiver operator characteristic of daytime SD SBP was greater than the area under the receiver operator characteristic of nocturnal SBP dipping (0.79 [0.66‐0.91] versus 0.73 [0.58‐0.87], respectively). Conclusions Daytime SD of SBP is a better screening tool than nondipping status in detecting autonomic dysfunction.

Background: Proper dynamics of RNA polymerase II, such as promoter recruitment and elongation, are essential for transcription. PGC-1α (peroxisome proliferator-activated receptor [PPAR]-γ coactivator-1α), also termed PPARGC1a, is a transcriptional coactivator that stimulates energy metabolism, and PGC-1α target genes are downregulated in the failing heart. However, whether the dysregulation of polymerase II dynamics occurs in PGC-1α target genes in heart failure has not been defined. Methods and Results: Chromatin immunoprecipitation-sequencing revealed that reduced promoter occupancy was a major form of polymerase II dysregulation on PGC-1α target metabolic gene promoters in the pressure-overload–induced heart failure model. PGC-1α-cKO (cardiac-specific PGC-1α knockout) mice showed phenotypic similarity to the pressure-overload–induced heart failure model in wild-type mice, such as contractile dysfunction and downregulation of PGC-1α target genes, even under basal conditions. However, the protein levels of PGC-1α were neither changed in the pressure-overload model nor in human failing hearts. Chromatin immunoprecipitation assays revealed that the promoter occupancy of polymerase II and PGC-1α was consistently reduced both in the pressure-overload model and PGC-1α-cKO mice. In vitro DNA binding assays using an endogenous PGC-1α target gene promoter sequence confirmed that PGC-1α recruits polymerase II to the promoter. Conclusions: These results suggest that PGC-1α promotes the recruitment of polymerase II to the PGC-1α target gene promoters. Downregulation of PGC-1α target genes in the failing heart is attributed, in part, to a reduction of the PGC-1α occupancy and the polymerase II recruitment to the promoters, which might be a novel mechanism of metabolic perturbations in the failing heart.

ObjectivesPrevious studies have implicated therapeutic drug monitoring (TDM), by measuring serum or urine drug levels, as a highly reliable technique for detecting medication non-adherence but the attitudes of patients and physicians toward TDM have not been evaluated previously. Accordingly, we solicited input from patients with uncontrolled hypertension and their physicians about their views on TDM.DesignProspective analysis of responses to a set of questions during semistructured interviews.SettingOutpatient clinics in an integrated health system which provides care for a low-income, uninsured population.ParticipantsPatients with uncontrolled hypertension with either systolic blood pressure of at least 130 mm Hg or diastolic blood pressure of at least 80 mm Hg despite antihypertensive drugs and providers in the general cardiology and internal medicine clinics.Primary and secondary outcome measuresAttitudes towards TDM and the potential impact on physician–patient relationship.ResultsWe interviewed 11 patients and 10 providers and discussed the findings with 13 community advisory panel (CAP) members. Of the patients interviewed, 91% (10 of 11) and all 10 providers thought TDM was a good idea and should be used regularly to better understand the reasons for poorly controlled hypertension. However, 63% (7 of 11) of patients and 20% of providers expressed reservations that TDM could negatively impact the physician–patient relationship. Despite some concerns, the majority of patients, providers and CAP members believed that if test results are communicated without blaming patients, the potential benefits of TDM in identifying suboptimal adherence and eliciting barriers to adherence outweighed the risks.ConclusionThe idea of TDM is well accepted by patients and their providers. TDM information if delivered in a non-judgmental manner, to encourage an honest conversation between patients and physicians, has the potential to reduce patient–physician communication obstacles and to identify barriers to adherence which, when overcome, can improve health outcomes.

Extrapyramidal symptoms are an uncommon but well-recognized side effect after the administration of general anesthesia in patients without a significant neurologic history. Several case reports implicate propofol as the likely causative agent producing these symptoms, which include ballismus, dystonia, choreoathetosis, and opisthotonus. Currently, there is no clear consensus on first-line treatment of these symptoms. In each of the published cases, anticholinergic medications and benzodiazepines were central to initial management, although the speed and extent of symptom resolution were variable. Here we present a case of a 17-year-old boy with ulcerative colitis who presented with ballismus, torticollis, tongue thrusting, and oculogyric movements after colonoscopy under general anesthesia with propofol. The patient responded promptly to treatment with diphenhydramine. This is the first reported case in which diphenhydramine was successfully used as the primary treatment of severe extrapyramidal symptoms in a pediatric patient after propofol administration.

Thioredoxin 1 (Trx1) is a 12-kDa oxidoreductase that catalyzes thiol-disulfide exchange reactions to reduce proteins with disulfide bonds. As such, Trx1 helps protect the heart against stresses, such as ischemia and pressure overload. Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth, metabolism, and survival. We have shown previously that mTOR activity is increased in response to myocardial ischemia–reperfusion injury. However, whether Trx1 interacts with mTOR to preserve heart function remains unknown. Using a substrate-trapping mutant of Trx1 (Trx1C35S), we show here that mTOR is a direct interacting partner of Trx1 in the heart. In response to H2O2 treatment in cardiomyocytes, mTOR exhibited a high molecular weight shift in non-reducing SDS-PAGE in a 2-mercaptoethanol-sensitive manner, suggesting that mTOR is oxidized and forms disulfide bonds with itself or other proteins. The mTOR oxidation was accompanied by reduced phosphorylation of endogenous substrates, such as S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1) in cardiomyocytes. Immune complex kinase assays disclosed that H2O2 treatment diminished mTOR kinase activity, indicating that mTOR is inhibited by oxidation. Of note, Trx1 overexpression attenuated both H2O2-mediated mTOR oxidation and inhibition, whereas Trx1 knockdown increased mTOR oxidation and inhibition. Moreover, Trx1 normalized H2O2-induced down-regulation of metabolic genes and stimulation of cell death, and an mTOR inhibitor abolished Trx1-mediated rescue of gene expression. H2O2-induced oxidation and inhibition of mTOR were attenuated when Cys-1483 of mTOR was mutated to phenylalanine. These results suggest that Trx1 protects cardiomyocytes against stress by reducing mTOR at Cys-1483, thereby preserving the activity of mTOR and inhibiting cell death.

Increased BP lability is a hallmark of autonomic dysfunction, which may be captured by 24-hour ambulatory BP monitoring (ABPM). However, usefulness of different measures of BP variability (BPV) in detecting autonomic failure (AF) has not been determined. We assessed BPV in 273 patients undergoing

Obesity is a major risk factor for heart disease. Metaflammation is a metabolically driven, chronic, low-grade inflammatory reaction that is seen in the heart under obese conditions. Cardiac myocytes are known to produce inflammatory cytokines such as interleukin-6 (IL-6). However, whether and how cardiac myocytes mediate metaflammation is unknown. Silent information regulator 1 (Sirt1), a histone deacetylase involved in numerous metabolic pathways, facilitates an anti-inflammatory function through inhibition and deacetylation of the NFkB p65 subunit. This project aims to examine whether Sirt1 plays a role in cardiac local metaflammation. Mice with cardiac specific Sirt1 gene deletion (c-Sirt1 KO), Sirt1 overexpression (Tg-Sirt1), and relevant controls (Flox/Flox and WT respectively) were each placed on high fat and regular chow diets. The mice were euthanized after 3 months and their hearts were extracted for genetic and molecular analyses. Sirt1 mRNA and protein levels were significantly decreased under HFD feeding conditions (50% reduction in HFD feeding compared to normal diet, P

Peroxisome proliferator-activated receptor-α (PPARα), a nuclear receptor, plays an important role in the transcription of genes involved in fatty acid metabolism through heterodimerization with the retinoid x receptor (RXR). The consensus sequence of the PPAR response element (PPRE) is composed of two AGGTCA-like sequences directionally aligned with a single nucleotide spacer. PPARα and RXR bind to the 5’ and 3’ hexad sequences, respectively. However, the precise sequence definition of the PPRE remains obscure, and thus, the consensus sequence currently available remains AGGTCANAGGTCA with unknown redundancy. The vague PPRE sequence definition poses an obstacle to understanding how PPARα regulates fatty acid metabolism. Here we show that, rather than the generally accepted 6-bp sequence, PPARα actually recognized a 12-bp DNA sequence, of which the preferred binding sequence was WAWVTRGGBBAH. Additionally, the optimized RXRα hexad binding sequence was RGKTYA. Thus, the optimal PPARα/RXRα heterodimer binding sequence was WAWVTRGGBBAHRGKTYA. The single nucleotide substitution, which reduces binding of RXRα to DNA, attenuated PPARα-induced transcriptional activation, but this is not always true for PPARα. Using the definition of the PPRE sequence, novel PPREs were successfully identified. Taken altogether, the provided PPRE sequence definition contributes to the understanding of PPARα signaling by identifying PPARα direct target genes with functional PPARα response elements.