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Background: Per treatment guidelines, resistant hypertension is defined as uncontrolled blood pressure (BP) while taking 3 concomitant antihypertensives (AHTs) or controlled BP while taking ≥4 AHTs. Characteristics, AHT therapy use, and BP control were analyzed in US patients with hypertension who were prescribed ≥3 classes of AHT medications. Methods: This retrospective analysis of the Optum® Electronic Health Record Database evaluated patients ≥18 years of age with a diagnosis of hypertension classified based on the number of prescribed AHT medication classes (3, 4, or ≥5). For the primary analysis, uncontrolled hypertension was defined as systolic BP (SBP) ≥140 mmHg or diastolic BP (DBP) ≥90 mmHg. For secondary analyses, uncontrolled hypertension was defined as SBP ≥130 mmHg or DBP ≥80 mmHg. Results: 207,705 patients with hypertension and concurrent use of ≥3 AHT medication classes were included. Diuretics, beta blockers, ACE inhibitors and/or ARBs, and CCBs were the most prescribed classes; thiazides and thiazide-like agents were the most prescribed diuretics. Among patients who were prescribed 3, 4, or ≥5 AHT medication classes, approximately 70% achieved a BP goal of <140/90 mmHg; approximately 40% achieved BP <130/80 mmHg. After ≥1 year of follow-up, the number of concurrent AHT medication classes was unchanged from baseline in the majority of patients and the prevalence of uncontrolled hypertension (≥140/90 mmHg) was similar. Conclusions: This study illustrates suboptimal BP control in many patients with apparent resistant hypertension despite the use of multidrug regimens and suggests a need for new drug classes and regimens that effectively manage resistant hypertension.
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INTRODUCTION: Angiographic vasospasm (VSP), the narrowing of intracranial arteries, is a complication of aneurysmal subarachnoid hemorrhage (aSAH) and often results in delayed cerebral ischemia (DCI) and cerebral infarction. The objective of this systematic review was to summarize the clinical burden of angiographic VSP and its related complications (DCI and cerebral infarction) after aSAH. METHODS: Systematic searches of MEDLINE, Embase, and the Cochrane Library were conducted (in January 2021) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies reporting clinical outcomes of angiographic VSP and its related complications after aSAH. Study outcomes included measures of functional status (modified Rankin Scale [mRS], Glasgow Outcome Scale [GOS], extended Glasgow Outcome Scale [GOS-E], modified Barthel Index, or the modified National Institutes of Health Stroke Scale), cognitive status (Montreal Cognitive Assessment or the Mini Mental State Exam), clinical events (rebleeding), and mortality. Study selection, data extraction, and qualitative analyses were conducted. RESULTS: Of 5704 abstracts reviewed, 110 studies were selected: 20 comparative and 39 regression-based studies were included in the qualitative synthesis, 51 descriptive studies were excluded. Most studies (51) were observational and conducted in a single country (53). The occurrence of angiographic VSP and its related complications after aSAH resulted in significantly poorer functional outcomes in three of nine comparative and 11 of 13 regression-based studies, measured by the mRS, and in five of six comparative and eight of nine regression-based studies, measured by the GOS and GOS-E. Angiographic VSP and its related complications were significantly associated with poor cognitive status in all five regression-based studies. Numerically or significantly higher mortality rates in patients with versus those without angiographic VSP and its related complications were reported in five of ten comparative studies and in eight of nine regression-based studies. Six studies looked at specific VSP populations (e.g., by severity or timing of VSP). CONCLUSION: Patients with angiographic VSP and its related complications often had poor functional, neurological, and cognitive outcomes and reduced odds of survival both in hospital and at follow-up. We estimate that angiographic VSP and its related complications, DCI and cerebral infarction, lead to an approximately threefold higher odds of poor functional and cognitive outcomes, and about a twofold increase in the odds of death.
Aneurysmal subarachnoid hemorrhage is a medical emergency in which an aneurysm, a weakened outpouching of a cerebral blood vessel, ruptures causing bleeding in the subarachnoid space. Components from the bleeding can trigger a process leading to the constriction of cerebral arteries, called angiographic vasospasm. Angiographic vasospasm is a frequent occurrence after aneurysmal subarachnoid hemorrhage and can also result in delayed cerebral ischemia and cerebral infarction, which can severely impact patients' health. This study summarizes the published literature to describe the clinical burden that patients may experience due to angiographic vasospasm, delayed cerebral ischemia, and cerebral infarction after aneurysmal subarachnoid hemorrhage. The evidence from these studies emphasizes numerous clinical consequences that patients may experience. These patients may suffer from diminished neurological and intellectual activity, leading to disability and a loss of functional independence in everyday activities. Angiographic vasospasm and its related complications also reduce the chances of survival, both in the hospital and at follow-up. The considerable clinical burden associated with angiographic vasospasm, delayed cerebral ischemia, and cerebral infarction highlights the importance of their prevention.
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INTRODUCTION: Cerebral vasospasm (VSP) is the leading risk factor of neurological deterioration (i.e., delayed cerebral ischemia [DCI] and cerebral infarction) after aneurysmal subarachnoid hemorrhage (aSAH) and a cause of morbidity and mortality. The objective of this systematic literature review is to summarize the economic and humanistic burden of VSP and its related complications after aSAH. METHODS: A predefined protocol was designed, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Systematic searches were conducted in MEDLINE, Embase, and Cochrane (in January 2021) to identify studies reporting economic and/or humanistic (i.e., health-related quality of life [HRQoL]) outcomes for patients with asymptomatic and symptomatic VSP after aSAH. Related conferences and additional sources were searched manually. Dual screening, data extraction, and qualitative analysis were conducted. RESULTS: Of 3818 abstracts identified for review, 43 full-text articles representing 42 single studies met the inclusion criteria and were included. Most studies (33) were observational; nine were randomized clinical trials (RCTs). Economic outcomes were reported in 31 studies, and alongside HRQoL outcomes in 4 studies; 7 studies reported HRQoL outcomes only. Forty studies were conducted in single countries, while only 2 RCTs were conducted in multiple countries. Patients diagnosed with VSP or DCI spent between 2.1 and 7.4 days longer in intensive care and between 4.7 and 17 days longer in hospital (total) compared with patients without VSP or DCI. A significantly higher cost burden of US$33,945 (2021 £26,712) was identified for patients with VSP and £9370 (2021 £13,733) for patients with DCI compared with patients without. Patients with DCI were also disadvantaged by being employed for 62 fewer days (during 24-month follow-up), with an estimated mean cost of £3821 (2021 £5600) for days off work. Poor HRQoL was associated with ≥ 1 days with VSP symptoms (odds ratio [OR]: 2.8, 95% confidence interval [CI]: 1.4-5.3), symptomatic VSP (OR: 1.9, 95% CI: 1.0-3.6), and DCI (OR: 2.3, 95% CI: 1.3-4.2), although this was not consistent across all studies. Symptomatic VSP and DCI were identified as significant risk factors for depressed mood (OR: 2.2, 95% CI: 1.0-4.9) and global cognitive impairment (OR: 2.3) at 12 months, respectively. The severity of VSP was a critical predictor of post-aSAH economic and humanistic burden. Similar trends in economic and humanistic burden were identified in the general aSAH patient population. Study design and patient heterogeneity precluded direct metaanalysis of the results. CONCLUSION: A substantial direct and indirect economic burden is linked to VSP and its related complications after aSAH. Although limited evidence was identified for humanistic burden, these patients seem to suffer from poor HRQoL with long-lasting burden. Overall, there is an urgent need to understand better the concept of "burden of illness" of VSP and its related complications after aSAH.
Aneurysmal subarachnoid hemorrhage is a sudden, life-threatening emergency caused by bleeding in the subarachnoid space between the brain and skull. Vasospasm of the arteries surrounding the hemorrhage occurs in most patients and may lead to permanent brain damage. This study summarizes the published literature to describe the burden that patients may experience due to vasospasm and its related complications after aneurysmal subarachnoid hemorrhage, focusing on financial and life quality aspects. We show that the burden of vasospasm, and its related complications, is huge. Patients often experience reduced quality of life due to their poor health and are more likely to suffer from depression and intellectual impairment. There is also a substantial financial burden linked to vasospasm and its related complications, driven by the need for more intensive care, hospitalization, and higher investigative costs associated with the treatment and management of these patients. In addition, days off work and unemployment can cause a substantial indirect financial burden. Our study highlights the need for additional research to understand further the "burden of illness" of vasospasm and its related complications after aneurysmal subarachnoid hemorrhage.
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Mitochondrial uncoupling proteins only catalyse proton transport when they are activated. Activators include superoxide and reactive alkenals, suggesting new physiological functions for UCP2 and UCP3: their activation by superoxide when protonmotive force is high causes mild uncoupling, which lowers protonmotive force and attenuates superoxide generation by the electron transport chain. This feedback loop acts to prevent excessive mitochondrial superoxide production. Superoxide inactivates aconitase in the mitochondrial matrix, so aconitase activity provides a sensitive measure of the effects of UCPs on matrix superoxide. We find that inhibition of UCP3 in isolated skeletal muscle mitochondria by GDP decreases aconitase activity by 25% after 20 min incubation. The GDP effect is absent in skeletal muscle mitochondria from UCP3 knockout mice, showing that it is mediated by UCP3. Protection of aconitase by UCP3 in the absence of nucleotides does not require added fatty acids. The purine nucleoside diphosphates and triphosphates cause aconitase inactivation, but the monophosphates and CDP do not, consistent with the known nucleotide specificity of UCP3. The IC(50) for GDP is about 100 microM. These findings support the proposal that UCP3 attenuates endogenous radical production by the mitochondrial electron transport chain at high protonmotive force.
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Aconitato Hidratasa/antagonistas & inhibidores , Proteínas Portadoras/metabolismo , Guanosina Difosfato/metabolismo , Mitocondrias Musculares/enzimología , Músculo Esquelético/enzimología , Fuerza Protón-Motriz/fisiología , Animales , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/genética , Femenino , Guanosina Difosfato/farmacología , Canales Iónicos , Ratones , Ratones Noqueados , Mitocondrias Musculares/efectos de los fármacos , Proteínas Mitocondriales , Músculo Esquelético/metabolismo , Nucleótidos/metabolismo , Nucleótidos/farmacología , Fuerza Protón-Motriz/efectos de los fármacos , Fuerza Protón-Motriz/genética , Ratas , Ratas Wistar , Albúmina Sérica Bovina/farmacología , Proteína Desacopladora 3RESUMEN
Two theories of how energy metabolism should be associated with longevity, both mediated via free-radical production, make completely contrary predictions. The 'rate of living-free-radical theory' (Pearl, 1928; Harman, 1956; Sohal, 2002) suggests a negative association, the 'uncoupling to survive' hypothesis (Brand, 2000) suggests the correlation should be positive. Existing empirical data on this issue is contradictory and extremely confused (Rubner, 1908; Yan & Sohal, 2000; Ragland & Sohal, 1975; Daan et al., 1996; Wolf & Schmid-Hempel, 1989]. We sought associations between longevity and individual variations in energy metabolism in a cohort of outbred mice. We found a positive association between metabolic intensity (kJ daily food assimilation expressed as g/body mass) and lifespan, but no relationships of lifespan to body mass, fat mass or lean body mass. Mice in the upper quartile of metabolic intensities had greater resting oxygen consumption by 17% and lived 36% longer than mice in the lowest intensity quartile. Mitochondria isolated from the skeletal muscle of mice in the upper quartile had higher proton conductance than mitochondria from mice from the lowest quartile. The higher conductance was caused by higher levels of endogenous activators of proton leak through the adenine nucleotide translocase and uncoupling protein-3. Individuals with high metabolism were therefore more uncoupled, had greater resting and total daily energy expenditures and survived longest - supporting the 'uncoupling to survive' hypothesis.
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Peso Corporal/fisiología , Metabolismo Energético/fisiología , Longevidad/fisiología , Mitocondrias/metabolismo , Animales , Femenino , Cinética , Potenciales de la Membrana/fisiología , RatonesRESUMEN
Juvenile king penguins develop adaptive thermogenesis after repeated immersion in cold water. However, the mechanisms of such metabolic adaptation in birds are unknown, as they lack brown adipose tissue and uncoupling protein-1 (UCP1), which mediate adaptive non-shivering thermogenesis in mammals. We used three different groups of juvenile king penguins to investigate the mitochondrial basis of avian adaptive thermogenesis in vitro. Skeletal muscle mitochondria isolated from penguins that had never been immersed in cold water showed no superoxide-stimulated proton conductance, indicating no functional avian UCP. Skeletal muscle mitochondria from penguins that had been either experimentally immersed or naturally adapted to cold water did possess functional avian UCP, demonstrated by a superoxide-stimulated, GDP-inhibitable proton conductance across their inner membrane. This was associated with a markedly greater abundance of avian UCP mRNA. In the presence (but not the absence) of fatty acids, these mitochondria also showed a greater adenine nucleotide translocase-catalysed proton conductance than those from never-immersed penguins. This was due to an increase in the amount of adenine nucleotide translocase. Therefore, adaptive thermogenesis in juvenile king penguins is linked to two separate mechanisms of uncoupling of oxidative phosphorylation in skeletal muscle mitochondria: increased proton transport activity of avian UCP (dependent on superoxide and inhibited by GDP) and increased proton transport activity of the adenine nucleotide translocase (dependent on fatty acids and inhibited by carboxyatractylate).
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Adaptación Fisiológica/fisiología , Proteínas Portadoras/metabolismo , Frío , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Translocasas Mitocondriales de ADP y ATP/metabolismo , Spheniscidae/metabolismo , Animales , Regulación de la Temperatura Corporal/fisiología , Ácidos Grasos/metabolismo , Femenino , Canales Iónicos , Masculino , Proteínas Mitocondriales , Músculo Esquelético/metabolismo , Protones , Superóxidos/metabolismo , Proteína Desacopladora 1RESUMEN
Superoxide generated using exogenous xanthine oxidase indirectly activates an uncoupling protein (UCP)-mediated proton conductance of the mitochondrial inner membrane. We investigated whether endogenous mitochondrial superoxide production could also activate proton conductance. When respiring on succinate, rat skeletal muscle mitochondria produced large amounts of matrix superoxide. Addition of GDP to inhibit UCP3 markedly inhibited proton conductance and increased superoxide production. Both superoxide production and the GDP-sensitive proton conductance were suppressed by rotenone plus an antioxidant. Thus, endogenous superoxide can activate the proton conductance of UCP3, which in turn limits mitochondrial superoxide production. These observations provide a departure point for studies under more physiological conditions.
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Proteínas Portadoras/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Mitocondrias Musculares/metabolismo , Superóxidos/metabolismo , Animales , Proteínas Portadoras/antagonistas & inhibidores , Guanosina Difosfato/farmacología , Peróxido de Hidrógeno/análisis , Peróxido de Hidrógeno/metabolismo , Canales Iónicos , Cinética , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Proteínas Mitocondriales , Consumo de Oxígeno/efectos de los fármacos , Consumo de Oxígeno/fisiología , Protones , Ratas , Ratas Wistar , Rotenona/farmacología , Ácido Succínico/metabolismo , Proteína Desacopladora 3 , Vitamina E/análogos & derivados , Vitamina E/farmacologíaRESUMEN
Mitochondria are a major source of superoxide, formed by the one-electron reduction of oxygen during electron transport. Superoxide initiates oxidative damage to phospholipids, proteins and nucleic acids. This damage may be a major cause of degenerative disease and aging. In isolated mitochondria, superoxide production on the matrix side of the membrane is particularly high during reversed electron transport to complex I driven by oxidation of succinate or glycerol 3-phosphate. Reversed electron transport and superoxide production from complex I are very sensitive to proton motive force, and can be strongly decreased by mild uncoupling of oxidative phosphorylation. Both matrix superoxide and the lipid peroxidation product 4-hydroxy-trans-2-nonenal can activate uncoupling through endogenous UCPs (uncoupling proteins). We suggest that superoxide releases iron from aconitase, leading to a cascade of lipid peroxidation and the release of molecules such as hydroxy-nonenal that covalently modify and activate the proton conductance of UCPs and other proteins. A function of the UCPs may be to cause mild uncoupling in response to matrix superoxide and other oxidants, leading to lowered proton motive force and decreased superoxide production. This simple feedback loop would constitute a self-limiting cycle to protect against excessive superoxide production, leading to protection against aging, but at the cost of a small elevation of respiration and basal metabolic rate.
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Envejecimiento , Proteínas Portadoras/metabolismo , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Modelos Biológicos , Superóxidos/metabolismo , Animales , Canales Iónicos , Proteínas Mitocondriales , Fosforilación Oxidativa , Especies Reactivas de Oxígeno/metabolismo , Proteína Desacopladora 1RESUMEN
We present the partial nucleotide sequence of the avian uncoupling protein (avUCP) gene from king penguin (Aptenodytes patagonicus), showing that the protein is 88-92% identical to chicken (Gallus gallus), turkey (Meleagris gallopavo), and hummingbird (Eupetomena macroura). We show that superoxide activates the proton conductance of mitochondria isolated from king penguin skeletal muscle. GDP abolishes the superoxide-activated proton conductance, indicating that it is mediated via avUCP. In the absence of superoxide there is no GDP-sensitive component of the proton conductance from penguin muscle mitochondria demonstrating that avUCP plays no role in the basal proton leak.
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Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Membrana Celular/fisiología , Respiración de la Célula/fisiología , Guanosina Difosfato/metabolismo , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Mitocondrias Musculares/química , Mitocondrias Musculares/fisiología , Superóxidos/metabolismo , Animales , Secuencia de Bases , Aves , Proteínas Portadoras/clasificación , Proteínas Portadoras/genética , Células Cultivadas , Pollos , Conductividad Eléctrica , Canales Iónicos , Potenciales de la Membrana/fisiología , Proteínas de la Membrana/clasificación , Proteínas de la Membrana/genética , Proteínas Mitocondriales , Datos de Secuencia Molecular , Músculo Esquelético/química , Músculo Esquelético/fisiología , Oxígeno/metabolismo , Bombas de Protones/fisiología , Protones , Alineación de Secuencia , Homología de Secuencia de Ácido Nucleico , Especificidad de la Especie , Pavos , Proteína Desacopladora 1RESUMEN
Superoxide activates nucleotide-sensitive mitochondrial proton transport through the uncoupling proteins UCP1, UCP2, and UCP3 (Echtay, K. S., et al. (2002) Nature 415, 1482-1486). Two possible mechanisms were proposed: direct activation of the UCP proton transport mechanism by superoxide or its products and a cycle of hydroperoxyl radical entry coupled to UCP-catalyzed superoxide anion export. Here we provide evidence for the first mechanism and show that superoxide activates UCP2 in rat kidney mitochondria from the matrix side of the mitochondrial inner membrane: (i) Exogenous superoxide inhibited matrix aconitase, showing that external superoxide entered the matrix. (ii) Superoxide-induced uncoupling was abolished by low concentrations of the mitochondrially targeted antioxidants 10-(6'-ubiquinonyl)decyltriphenylphosphonium (mitoQ) or 2-[2-(triphenylphosphonio)ethyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol bromide (mitoVit E), which are ubiquinone (Q) or tocopherol derivatives targeted to the matrix by covalent attachment to triphenylphosphonium cation. However, superoxide-induced uncoupling was not affected by similar concentrations of the nontargeted antioxidants Q(o), Q(1), decylubiquinone, vitamin E, or 6-hydroxy-2,5,7,8-tetramethylchroman 2-carboxylic acid (TROLOX) or of the mitochondrially targeted but redox-inactive analogs decyltriphenylphosphonium or 4-chlorobutyltriphenylphosphonium. Thus matrix superoxide appears to be necessary for activation of UCP2 by exogenous superoxide. (iii) When the reduced to oxidized ratio of mitoQ accumulated by mitochondria was increased by inhibiting cytochrome oxidase, it induced nucleotide-sensitive uncoupling that was not inhibited by external superoxide dismutase. Under these conditions quinols are known to produce superoxide, and because mitoQ is localized within the mitochondrial matrix this suggests that production of superoxide in the matrix was sufficient to activate UCP2. Furthermore, the superoxide did not need to be exported or to cycle across the inner membrane to cause uncoupling. We conclude that superoxide (or its products) exerts its uncoupling effect by activating the proton transport mechanism of uncoupling proteins at the matrix side of the mitochondrial inner membrane.