RESUMEN
Normal pregnancy is associated with vast adjustments in cardiovascular autonomic control. Sympathetic baroreflex sensitivity has been reported to be attenuated during pregnancy in animal models, but most studies in humans are cross-sectional and findings from longitudinal case studies are inconclusive. It remains unclear how sympathetic baroreflex sensitivity is altered longitudinally during pregnancy within an individual in different body postures. Therefore, this study examined the impact of posture on sympathetic baroreflex sensitivity in 24 normal-weight normotensive pregnant women. Spontaneous sympathetic baroreflex sensitivity was assessed during early (6-11 weeks) and late (32-36 weeks) pregnancy and 6-10 weeks postpartum in the supine posture and graded head-up tilt (30° and 60°). In addition, data from the postpartum period were compared with (and no different to) 18 age-matched non-pregnant women to confirm that the postpartum period was reflective of a non-pregnant condition (online supplement). When compared with postpartum (-3.8 ± 0.4 bursts/100 heartbeats/mmHg), supine sympathetic baroreflex sensitivity was augmented during early pregnancy (-5.9 ± 0.4 bursts/100 heartbeats/mmHg, P < 0.001). However, sympathetic baroreflex sensitivity at 30° or 60° head-up tilt was not different between any phase of gestation (P > 0.05). When compared to supine, sympathetic baroreflex sensitivity at 60° head-up tilt was significantly blunted during early (Δ2.0 ± 0.7 bursts/100 heartbeats/mmHg, P = 0.024) and late (Δ1.5 ± 0.6 bursts/100 heartbeats/mmHg, P = 0.049) pregnancy but did not change postpartum (Δ0.4 ± 0.6 bursts/100 heartbeats/mmHg, P = 1.0). These data show that time-course changes in sympathetic baroreflex sensitivity are dependent on the posture it is examined in and provides a foundation of normal blood pressure regulation during pregnancy for future studies in women at risk for adverse pregnancy outcomes.
Asunto(s)
Barorreflejo , Postura , Animales , Embarazo , Femenino , Humanos , Estudios Transversales , Frecuencia Cardíaca , Sistema Nervioso AutónomoRESUMEN
Muscle sympathetic nerve activity (MSNA) increases during isometric exercise via increased firing of low-threshold action potentials (AP), recruitment of larger, higher-threshold APs, and synaptic delay modifications. Recent work found that women with post-traumatic stress disorder (PTSD) demonstrate exaggerated early-onset MSNA responses to exercise; however, it is unclear how PTSD affects AP recruitment patterns during fatiguing exercise. We hypothesized that women with PTSD (n = 11, 43 [11] [SD] years) would exhibit exaggerated sympathetic neural recruitment compared to women without PTSD (controls; n = 13, 40 [8] years). MSNA and AP discharge patterns (via microneurography and a continuous wavelet transform) were measured during 1 min of baseline, isometric handgrip exercise (IHG) to fatigue, 2 min of post-exercise circulatory occlusion (PECO), and 3 min of recovery. Women with PTSD were unable to increase AP content per burst compared to controls throughout IHG and PECO (main effect of group: P = 0.026). Furthermore, relative to controls, women with PTSD recruited fewer AP clusters per burst during the first (controls: ∆1.3 [1.2] vs. PTSD: ∆-0.2 [0.8]; P = 0.016) and second minute (controls: ∆1.2 [1.1] vs. PTSD: ∆-0.1 [0.8]; P = 0.022) of PECO, and fewer subpopulations of larger, previously silent axons during the first (controls: ∆5 [4] vs. PTSD: ∆1 [2]; P = 0.020) and second minute (controls: ∆4 [2] vs. PTSD: ∆1 [2]; P = 0.021) of PECO. Conversely, PTSD did not modify the AP cluster size-latency relationship during baseline, the end of IHG, or PECO (all P = 0.658-0.745). Collectively, these data indicate that women with PTSD demonstrate inherent impairments in the fundamental neural coding patterns elicited by the sympathetic nervous system during IHG and exercise pressor reflex activation.
Asunto(s)
Trastornos por Estrés Postraumático , Ejercicio Físico , Fatiga , Femenino , Fuerza de la Mano , Humanos , Reflejo , Sistema Nervioso Simpático , VasoconstrictoresRESUMEN
Previous studies have demonstrated that sympathetic baroreflex sensitivity (BRS) increases during orthostatic stress in humans. We recently showed that dietary salt intake affects sympathetic neural control in healthy premenopausal women. This study aimed to determine whether salt loading versus salt reduction would impact sympathetic BRS during orthostasis in premenopausal women with a history of normal pregnancy. Nine healthy women [42 ± 3 (SD) yr] were given a standardized isocaloric high-salt (250 mEq sodium/day) or low-salt (50 mEq sodium/day) diet for 1 wk each (â¼2 mo apart with the order randomized), whereas water intake was ad libitum. Laboratory testing was performed following each high- and low-salt period in the midluteal phase of the menstrual cycle. Hemodynamics and muscle sympathetic nerve activity (MSNA) were measured at baseline (supine; 2 min) and during a graded head-up tilt (30° for 5 min and 60° for 20 min). Sympathetic BRS was assessed during baseline and head-up tilt. Hemodynamics were not different between salt conditions during baseline or tilt. Both supine and upright MSNA indices were lower in high salt than low salt (all P < 0.05), however, there was no interaction effect (P = 0.507-0.996). On moving from supine to upright, sympathetic BRS remained unchanged in high salt but increased in low salt (P = 0.028 for interaction). Thus, salt loading diminishes the responsiveness of sympathetic BRS during orthostasis compared with salt reduction in healthy premenopausal women with prior normal pregnancy. Whether this is one underlying mechanism for salt-induced development of hypertension during ambulation remains to be determined.
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Barorreflejo , Dieta Hiposódica , Mareo/fisiopatología , Hemodinámica , Músculo Esquelético/inervación , Cloruro de Sodio Dietético/efectos adversos , Sistema Nervioso Simpático/fisiopatología , Adulto , Presión Sanguínea , Estudios Cruzados , Mareo/diagnóstico , Femenino , Frecuencia Cardíaca , Humanos , Persona de Mediana Edad , Embarazo , Distribución Aleatoria , Texas , Pruebas de Mesa Inclinada , Factores de TiempoRESUMEN
Excessive salt intake is considered a risk factor for the development of hypertension. Additionally, aberrant neurocirculatory responses to a cold stimulus are associated with an increased risk of hypertension. This study aimed to determine whether salt loading versus salt reduction would impact hemodynamic and sympathetic neural responses during the cold pressor test (CPT) in premenopausal women with a history of normal pregnancy. Nine healthy premenopausal women [42 ± 3 (SD) yr] were given a standardized isocaloric high-salt (HS; 250 mEq sodium/day) or low-salt (LS; 50 mEq sodium/day) diet for 1-wk each (â¼2 mo apart with the order randomized), while water intake was ad libitum. Laboratory testing was performed following each HS and LS period in the mid-luteal phase of the menstrual cycle. Subjects were in the supine position and beat-by-beat blood pressure (BP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were continuously measured during 1-min baseline followed by 2-min CPT, and 3-min recovery. BP and HR increased during the CPT (both P < 0.001); the responses were similar between HS and LS. MSNA increased during the CPT, but the increment (Δ) was greater during HS than LS (29 ± 6 vs. 15 ± 4 bursts/min; P < 0.001). The transduction of MSNA for vasoconstriction during the CPT was lower in HS (P < 0.05). Thus, salt loading augments sympathetic neural reactivity to the cold stimulus with similar pressor responses compared with salt reduction, which may be attributed to the blunted neurovascular transduction-a compensatory mechanism for hemodynamic homeostasis in premenopausal women with a history of normal pregnancy.
Asunto(s)
Sistema Cardiovascular/inervación , Frío , Dieta Hiposódica , Hemodinámica , Músculo Esquelético/inervación , Premenopausia , Cloruro de Sodio Dietético/administración & dosificación , Sistema Nervioso Simpático/fisiología , Adulto , Presión Sanguínea , Femenino , Frecuencia Cardíaca , Humanos , Persona de Mediana Edad , Paridad , Embarazo , Distribución Aleatoria , Factores de Tiempo , VasoconstricciónRESUMEN
In this brief review, we summarize the current knowledge on the complex interplay between metabolism, sympathetic activity and hypertension with a focus on sex differences and changes with age in humans. Evidence suggests that in premenopausal women, sex hormones, particularly estrogen exerts a profound cardioprotective effect which may be associated with favorable metabolic profiles, as well as lower sympathetic activity and blood pressure at rest and any given physiological and environmental stimuli compared with men of a similar age. Along this line, premenopausal women seem to be generally protected from obesity-induced metabolic and cardiovascular complications. However, postmenopausal estrogen deprivation during midlife and older age has a detrimental impact on metabolism, may lead to adipose tissue redistribution from the subcutaneous to abdominal area, and augments sympathetic activity. All these changes could contribute significantly to the higher prevalence of hypertension and greater cardiometabolic risk in older women than older men. It is proposed that obesity-related hypertension has a neurogenic component which is characterized by sympathetic overactivity, but the impact of sex and age remains largely unknown. Understanding sex and age-specific differences in obesity and sympathetic neural control of blood pressure is important in the prevention and/or risk reduction of cardiometabolic disorders for both men and women.
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Presión Sanguínea/fisiología , Metabolismo Energético/fisiología , Hipertensión/fisiopatología , Sistema Nervioso Simpático/fisiología , Factores de Edad , Femenino , Humanos , Masculino , Obesidad/metabolismo , Obesidad/fisiopatología , Factores SexualesRESUMEN
PURPOSE: There is considerable interindividual variability in the perception of pain. Given that pain management is a major public health problem, gaining insight into the underlying physiology of these perceptual differences is important. We tested the hypothesis that when interindividual variability in initial muscle sympathetic nerve activity (MSNA) responses to a cold pressor test (CPT) is identified, the divergent responses will be linked to differences in pain perception in healthy young men and women. METHODS: In the supine position, blood pressure (BP) and MSNA were measured at baseline and during a 2-min CPT. Immediately following the CPT, pain was rated (range 0-10). RESULTS: Two groups were established: positive responders (Pos, n = 12) and negative responders (Neg, n = 12) based on the initial (first 30 s) MSNA response profiles (Pos: 12 ± 9, Neg: -3 ± 3 bursts/min, P < 0.0001). MSNA response profiles throughout the CPT were different between groups (P < 0.0001). Peak MSNA increases were different (Pos: 27 ± 11, Neg: 9 ± 5 bursts/min, P < 0.0001) and corresponded with initial MSNA responses (R2 = 0.6881, P < 0.0001). Blood pressure responses were also different throughout the CPT (P < 0.0001). Most importantly, the perception of pain induced by the CPT was different between the two groups (Pos: 8 ± 1, Neg: 4 ± 1, P < 0.0001). CONCLUSIONS: The results indicate that in healthy young men and women, there are divergent initial sympathetic neural responses to a given painful stimulus that are linked to the magnitude of pain perception. These findings highlight the distinctive sympathetic patterns that may contribute to the considerable interindividual variability in the perception of pain.
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Músculo Esquelético , Sistema Nervioso Simpático , Vías Autónomas , Presión Sanguínea , Frío , Femenino , Frecuencia Cardíaca , Humanos , Masculino , Percepción del DolorRESUMEN
KEY POINTS: Haemorrhage is the leading cause of battlefield and civilian trauma deaths. Given that a haemorrhagic injury on the battlefield is almost always associated with pain, it is paramount that the administered pain medication does not disrupt the physiological mechanisms that are beneficial in defending against the haemorrhagic insult. Current guidelines from the US Army's Committee on Tactical Combat Casualty Care (CoTCCC) for the selection of pain medications administered to a haemorrhaging soldier are based upon limited scientific evidence, with the clear majority of supporting studies being conducted on anaesthetized animals. Specifically, the influence of low-dose ketamine, one of three analgesics employed in the pre-hospital setting by the US Army, on haemorrhagic tolerance in humans is unknown. For the first time in conscious males and females, the findings of the present study demonstrate that the administration of an analgesic dose of ketamine does not compromise tolerance to a simulated haemorrhagic insult. Increases in muscle sympathetic nerve activity during progressive lower-body negative pressure were not different between trials. Despite the lack of differences for muscle sympathetic nerve activity responses, mean blood pressure and heart rate were higher during moderate hypovolemia after ketamine vs. placebo administration. ABSTRACT: Haemorrhage is the leading cause of battlefield and civilian trauma deaths. For a haemorrhaging soldier, there are several pain medications (e.g. ketamine) recommended for use in the prehospital, field setting. However, the data to support these recommendations are primarily limited to studies in animals. Therefore, it is unknown whether ketamine adversely affects physiological mechanisms responsible for maintenance of arterial blood pressure (BP) during haemorrhage in humans. In humans, ketamine has been demonstrated to raise resting BP, although it has not been studied with the concomitant central hypovolemia that occurs during haemorrhage. Thus, the present study aimed to test the hypothesis that ketamine does not impair haemorrhagic tolerance in humans. Thirty volunteers (15 females) participated in this double-blinded, randomized, placebo-controlled trial. A pre-syncopal limited progressive lower-body negative pressure (LBNP; a validated model for simulating haemorrhage) test was conducted following the administration of ketamine (20 mg) or placebo (saline). Tolerance was quantified as a cumulative stress index and compared between trials using a paired, two-tailed t test. We compared muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat BP (photoplethysmography) and heart rate (electrocardiogram) responses during the LBNP test using a mixed effects model (time [LBNP stage] × drug). Tolerance to the LBNP test was not different between trials (Ketamine: 635 ± 391 vs. Placebo: 652 ± 360 mmHgâ§min, p = 0.77). Increases in MSNA burst frequency (time: P < 0.01, trial: p = 0.27, interaction: p = 0.39) during LBNP stages were no different between trials. Despite the lack of differences for MSNA responses, mean BP (time: P < 0.01, trial: P < 0.01, interaction: p = 0.01) and heart rate (time: P < 0.01, trial: P < 0.01, interaction: P < 0.01) were higher during moderate hypovolemia after ketamine vs. placebo administration (P < 0.05 for all, post hoc), but not at the end of LBNP. These data, which are the first to be obtained in conscious humans, demonstrate that the administration of low-dose ketamine does not impair tolerance to simulated haemorrhage or mechanisms responsible for maintenance of BP.
Asunto(s)
Hipovolemia , Ketamina , Presión Sanguínea , Femenino , Frecuencia Cardíaca , Humanos , Presión Negativa de la Región Corporal Inferior , Masculino , Músculos , Sistema Nervioso SimpáticoRESUMEN
Recent evidence suggests an elevated risk of cardiovascular disease development in multiparous women. Therefore, we investigated the effects of multiparity on within-pregnancy sympathetic neural regulation in normotensive, pregnant women. We retrospectively analyzed heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA; n = 8) data from 10 women whom participated in microneurographic research studies during two sequential pregnancies (i.e., PREG1 and PREG2). There was no difference in resting BP between pregnancies (P > 0.05), whereas HR trended higher in PREG2 versus PREG1 (P = 0.06). MSNA burst frequency was greater in PREG2 versus PREG1 after adjusting for age (32 ± 12 vs. 22 ± 12 bursts/min; P = 0.049), whereas burst incidence did not differ (40 ± 16 vs. 34 ± 17 bursts/100 heartbeats; P = 0.21). Sympathetic baroreflex sensitivity was not different between PREG1 and PREG2 (P > 0.05). Our results may highlight a possible role of altered within-pregnancy sympathetic neural regulation in the observed relationship in women between parity and future cardiovascular disease risk.NEW & NOTEWORTHY To our knowledge, this is the first study to investigate the effects of multiparity on within-pregnancy sympathetic neural regulation. We observed augmented muscle sympathetic nerve activity in women's second studied pregnancy versus their first. Conversely, blood pressure and sympathetic baroreflex sensitivity did not differ, whereas a trend for increased heart rate was observed. Our results highlight a possible role of altered within-pregnancy sympathetic neural regulation in the relationship between increased parity and cardiovascular disease development.
Asunto(s)
Paridad , Embarazo/fisiología , Sistema Nervioso Simpático/fisiología , Adulto , Presión Sanguínea , Femenino , Frecuencia Cardíaca , Humanos , Músculo Liso Vascular/fisiologíaRESUMEN
Salt intake may alter blood pressure (BP) regulation, but no study has investigated the impact of salt reduction versus salt loading on morning blood pressure surge (MBPS) and sympathetic neural control in premenopausal women with a history of normal pregnancy. Nine healthy women (42 ± 3 yr; mean ± SD) were given a low-salt diet (LS; 50 mEq sodium/day) and high-salt diet (HS; 250 mEq sodium/day) for 1 wk each (~2 mo apart with the order randomized), while water intake was ad libitum. Ambulatory BP at 24 h was measured, and the percent change in blood volume (BV) was calculated following LS and HS. MBPS was defined as the morning systolic BP (averaged for 2 h after wake-up) minus the lowest nocturnal systolic BP. Beat-by-beat BP, heart rate, and muscle sympathetic nerve activity (MSNA) were measured during supine rest. Signal averaging was used to characterize changes in beat-by-beat mean arterial pressure and total vascular conductance following spontaneous MSNA bursts to assess sympathetic vascular transduction. Ambulatory BP and MBPS (32 ± 7 vs. 26 ± 12 mmHg, P = 0.208) did not differ between LS and HS. From LS to HS, BV increased by 4.3 ± 3.7% (P = 0.008). MSNA (30 ± 20 vs. 18 ± 13 bursts/100 heartbeats, P = 0.005) was higher, whereas sympathetic vascular transduction was lower in LS than HS (both, P < 0.01). Changes in MSNA from LS to HS were correlated to percent changes in BV (r = -0.673; P = 0.047). Thus, salt intake affects sympathetic neural control but not MBPS in premenopausal women with a history of normal pregnancy. The underlying mechanisms remain unknown; however, alterations in sympathetic vascular transduction may, in part, contribute.NEW & NOTEWORTHY This is the first study to demonstrate that MBPS and ambulatory BP were not affected by salt intake despite a significant change in sympathetic outflow in healthy premenopausal women with a history of normal pregnancy. This may be due to compensatory adaptations in MSNA and sympathetic vascular transduction during salt reduction versus salt loading.
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Presión Sanguínea , Sistema Cardiovascular/inervación , Ritmo Circadiano , Dieta Hiposódica , Músculo Esquelético/inervación , Cloruro de Sodio Dietético/administración & dosificación , Sistema Nervioso Simpático/fisiología , Adaptación Fisiológica , Adulto , Estudios Cruzados , Femenino , Frecuencia Cardíaca , Humanos , Persona de Mediana Edad , Paridad , Embarazo , Premenopausia , Estudios Prospectivos , Distribución Aleatoria , Factores de TiempoRESUMEN
Posttraumatic stress disorder (PTSD) is a psychiatric illness that is more prevalent in women, and accumulating evidence suggests a link between PTSD and future development of cardiovascular disease. The underlying mechanisms are unclear, but augmented sympathetic reactivity to daily stressors may be involved. We measured muscle sympathetic nerve activity (MSNA), blood pressure (BP), and heart rate responses in 14 women with PTSD and 14 healthy women (controls) during static handgrip (SHG) exercise to fatigue at 40% of maximal voluntary contraction (MVC). Two minutes of postexercise circulatory arrest (PECA) was followed immediately after SHG to fatigue. MVC and the time to fatigue during SHG did not differ between groups (both P > 0.05). At the first 30 s of SHG, women with PTSD showed augmented sympathetic neural [mean ± SD, ∆MSNA burst frequency (BF): 5 ± 4 vs. 2 ± 3 bursts/30 s, P = 0.02 and ∆MSNA total activity (TA): 82 ± 58 vs. 25 ± 38 arbitrary units/30 s, P = 0.004] and pressor (∆systolic BP: 10 ± 5 vs. 4 ± 3 mmHg, P = 0.003) responses compared with controls. However, MSNA and BP responses at fatigue and during PECA were not different between groups. More interestingly, the augmented initial neural and pressor responses to SHG were associated with greater awake systolic BP variability during ambulation in women with PTSD (MSNA BF: r = 0.55, MSNA TA: r = 0.62, and SBP: r = 0.69, all P < 0.05). These results suggest that early onset exercise pressor response in women with PTSD may be attributed to enhanced mechano- rather than metaboreflexes, which might contribute to the mechanisms underlying the link between PTSD and cardiovascular risk.NEW & NOTEWORTHY The novel findings of the current study are that women with posttraumatic stress disorder (PTSD) exhibited augmented sympathetic neural and pressor responses at the first 30 s of submaximal isometric muscle contraction. More interestingly, exaggerated neurocirculatory responses at the onset of muscle contraction were associated with greater ambulatory awake systolic blood pressure fluctuations in women with PTSD. Our findings expand the knowledge on the physiological mechanisms that perhaps contribute to increased risk of cardiovascular disease in such a population.
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Presión Sanguínea , Ejercicio Físico , Contracción Isométrica , Músculo Esquelético/inervación , Trastornos por Estrés Postraumático/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Adulto , Estudios de Casos y Controles , Femenino , Fuerza de la Mano , Frecuencia Cardíaca , Humanos , Mecanorreceptores/metabolismo , Persona de Mediana Edad , Fatiga Muscular , Reflejo , Trastornos por Estrés Postraumático/diagnóstico , Trastornos por Estrés Postraumático/psicología , Factores de Tiempo , Adulto JovenRESUMEN
Posttraumatic stress disorder (PTSD) is more prevalent in women and associated with greater risk of major forms of cardiovascular disease, but physiological mechanisms underlying this association remain unknown. We hypothesized that abnormal sympathetic responses to sympathoexcitatory stimuli might predispose PTSD patients to a greater risk of cardiovascular disease. We examined changes in integrated muscle sympathetic nerve activity (MSNA) burst and multiunit action potential (AP) recruitment patterns as well as hemodynamic responses during cold pressor test (CPT) in 14 women with PTSD and 14 healthy control subjects. Data were collected during 1-min baseline, 2-min CPT, and 3-min recovery. At baseline, blood pressure (BP) was not different between groups; however, heart rate and sympathetic neural activity were greater in women with PTSD [MSNA burst frequency (BF): 27 ± 13 vs. 18 ± 14 bursts/min (P = 0.04); AP frequency: 272 ± 152 vs. 174 ± 146 spikes/min (P = 0.03)]. In response to CPT, BP responses exhibited a significant group × time interaction (P = 0.01) highlighted by a significant diastolic BP main group effect (P = 0.048) despite the finding that increases in integrated MSNA burst responses were not different between groups (P > 0.05). However, compared with control subjects, AP firing frequency (group × time interaction P = 0.0001, group P = 0.02) and AP per burst (group × time interaction P = 0.03, group P = 0.03) were augmented in women with PTSD. Collectively, women with PTSD exhibited a greater pressor response and an exaggerated sympathetic neural recruitment pattern during sympathoexcitatory stimuli that may, in part, explain the propensity toward developing hypertension and cardiovascular disease later in life.NEW & NOTEWORTHY The novel findings of the present study are that women with posttraumatic stress disorder (PTSD) have an augmented pressor response to the sympathoexcitatory stimulus of a cold pressor test (CPT) compared with healthy control subjects. Although integrated muscle sympathetic nerve activity burst responses were not significantly different between groups, total sympathetic action potential discharge in response to the CPT was markedly elevated in women with PTSD exhibiting increased firing of low-threshold axons as well as the recruitment of latent subpopulations of larger-sized axons that are otherwise silent at baseline. Aberrant autonomic circulatory control in response to sympathoexcitatory stimulus may in part explain the propensity toward developing hypertension and cardiovascular disease in this population.
Asunto(s)
Presión Sanguínea , Reclutamiento Neurofisiológico , Reflejo , Trastornos por Estrés Postraumático/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Potenciales de Acción , Adulto , Frío , Femenino , Humanos , Persona de Mediana EdadRESUMEN
Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to develop therapeutic countermeasures. In this regard, autophagy is a complex catabolic process that is increased in the heart following DOX exposure. However, conflicting evidence exists regarding the role of autophagy dysregulation in the etiology of DOX-induced cardiac dysfunction. This study aimed to clarify the contribution of autophagy to DOX-induced cardiotoxicity by specifically inhibiting autophagosome formation using a dominant negative autophagy gene 5 (ATG5) adeno-associated virus construct (rAAV-dnATG5). Acute (2-day) and delayed (9-day) effects of DOX (20 mg/kg intraperitoneal injection (i.p.)) on the hearts of female Sprague-Dawley rats were assessed. Our data confirm established detrimental effects of DOX on left ventricular function, redox balance and mitochondrial function. Interestingly, targeted inhibition of autophagy in the heart via rAAV-dnATG5 in DOX-treated rats ameliorated the increase in mitochondrial reactive oxygen species emission and the attenuation of cardiac and mitochondrial function, but only at the acute timepoint. Deviation in the effects of autophagy inhibition at the 2- and 9-day timepoints appeared related to differences in ATG5-ATG12 conjugation, as this marker of autophagosome formation was significantly elevated 2 days following DOX exposure but returned to baseline at day 9. DOX exposure may transiently upregulate autophagy signaling in the rat heart; thus, long-term inhibition of autophagy may result in pathological consequences.
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Antibióticos Antineoplásicos/toxicidad , Proteína 5 Relacionada con la Autofagia/metabolismo , Autofagia , Cardiotoxicidad/prevención & control , Doxorrubicina/toxicidad , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Animales , Proteína 5 Relacionada con la Autofagia/genética , Cardiotoxicidad/etiología , Cardiotoxicidad/patología , Masculino , Potencial de la Membrana Mitocondrial , Ratas , Ratas Sprague-Dawley , Transducción de SeñalAsunto(s)
Hipertensión , Embarazo , Femenino , Humanos , Potenciales de Acción , Presión Sanguínea/fisiología , Músculos , Sistema Nervioso SimpáticoRESUMEN
Heart failure with reduced ejection fraction (HFREF) increases neutral sphingomyelinase (NSMase) activity and mitochondrial reactive oxygen species (ROS) emission and causes diaphragm weakness. We tested whether a systemic pharmacological NSMase inhibitor or short-hairpin RNA (shRNA) targeting NSMase isoform 3 (NSMase3) would prevent diaphragm abnormalities induced by HFREF caused by myocardial infarction. In the pharmacological intervention, we used intraperitoneal injection of GW4869 or vehicle. In the genetic intervention, we injected adeno-associated virus serotype 9 (AAV9) containing shRNA targeting NSMase3 or a scrambled sequence directly into the diaphragm. We also studied acid sphingomyelinase-knockout mice. GW4869 prevented the increase in diaphragm ceramide content, weakness, and tachypnea caused by HFREF. For example, maximal specific forces (in N/cm2) were vehicle [sham 31 ± 2 and HFREF 26 ± 2 ( P < 0.05)] and GW4869 (sham 31 ± 2 and HFREF 31 ± 1). Respiratory rates were (in breaths/min) vehicle [sham 61 ± 3 and HFREF 84 ± 11 ( P < 0.05)] and GW4869 (sham 66 ± 2 and HFREF 72 ± 2). AAV9-NSMase3 shRNA prevented heightening of diaphragm mitochondrial ROS and weakness [in N/cm2, AAV9-scrambled shRNA: sham 31 ± 2 and HFREF 27 ± 2 ( P < 0.05); AAV9-NSMase3 shRNA: sham 30 ± 1 and HFREF 30 ± 1] but displayed tachypnea. Both wild-type and ASMase-knockout mice with HFREF displayed diaphragm weakness. Our study suggests that activation of NSMase3 causes diaphragm weakness in HFREF, presumably through accumulation of ceramide and elevation in mitochondrial ROS. Our data also reveal a novel inhibitory effect of GW4869 on tachypnea in HFREF likely mediated by changes in neural control of breathing.
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Diafragma/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Debilidad Muscular/prevención & control , ARN Interferente Pequeño/genética , Esfingomielina Fosfodiesterasa/antagonistas & inhibidores , Esfingomielina Fosfodiesterasa/genética , Compuestos de Anilina/farmacología , Animales , Compuestos de Bencilideno/farmacología , Diafragma/enzimología , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/terapia , Humanos , Masculino , Ratones , Ratones Noqueados , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , Ratas , Ratas Wistar , Esfingomielina Fosfodiesterasa/deficiencia , Volumen Sistólico/genética , Volumen Sistólico/fisiologíaRESUMEN
Women are two to three times more likely to develop posttraumatic stress disorder (PTSD) compared with men after exposure to a major trauma, and PTSD is associated with increased risk for cardiovascular disease in later life. The underlying mechanisms are unclear, but alterations in cardiac function may be involved. We hypothesized that women with PTSD have reduced left ventricular (LV) diastolic function. We studied 14 women with PTSD (PTSD group) and 14 women without PTSD (controls) using echocardiography Doppler to evaluate LV diastolic function, including peak velocities (E and A waves) in transmitral flow; diastolic, atrial kick, and systolic waveform velocities (e', a', and s') in tissue Doppler; the ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e'); and velocity of propagation (Vp) . Baseline characteristics including age, body size, blood pressure, and heart rate were not significantly different between the two groups. Compared with the control group, women with PTSD showed greater E/e' (controls vs. PTSD group: 7.0 ± 1.3 vs. 9.1 ± 1.3, P = 0.002) and smaller Vp (controls vs. PTSD group: 63.7 ± 11.3 vs. 47.5 ± 6.9 cm/s, P = 0.003). These results suggest that women with PTSD have reduced LV diastolic function, which may contribute, at least in part, to the increased risk of cardiovascular disease later in life.
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Diástole/fisiología , Trastornos por Estrés Postraumático , Función Ventricular Izquierda/fisiología , Adulto , Estudios de Casos y Controles , Epinefrina/sangre , Femenino , Humanos , Persona de Mediana Edad , Norepinefrina/sangreAsunto(s)
Trastornos por Estrés Postraumático , Humanos , Femenino , Mareo , Sistema Nervioso SimpáticoRESUMEN
Women with a history of gestational hypertensive disorders (GHD) are at increased risk for developing perinatal cardiovascular complications (e.g., gestational hypertension, preeclampsia, etc.) in subsequent pregnancies. The underlying mechanisms remain uncertain, but impaired maternal left ventricular function may be one contributing factor for these complications. We evaluated the time course of changes in left ventricular function before, during, and after pregnancy in women with prior GHD. Sixteen women with a history of GHD (the high-risk group) and 25 women without such a history (controls) were enrolled. Resting hemodynamic and echocardiographic measurements were longitudinally performed before pregnancy, during early pregnancy (4-8 wk of gestation), during late pregnancy (32-36 wk of gestation), and postpartum (6-10 wk after delivery). Pregnancy outcomes were obtained after delivery. At prepregnancy, there was no difference in blood pressure and heart rate between the groups. Corrected isovolumic relaxation time was longer, E/ e' was larger, and Tei index was greater in the high-risk group than controls. Moreover, the rate of GHD during the study was significantly greater in the high-risk group than controls [odds ratio = 8.94 (95% confidence interval: 1.55-51.5), P = 0.007]. Multiple logistic regression analysis adjusted for age demonstrated that prepregnancy E/ e' was an independent predictor for GHD ( P = 0.017). Thus, women with a history of GHD have modestly impaired cardiac function prepregnancy compared with controls, which identifies an increased susceptibility to developing cardiovascular complications during a subsequent pregnancy.
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Ventrículos Cardíacos/fisiopatología , Hipertensión Inducida en el Embarazo/fisiopatología , Contracción Miocárdica , Función Ventricular Izquierda , Adulto , Estudios de Casos y Controles , Ecocardiografía Doppler , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Hemodinámica , Humanos , Hipertensión Inducida en el Embarazo/diagnóstico por imagen , Hipertensión Inducida en el Embarazo/epidemiología , Incidencia , Paridad , Embarazo , Texas/epidemiología , Factores de TiempoRESUMEN
NEW FINDINGS: What is the central question of this study? The venoarteriolar response (VAR) contributes substantially to the maintenance of orthostatic tolerance in humans. Despite its importance in haemodynamic homeostasis, the impact of ageing on the VAR remains understudied. What is the main finding and its importance? Older adults exhibit an augmented VAR in response to leg dependency. The age-related augmentation of the VAR might be linked with progressive increases of peripheral vascular resistance with ageing. We found a modest but significant correlation between the leg VAR and the morning blood pressure surge in older adults. Augmented leg VAR might contribute to the blood pressure elevation in the early morning. ABSTRACT: The venoarteriolar response (VAR) is a non-adrenergic, non-baroreflex-mediated mechanism of vasoconstriction, which has been proposed to contribute â¼45% of the increase in total peripheral resistance during orthostasis. Despite its importance in human cardiovascular control during orthostatic stress, there is no information available regarding the impact of age and sex on the VAR or its role in diurnal blood pressure (BP) variation. We studied 33 (15 women) young (mean ± SD; 28 ± 4 years old) and 26 (12 women) older (71 ± 3 years old) healthy individuals. Brachial and femoral blood flow were measured using Doppler ultrasound. The percentage reduction in vascular conductance (blood flow/mean BP) during 4 min of limb dependency (35-40 cm below the heart level) was used to assess the VAR. The morning surge in BP was assessed using 24 h ambulatory BP monitoring. Peak VAR in the lower limb, but not in the upper limb, was significantly higher in the older than the younger adults (33 ± 4 versus 26 ± 6%, older versus young; P < 0.05). There was no sex difference in the VAR in either the young or the older group. A greater leg VAR was related to a greater morning surge in BP in older adults (r = -0.4, P = 0.02) but not in the young adults (r = -0.26, P = 0.1). Thus, advancing age enhances the VAR in the lower limb and is associated with the morning blood pressure surge in older adults. Sex does not affect this local axonal reflex in healthy humans.
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Envejecimiento/fisiología , Presión Sanguínea/fisiología , Ritmo Circadiano/fisiología , Reflejo/fisiología , Vasoconstricción/fisiología , Adulto , Anciano , Arteria Braquial/diagnóstico por imagen , Arteria Braquial/fisiología , Femenino , Arteria Femoral/diagnóstico por imagen , Arteria Femoral/fisiología , Frecuencia Cardíaca/fisiología , Hemodinámica/fisiología , Humanos , Masculino , Flujo Sanguíneo Regional/fisiología , Ultrasonografía Doppler , Adulto JovenRESUMEN
Although doxorubicin (DOX) is a highly effective anti-tumour agent used to treat a variety of cancers, DOX administration is associated with significant side effects, including myopathy of both cardiac and skeletal muscles. The mechanisms responsible for DOX-mediated myopathy remain a topic of debate. We tested the hypothesis that both increased mitochondrial reactive oxygen species (ROS) emission and activation of the cysteine protease calpain are required for DOX-induced myopathy in rat cardiac and skeletal muscle. Cause and effect was determined by administering a novel mitochondrial-targeted anti-oxidant to prevent DOX-induced increases in mitochondrial ROS emission, whereas a highly-selective pharmacological inhibitor was exploited to inhibit calpain activity. Our findings reveal that mitochondria are a major site of DOX-mediated ROS production in both cardiac and skeletal muscle fibres and the prevention of DOX-induced increases in mitochondrial ROS emission protects against fibre atrophy and contractile dysfunction in both cardiac and skeletal muscles. Furthermore, our results indicate that DOX-induced increases in mitochondrial ROS emission are required to activate calpain in heart and skeletal muscles and, importantly, calpain activation is a major contributor to DOX-induced myopathy. Taken together, these findings show that increased mitochondrial ROS production and calpain activation are significant contributors to the development of DOX-induced myopathy in both cardiac and skeletal muscle fibres.
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Calpaína/metabolismo , Doxorrubicina/farmacología , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Enfermedades Musculares/metabolismo , Miocardio/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Femenino , Corazón/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/patología , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Posttraumatic stress disorder (PTSD) is associated with an increased risk of developing cardiovascular disease, especially in women. Evidence indicates that men with PTSD exhibit lower maximal oxygen uptake (VÌo2max) relative to controls; however, whether VÌo2max is blunted in women with PTSD remains unknown. Furthermore, it is unclear what determinants (i.e., central and/or peripheral) of VÌo2max are impacted by PTSD. Therefore, we evaluated the central (i.e., cardiac output; QÌc) and peripheral (i.e., arteriovenous oxygen difference) determinants of VÌo2max in women with PTSD; hypothesizing that VÌo2max would be lower in women with PTSD compared with women without PTSD (controls), primarily due to smaller increases in stroke volume (SV), and therefore QÌc. Oxygen uptake (VÌo2), heart rate (HR), QÌc, SV, and arteriovenous oxygen difference were measured in women with PTSD (n = 14; mean [SD]: 43 [11] yr,) and controls (n = 17; 45 [11] yr) at rest, and during an incremental maximal treadmill exercise test, and the QÌc/VÌo2 slope was calculated. VÌo2max was not different between women with and without PTSD (24.3 [5.6] vs. 26.4 [5.0] mL/kg/min; P = 0.265). However, women with PTSD had higher QÌc [P = 0.002; primarily due to greater SV (P = 0.069), not HR (P = 0.285)], and lower arteriovenous oxygen difference (P = 0.002) throughout exercise compared with controls. Furthermore, the QÌc/VÌo2 slope was steeper in women with PTSD relative to controls (6.6 [1.4] vs. 5.7 [1.0] AU; P = 0.033). Following maximal exercise, women with PTSD exhibited slower HR recovery than controls (P = 0.046). Thus, despite attenuated peripheral oxygen extraction, VÌo2max is not reduced in women with PTSD, likely due to larger increases in QÌc.NEW & NOTEWORTHY The current study indicates that VÌo2max is not different between women with and without PTSD; however, women with PTSD exhibit blunted peripheral extraction of oxygen, thus requiring an increase in QÌc to meet metabolic demand during exercise. Furthermore, following exercise, women with PTSD demonstrate impaired autonomic cardiovascular control relative to sedentary controls. We interpret these data to indicate that women with PTSD demonstrate aberrant cardiovascular responses during and immediately following fatiguing exercise.