RESUMEN
BACKGROUND: Septal myectomy (SM) is offered to symptomatic patients with obstructive hypertrophic cardiomyopathy (oHCM) despite medical therapy. Frequently, patients undergo concomitant planned or ad-hoc mitral valve replacement (MVR), aortic valve replacement (SAVR), or coronary artery bypass grafting (CABG). OBJECTIVES: We sought to assess characteristics and outcomes of patients with oHCM undergoing concomitant surgical interventions at the time of SM. METHODS: The National Readmission Databases were used to identify all SM admissions in the United States (2010-2019). Patients undergoing SM were stratified into: isolated SM (±MV repair), SM + CABG only, SM + MVR, SM + SAVR, and SM + MVR + SAVR. Primary outcomes were in-hospital mortality, in-hospital adverse events, and 30-day readmission. RESULTS: 12,063 encounters of patients who underwent SM were included (56.1% isolated SM, 9.0% SM + CABG only, 17.5% SM + MVR, 13.1% SM + SAVR, and 4.3% SM + MVR + SAVR). Patients who underwent isolated SM were younger (54.3 vs. 67.1 years-old, p < 0.01) and had lower overall comorbidity burden. In-hospital mortality was lowest in isolated SM, followed by CABG only, SM + SAVR, SM + MVR, and SM + SAVR+MVR groups (2.3% vs. 3.7% vs. 5.3% vs. 6.7% vs. 13.7%, p < 0.01), respectively. SM with combined surgical interventions was associated with higher adverse in-hospital events (24.3% vs. 11.1%, p < 0.01) and 30-day readmissions (16.9% vs. 10.4%, p < 0.01). MV repair performed concomitantly with SM was not associated with increased in-hospital mortality (3.9% vs. 3.4%, p = 0.72; aOR 0.99; 95% CI: 0.54-1.80, p = 0.97]) or adverse clinical events. CONCLUSIONS: In SM for oHCM, patients undergoing concomitant surgical interventions were characteristically distinct. Aside from MV repair, concomitant interventions were associated with worse in-hospital death, adverse in-hospital events, and 30-day readmission.
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Cardiomiopatía Hipertrófica , Implantación de Prótesis de Válvulas Cardíacas , Humanos , Estados Unidos , Anciano , Mortalidad Hospitalaria , Resultado del Tratamiento , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/cirugía , Cardiomiopatía Hipertrófica/complicaciones , Puente de Arteria CoronariaRESUMEN
Background Transthyretin cardiac amyloidosis (ATTR-CM), found in 6% to 15% of cohorts with heart failure with preserved ejection fraction, has long been considered a rare disease with poor prognosis. New treatments have made it one of the few directly treatable causes of heart failure. This study sought to determine whether patients with ATTR-CM, particularly those treated with tafamidis, have comparable survival to an unselected cohort with heart failure with preserved ejection fraction. Methods and Results We compared the clinical characteristics and outcomes between a single-center cohort of patients with ATTR-CM (n=114) and patients with heart failure with preserved ejection fraction enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial (n=1761, excluding Russia and Georgia). The primary outcome was a composite of all-cause death, heart failure hospitalization, myocardial infarction, and stroke. Subgroup analysis of patients with ATTR-CM treated with tafamidis was also performed. Patients with ATTR-CM had higher rates of the primary composite outcome compared with patients enrolled in the TOPCAT trial (hazard ratio [HR], 1.44 [95% CI, 1.09-1.91]; P=0.01), with similar rates of all-cause death (HR, 1.43 [95% CI, 0.99-2.06]; P=0.06) but higher rates of heart failure hospitalizations (HR, 1.62 [95% CI, 1.15-2.28]; P<0.01). Compared with patients enrolled in TOPCAT, patients with ATTR-CM treated with tafamidis had similar rates of the primary composite outcome (HR, 1.30 [95% CI, 0.86-1.96]; P=0.21) and all-cause death (HR, 1.10 [95% CI, 0.57-2.14]; P=0.78) but higher rates of heart failure hospitalizations (HR, 1.96 [95% CI, 1.27-3.02]; P<0.01). Conclusions Patients with ATTR-CM treated with tafamidis have similar rates of all-cause death compared with patients with heart failure with preserved ejection fraction, with higher rates of heart failure hospitalizations.
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Amiloidosis , Cardiomiopatías , Insuficiencia Cardíaca , Humanos , Cardiomiopatías/tratamiento farmacológico , Prealbúmina/uso terapéutico , Espironolactona/uso terapéutico , Volumen Sistólico , Resultado del TratamientoRESUMEN
Background Prior national data showed a substantial in-hospital mortality in septal myectomy (SM) with an inverse volume-outcomes relationship. This study sought to assess the contemporary outcomes of septal reduction therapy and volume-outcome relationship in obstructive hypertrophic cardiomyopathy. Methods and Results All septal reduction therapy admissions between 2010 to 2019 in the United States were analyzed using the National Readmission Databases. Hospitals were stratified into tertiles of low-, medium-, and high-volume based on annualized procedural volume of alcohol septal ablation and SM. Of 19 007 patients with obstructive hypertrophic cardiomyopathy who underwent septal reduction therapy, 12 065 (63%) had SM. Two-thirds of hospitals performed ≤5 SM or alcohol septal ablation annually. In all SM encounters, 482 patients (4.0%) died in-hospital post-SM. In-hospital mortality was <1% in 1505 (88.4%) hospitals, 1% to 10% in 30 (1.8%) hospitals, and ≥10% in 167 (9.8%) hospitals. There were 63 (3.7%) hospitals (averaging 2.2 SM cases/year) with 100% in-hospital mortality. Post-SM (in low-, medium-, and high-volume centers, respectively), in-hospital mortality (5.7% versus 3.9% versus 2.4%, P=0.003; adjusted odds ratio [aOR], 2.86 [95% CI, 1.70-4.80], P=0.001), adverse in-hospital events (21.30% versus 18.0% versus 12.6%, P=0.001; aOR, 1.88 [95% CI, 1.45-2.43], P=0.001), and 30-day readmission (17.1% versus 12.9% versus 9.7%, P=0.001; adjusted hazard ratio, 1.53 [95% CI, 1.27-1.96], P=0.001) were significantly higher in low- versus high-volume hospitals. For alcohol septal ablation, the incidence of in-hospital death and all other outcomes did not differ by hospital volume. Conclusions In-hospital SM mortality was 4% with an inverse volume-mortality relationship. Mortality post-alcohol septal ablation was similar across all volume tertiles. Morbidity associated with SM was substantial across all volume tertiles.
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Cardiomiopatía Hipertrófica , Etanol , Humanos , Estados Unidos/epidemiología , Mortalidad Hospitalaria , Resultado del Tratamiento , Tabiques Cardíacos/diagnóstico por imagen , Tabiques Cardíacos/cirugía , Cardiomiopatía Hipertrófica/cirugía , Hospitales de Alto VolumenRESUMEN
PURPOSE OF REVIEW: In this review, we will overview the baseline and longitudinal imaging modalities utilized in the care of patients with hypertrophic cardiomyopathy (HCM) with a focus on echocardiography and cardiac magnetic resonance (CMR) imaging, especially in the new era of cardiac myosin inhibitors (CMIs). RECENT FINDINGS: Traditional therapies for hypertrophic cardiomyopathy (HCM) have been well established for decades. Attempts to investigate new drug therapy in HCM resulted in neutral clinical trials, until the discovery of cardiac myosin inhibitors (CMIs). The introduction of this new class of small oral molecules which target the hypercontractility resulting from excessive actin-myosin cross-bridging at the sarcomere level is the first therapeutic option which directly addresses the underlying pathophysiology of HCM. While imaging has always played a central role in HCM diagnosis and management, CMIs introduced a new paradigm in the use of imaging to evaluate and monitor patients with HCM. Echocardiography and cardiac magnetic resonance imaging (CMR) are the central modalities in the care of patients with HCM, but their roles and our understanding of their strengths and limitations are evolving as newer therapeutics are being investigated in clinical trials and in daily practice. In this review, we will focus the recent CMI trials and discuss the role of baseline and longitudinal imaging with echocardiography and CMR in the care of patients with HCM in the era of CMIs.
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Cardiomiopatía Hipertrófica , Humanos , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/terapia , Corazón/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Ecocardiografía , Miosinas CardíacasRESUMEN
BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM), particularly wild type (wtATTR-CM), is thought to mainly affect men. Non-invasive diagnosis and approved therapeutics have been associated with increased disease recognition. We investigated the trajectory of ATTR-CM diagnosis in women. METHODS: This observational study utilized data collected on 140 consecutive ATTR-CM patients diagnosed between 2005 and 2022 who are followed at the Oregon Health and Science University Amyloidosis Clinic. Subgroup analysis was performed on patients with wtATTR-CM which included 113 subjects (80.1%). The proportion of women among patients diagnosed with ATTR-CM prior to 2019 was compared with that of those diagnosed 2019-2022 (2019 was the year of tafamidis approval by the FDA). The clinical characteristics of male and female ATTR-CM patients were compared as well. RESULTS: Of the 140 ATTR-CM patients, 16 (11.4%) were women (age 77 ± 9 years) and 124 (88.6%) were men (age 76 ± 9 years). There was an increase in the rate of women diagnosed with ATTR-CM from pre 2019 to 2019-2022 in the overall cohort (4/68 [5.9%] vs 12/72 [16.7%]) and wild type subgroup (0/51 [0%] vs 7/62 [11.3%]). There were several differences in baseline clinical characteristics between women and men in this cohort, yet all women had a clear clinical phenotype of ATTR-CM. CONCLUSIONS: There has been a significant increase in the rate of wtATTR-CM diagnoses in women, who presented with clear phenotypes of ATTR-CM. Further studies are needed to understand the effect of increased recognition of ATTR-CM in women on disease epidemiology, natural history, and outcomes.
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Neuropatías Amiloides Familiares , Cardiomiopatías , Masculino , Femenino , Humanos , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/epidemiología , Prealbúmina/genética , Cardiomiopatías/diagnóstico , Cardiomiopatías/epidemiología , Cardiomiopatías/complicacionesRESUMEN
We explored the utility of the real-time FLIPR Membrane Potential (FMP) assay as a method to assess kappa opioid receptor (KOR)-induced hyperpolarization. The FMP Blue dye was used to measure fluorescent signals reflecting changes in membrane potential in KOR expressing CHO (CHO-KOR) cells. Treatment of CHO-KOR cells with kappa agonists U50,488 or dynorphin [Dyn (1-13)NH2] produced rapid and concentration-dependent decreases in FMP Blue fluorescence reflecting membrane hyperpolarization. Both the nonselective opioid antagonist naloxone and the κ-selective antagonists nor-binaltorphimine (nor-BNI) and zyklophin produced rightward shifts in the U50,488 concentration-response curves, consistent with competitive antagonism of the KOR mediated response. The decrease in fluorescent emission produced by U50,488 was blocked by overnight pertussis toxin pretreatment, indicating the requirement for PTX-sensitive G proteins in the KOR mediated response. We directly compared the potency of U50,488 and Dyn (1-13)NH2 in the FMP and [35S]GTPγS binding assays, and found that both were approximately 10 times more potent in the cellular fluorescence assay. The maximum responses of both U50,488 and Dyn (1-13)NH2 declined following repeated additions, reflecting receptor desensitization. We assessed the efficacy and potency of structurally distinct KOR small molecule and peptide ligands. The FMP assay reliably detected both partial agonists and stereoselectivity. Using KOR-selective peptides with varying efficacies, we found that the FMP assay allowed high throughput quantification of peptide efficacy. These data demonstrate that the FMP assay is a sensitive method for assessing κ-opioid receptor induced hyperpolarization, and represents a useful approach for quantification of potency, efficacy and desensitization of KOR ligands.
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3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Analgésicos Opioides/farmacología , Bioensayo , Dinorfinas/farmacología , Potenciales de la Membrana/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Receptores Opioides kappa/agonistas , Animales , Células CHO , Cricetulus , Relación Dosis-Respuesta a Droga , Colorantes Fluorescentes/química , Ensayos Analíticos de Alto Rendimiento , Ligandos , Receptores Opioides kappa/genética , Receptores Opioides kappa/metabolismo , Espectrometría de Fluorescencia , Factores de TiempoRESUMEN
We tested the hypothesis that exposure of glut3+/- mice to a ketogenic diet ameliorates autism-like features, which include aberrant behavior and electrographic seizures. We first investigated the life course sex-specific changes in basal plasma-cerebrospinal fluid (CSF)-brain metabolic profile, brain glucose transport/uptake, glucose and monocarboxylate transporter proteins, and adenosine triphosphate (ATP) in the presence or absence of systemic insulin administration. Glut3+/- male but not female mice (5 months of age) displayed reduced CSF glucose/lactate concentrations with no change in brain Glut1, Mct2, glucose uptake or ATP. Exogenous insulin-induced hypoglycemia increased brain glucose uptake in glut3+/- males alone. Higher plasma-CSF ketones (ß-hydroxybutyrate) and lower brain Glut3 in females vs males proved protective in the former while enhancing vulnerability in the latter. As a consequence, increased synaptic proteins (neuroligin4 and SAPAP1) with spontaneous excitatory postsynaptic activity subsequently reduced hippocampal glucose content and increased brain amyloid ß1-40 deposition in an age-dependent manner in glut3+/- males but not females (4 to 24 months of age). We then explored the protective effect of a ketogenic diet on ultrasonic vocalization, sociability, spatial learning and memory, and electroencephalogram seizures in male mice (7 days to 6 to 8 months of age) alone. A ketogenic diet partially restored sociability without affecting perturbed vocalization, spatial learning and memory, and reduced seizure events. We conclude that (1) sex-specific and age-dependent perturbations underlie the phenotype of glut3+/- mice, and (2) a ketogenic diet ameliorates seizures caused by increased cortical excitation and improves sociability, but fails to rescue vocalization and cognitive deficits in glut3+/- male mice.
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Conducta Animal/fisiología , Encéfalo/metabolismo , Dieta Cetogénica , Transportador de Glucosa de Tipo 3/metabolismo , Convulsiones/dietoterapia , Conducta Social , Animales , Encéfalo/fisiopatología , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular Neuronal/metabolismo , Electroencefalografía , Femenino , Glucosa/metabolismo , Transportador de Glucosa de Tipo 3/genética , Masculino , Memoria/fisiología , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Convulsiones/metabolismo , Convulsiones/fisiopatología , Factores Sexuales , Aprendizaje Espacial/fisiología , Vocalización Animal/fisiologíaRESUMEN
Prenatal nutrient restriction (NR) culminating in intra-uterine growth restriction (IUGR) with postnatal catch up growth leads to diabesity. In contrast, postnatal NR with growth restriction (PNGR) superimposed on IUGR (IPGR) protects young and aging adults from this phenotype. We hypothesized that PNGR/IPGR will compromise the blood-brain metabolic profile impairing neurobehavior and predisposing to Alzheimer's disease (AD). NR (50%) in late gestation followed by cross-fostering of rat pups to either ad lib fed (CON) or NR (50%) lactating mothers generated CON, IUGR, PNGR and IPGR male (M) and female (F) offspring that were examined through the life span. In PNGR/IPGR plasma/CSF glucose and lactate decreased while ketones increased in (M) and (F) (PN21, PN50). In addition increased brain glucose transporters, Glut1 & Glut3, greater brain derived neurotrophic factor (BDNF), reduced Glut4, with unchanged serotonin transporter concentrations were noted in (F) (PN50-60). While (F) displayed more hyperactivity, both (F) and (M) exhibited anxiety although socially and cognitively unimpaired (PN25-28&50). Aging (15-17 m) (F) not (M), expressed low plasma insulin, reduced brain IRS-2, pAkt, and pGSK-3ß(Ser9), unchanged pPDK1, pTau or lipoprotein receptor related protein 1 (LRP1), higher glial fibrillary acidic protein (GFAP) and spinophilin but a 10-fold increased amyloid-ß42. We conclude that therapeutically superimposing PNGR on IUGR (IPGR) should be carefully weighed in light of unintended consequences related to perturbed neurobehavior and potential predilection for AD.
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Enfermedad de Alzheimer/etiología , Encéfalo/metabolismo , Restricción Calórica/efectos adversos , Retardo del Crecimiento Fetal/fisiopatología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Ansiedad , Modelos Animales de Enfermedad , Femenino , Retardo del Crecimiento Fetal/metabolismo , Hipercinesia/etiología , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , RatasRESUMEN
Mitochondria support the energy-intensive functions of brain endothelium but also produce damaging-free radicals that lead to disease. Previously, we found that estrogen treatment protects cerebrovascular mitochondria, increasing capacity for ATP production while decreasing reactive oxygen species (ROS). To determine whether these effects occur specifically in endothelium in vivo and also explore underlying transcriptional mechanisms, we studied freshly isolated brain endothelial preparations from intact and ovariectomized female mice. This preparation reflects physiologic influences of circulating hormones, hemodynamic forces, and cell-cell interactions of the neurovascular unit. Loss of ovarian hormones affected endothelial expression of the key mitochondrial regulator family, peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1), but in a unique way. Ovariectomy increased endothelial PGC-1α mRNA but decreased PGC-1ß mRNA. The change in PGC-1ß correlated with decreased mRNA for crucial downstream mitochondrial regulators, nuclear respiratory factor 1 and mitochondrial transcription factor A, as well as for ATP synthase and ROS protection enzymes, glutamate-cysteine ligase and manganese superoxide dismutase. Ovariectomy also decreased mitochondrial biogenesis (mitochondrial/nuclear DNA ratio). These results indicate ovarian hormones normally act through a distinctive regulatory pathway involving PGC-1ß to support cerebral endothelial mitochondrial content and guide mitochondrial function to favor ATP coupling and ROS protection.
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Corteza Cerebral/irrigación sanguínea , Endotelio Vascular/metabolismo , Estrógenos/fisiología , Mitocondrias Musculares/metabolismo , Ovario/fisiología , Factores de Transcripción/metabolismo , Animales , Western Blotting , Corteza Cerebral/metabolismo , ADN Mitocondrial/metabolismo , Regulación hacia Abajo , Endotelio Vascular/enzimología , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Ratones , Ratones Endogámicos C57BL , Mitocondrias Musculares/enzimología , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ovariectomía , Ovario/cirugía , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación hacia ArribaRESUMEN
We examined the effects of 45-min hypoxia (FiO(2) 0.08; Hx) vs. normoxia (FiO(2) 0.21; Nx) on the ipsilateral (Ipsi) and contralateral (Ctrl) sides of the brain in neuronal glucose transporter isoform 3 (Glut3) heterozygous null mice (glut3(+/-)) and their wild-type littermates (WT), undergoing unilateral carotid artery ligation. Glut3(+/-) mice, under Nx, demonstrated a compensatory increase in blood-brain barrier/glial Glut1 protein concentration and a concomitant increase in neuronal nitric oxide synthase (nNOS) enzyme activity and Bax protein, with a decrease in procaspase 3 protein (P < 0.05 each). After Hx, reoxygenation in FiO(2) of 0.21 led to no comparable adaptive up-regulation of the ipsilateral brain Glut3 or Glut1 protein at 4 hr and Glut1 at 24 hr in glut3(+/-) vs. WT. These brain Glut changes in glut3(+/-) but not WT mice were associated with an increase in proapoptotic Bax protein and caspase-3 enzyme activity (P < 0.01 each) and a decline in the antiapoptotic Bcl-2 and procaspase-3 proteins (P < 0.05 each). Glut3(+/-) mice after Hx demonstrated TUNEL-positive neurons with nuclear pyknosis in most ipsilateral (hypoxic-ischemia) brain regions. A subset (â¼55%) of glut3(+/-) mice developed spontaneous seizures after hypoxic-ischemia, confirmed by electroencephalography, but the WT mice remained seizure-free. Pentylenetetrazole testing demonstrated an increased occurrence of longer lasting clinical seizures at a lower threshold in glut3(+/-) vs. WT mice, with no detectable differences in monamine neurotransmitters. We conclude that hypoxic-ischemic brain injury in glut3(+/-) mice exacerbates cellular apoptosis and necrosis and precipitates spontaneous seizures.
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Apoptosis/fisiología , Transportador de Glucosa de Tipo 3/metabolismo , Hipoxia-Isquemia Encefálica/fisiopatología , Neuronas/patología , Convulsiones/fisiopatología , Animales , Western Blotting , Cromatografía Líquida de Alta Presión , Femenino , Técnica del Anticuerpo Fluorescente , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 3/genética , Heterocigoto , Hipoxia-Isquemia Encefálica/genética , Hipoxia-Isquemia Encefálica/metabolismo , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Neuronas/metabolismo , Fenotipo , Convulsiones/genética , Convulsiones/metabolismoRESUMEN
It has been shown that reactive oxygen species (ROS) contribute to the central effect of ANG II on blood pressure (BP). Recent studies have implicated an antihypertensive action of estrogen in ANG II-infused female mice. The present study used in vivo telemetry recording and in vitro living mouse brain slices to test the hypothesis that the central activation of estrogen receptors in male mice inhibits ANG II-induced hypertension via the modulation of the central ROS production. In male wild-type mice, the systemic infusion of ANG II induced a significant increase in BP (Delta30.1 +/- 2.5 mmHg). Either central infusion of Tempol or 17beta-estradiol (E2) attenuated the pressor effect of ANG II (Delta10.9 +/- 2.3 and Delta4.5 +/- 1.4 mmHg), and the protective effect of E2 was prevented by the coadministration of an estrogen receptor, antagonist ICI-182780 (Delta23.6 +/- 3.1 mmHg). Moreover, the ganglionic blockade on day 7 after the start of ANG II infusions resulted in a smaller reduction of BP in central Tempol- and in central E2-treated males, suggesting that estrogen inhibits the central ANG II-induced increases in sympathetic outflow. In subfornical organ slices, the application of ANG II resulted in a 21.5 +/- 2.5% increase in ROS production. The coadministration of irbesartan, an ANG II type 1 receptor antagonist, or the preincubation of brain slices with Tempol blocked ANG II-induced increases in ROS production (-1.8 +/- 1.6% and -1.0 +/- 1.8%). The ROS response to ANG II was also blocked by E2 (-3.2 +/- 2.4%). The results suggest that the central actions of E2 are involved in the protection from ANG II-induced hypertension and that estrogen modulation of the ANG II-induced effects may involve interactions with ROS production.