Showing papers by "Edward G. Lakatta published in 2002"
TL;DR: This review highlights some specific changes in resting cardiovascular structure and function and cardiovascular reserve capacity that occur with advancing age in healthy humans.
Abstract: In the United States, cardiovascular disease, e.g., atherosclerosis and hypertension, that lead to heart failure and stroke, is the leading cause of mortality, accounting for over 40 percent of deaths in those aged 65 years and above. Over 80 percent of all cardio-vascular deaths occur in the same age group. Thus, age, per se, is the major risk factor for cardiovascular disease. Clinical manifestations and prognosis of these cardiovascular diseases likely become altered in older persons with advanced age because interactions occur between age-associated cardiovascular changes in health and specific pathophysiologic mechanisms that underlie a disease. A fundamental understanding of age-associated changes in cardiovascular structure and function ranging in scope from humans to molecules is required for effective and efficient prevention and treatment of cardiovascular disease in older persons. A sustained effort over the past two decades has been applied to characterize the multiple effects of aging in health on cardiovascular structure and function in a single study population, the Baltimore Longitudinal Study on Aging. In these studies, community dwelling, volunteer participants are rigorously screened to detect both clinical and occult cardiovascular disease and characterized with respect to lifestyle, e.g. exercise habits, in an attempt to deconvolute interactions among lifestyle, cardiovascular disease and the aging process in health. This review highlights some specific changes in resting cardiovascular structure and function and cardiovascular reserve capacity that occur with advancing age in healthy humans. Observations from relevant experiments in animal models have been integrated with those in humans to provide possible mechanistic insight.
421 citations
TL;DR: Age-related changes in cardiovascular function and structure in healthy adult volunteer community dwelling subjects (from 20 to 85 years) is remarkable for changes in pump function, with a diminished capacity of the heart to adapt to physiological or pathological stress with advancing age.
Abstract: Age-related changes in cardiovascular function and structure in healthy adult volunteer community dwelling subjects (from 20 to 85 years) is remarkable for changes in pump function [impaired left ventricular (LV) ejection reserve capacity manifest by a reduced ejection fraction and accompanied by diminished cardioacceleration, LV dilation at end diastole and an altered diastolic filling pattern] and increased vascular afterloading. There is also evidence for a reduction in the number of cardiac myocytes with advancing age. Subcellular changes with aging (best understood in rodents) include certain regulatory factors of excitation–contraction–relaxation coupling (i.e. calcium handling), modulation by adrenergic receptor (AR) stimulation, and changes in the generation and sensitivity to the damaging effects of ROS. Coordinated changes in gene expression and/or protein function with aging result in a prolonged action potential (AP), Cai transient, and contraction. L-type Ca2+ current (ICa) inactivates more slowly, and outwardly-directed K+ currents are reduced, and likely contribute to AP-prolongation. The rate of Ca2+ sequestration by the sarcoplasmic reticulum (SR) decreases in the senescent myocardium, in part underlying the prolonged Cai transient. An age-associated reduction in transcription of the SERCA2 gene, coding for the SR Ca2+ pump, accounts in part for a decrease in the SR pump site density. The contractile response to both β1-AR and β2-AR stimulation diminishes with aging due to decreased adrenergic augmentation of ICa, and thus the Cai transient, in senescent vs. young hearts. The age-associated reduction in the postsynaptic response of myocardial cells to β1-AR stimulation appears to be due to multiple changes in molecular and biochemical receptor coupling and post-receptor mechanisms. An increased basal production of ROS is paralleled by increased ROS-sensitivity, markers of chronic ROS damage and mitochondrial functional decline. Overall, these changes lead to a diminished (but not necessarily exhausted) capacity of the heart to adapt to physiological or pathological stress with advancing age.
224 citations
TL;DR: The data suggest that heterodimerization between β1AR and β2AR inhibits the agonist-promoted internalization of the β2 AR and its ability to activate the ERK1/2 MAPK signaling pathway.
209 citations
TL;DR: In these elderly participants, aortic stiffness was positively associated with risk factors associated with the insulin resistance syndrome, increased common carotid intima-media thickness, heart rate, and decreased physical activity measured several years earlier.
205 citations
TL;DR: It is shown that the positive chronotropic effect of &bgr;-AR stimulation is critically dependent on localized subsarcolemmal ryanodine receptor (RyR) Ca2+ releases during diastolic depolarization (CRDD), which results in an augmentation of the amplitude of the local preaction potential subsar colemmAl Ca2- transient that accelerates the diastolization rate, leading to an increase in SANC firing rate.
Abstract: It has long been recognized that activation of sympathetic beta-adrenoceptors (beta-ARs) increases the spontaneous beating rate of sinoatrial nodal cells (SANCs); however, the specific links between stimulation of beta-ARs and the resultant increase in firing rate remain an enigma In the present study, we show that the positive chronotropic effect of beta-AR stimulation is critically dependent on localized subsarcolemmal ryanodine receptor (RyR) Ca(2+) releases during diastolic depolarization (CRDD) Specifically, isoproterenol (ISO; 01 micromol/L) induces a 3-fold increase in the number of CRDDs per cycle; a shift to higher CRDD amplitudes (from 200+/-004 to 217+/-003 F/F(0); P<005 [F and F(0) refer to peak and minimal fluorescence]); and an increase in spatial width (from 380+/-044 to 545+/-047 microm; P<005) The net effect results in an augmentation of the amplitude of the local preaction potential subsarcolemmal Ca(2+) transient that, in turn, accelerates the diastolic depolarization rate, leading to an increase in SANC firing rate When RyRs are disabled by ryanodine, beta-AR stimulation fails to amplify subsarcolemmal Ca(2+) releases, fails to augment the diastolic depolarization rate, and fails to increase the SANC firing rate, despite preserved beta-AR stimulation-induced augmentation of L-type Ca(2+) current amplitude Thus, the RyR Ca(2+) release acts as a switchboard to link beta-AR stimulation to an increase in SANC firing rate: recruitment of additional localized CRDDs and partial synchronization of their occurrence by beta-AR stimulation lead to an increase in the heart rate
202 citations
TL;DR: A sustained increase in MBG production in DS contributes to the chronic BP elevation induced by a sustained high NaCl intake, and an initial transient stimulation of OLC induced by NaCl loading of DS precedes an MBG response.
Abstract: Background— Digitalis-like sodium pump ligands (SPLs) effect natriuresis via inhibition of renal tubular Na+,K+-ATPase but may induce vasoconstriction. The present study investigated the potential roles of 2 putative endogenous SPLs, an ouabain-like compound (OLC) and an α1 Na+,K+-ATPase inhibitor, marinobufagenin (MBG), in regulating natriuresis and blood pressure (BP) responses to sustained and acute NaCl loading in Dahl salt-sensitive rats (DS). Methods and Results— During 4 weeks of an 8% NaCl diet, DS exhibited a progressive increase in MBG renal excretion (66±13 pmol/24 hours at week 4 versus 11±1 pmol/24 hours at baseline, n=48), which paralleled an increase in systolic BP (174±10 mm Hg at week 4 versus 110±2 mm Hg at baseline). By contrast, OLC excretion peaked at week 1 and returned to baseline levels. Administration of an anti-MBG, but not anti-ouabain antibody, to DS after 3 weeks of a high NaCl diet lowered BP (139±7 versus 175±5 mm Hg, P<0.001, n=5). Acute NaCl loading (2 hours) of DS (n=5) i...
168 citations
TL;DR: It is concluded that discordant regulation of factors that determine the activation status of type 2 matrix metalloprotease, coupled with an increase in the expression of its zymogen, occur with aging, which lead to an increased in the amount of activated protease.
Abstract: To elucidate potential mechanisms of enhanced type 2 matrix metalloprotease levels and activity within the thickened aged rat aorta, the present study measured its mRNA and protein levels and those of its membrane bound activator, MT1-MMP, its endogenous tissue inhibitor, TIMP-2, tissue type, and urokinase plasminogen activators and their receptors, and an inhibitor of plasminogen activation in aortae from Fisher 344X Brown Norway rats, 2 to 30 months of age. Semiquantitative immunohistochemistry, in situ hybridization, and in situ zymography of aortae detected a marked age-associated increase in gelatinolytic activity of type 2 metalloprotease within the thickened intima, internal elastic lamina, and elastic fibers in the inner part of the thickened tunica media, whereas the intimal tissue inhibitor of metalloprotease-2 mRNA and protein levels were not age related. Both activators of plasminogen and their receptors increased approximately 2-fold within the intima between 2 to 30 months. Similar, but not identical, age-associated changes in factors that regulate protease activity within the aortic media were also observed. We conclude that discordant regulation of factors that determine the activation status of type 2 matrix metalloprotease, coupled with an increase in the expression of its zymogen, occur with aging, which lead to an increase in the amount of activated protease. These factors are candidate mechanisms for age-associated vascular remodeling, a potent risk factor for vascular diseases with advancing age.
159 citations
TL;DR: MRI was used in 336 healthy, normotensive adults to measure LV mass, end-diastolic LV wall thickness, length, diameter, and shape, and no change occurred in echocardiographic LV mass with age in either gender, although echOCardiographicLV wall thickness increased in both.
Abstract: Echocardiographic left ventricular (LV) wall thickness increases with age, suggesting LV hypertrophy. However, autopsy studies have shown no change, or even a decrease, in LV mass with age. With many pathologies, LV remodeling results in changes in ventricular shape. Age-associated LV shape change might explain this discrepancy, although this has not been studied. Magnetic resonance imaging (MRI) was used in 336 healthy, normotensive adults (mean age 56 +/- 18 years; 200 women, 136 men) to measure LV mass, end-diastolic LV wall thickness, length, diameter, and shape. Echocardiographic LV mass was measured in a subset of 86 subjects by a standard algorithm. In women, LV wall thickness increased by 14% (r = 0.19, p <0.02), whereas LV length decreased by 9% (r = -0.26, p = 0.0006); LV diameter was unchanged. Thus, LV mass did not vary with age (r -0.04, p = 0.06) and the sphericity index decreased (r = -0.165, p <0.05). In men, LV wall thickness and diameter were unrelated to age, but there was an 11% decrease in LV length (r = -0.29, p = 0.003); therefore, there was an 11% decrease in LV mass (r = -0.20, p = 0.019) and a decrease in the sphericity index (r = -0.218, p <0.04). No change occurred in echocardiographic LV mass with age in either gender, although echocardiographic LV wall thickness increased in both. The left ventricle becomes more spherical with age in normal adults due to reduced LV length. In women, increased LV wall thickness offsets the decreasing LV length, whereas in men, LV wall thickness fails to compensate, resulting in decreased LV mass with age.
131 citations
TL;DR: It is concluded that a functional RyR2 is crucial to the progressive increase in heart rate during differentiation of ES cell-derived cardiomyocytes, consistent with a mechanism that couples Ca2+ release via RyR before an action potential with activation of an inward current that accelerates membrane depolarization.
Abstract: In adult myocardium, the heartbeat originates from the sequential activation of ionic currents in pacemaker cells of the sinoatrial node. Ca2+ release via the ryanodine receptor (RyR) modulates the rate at which these cells beat. In contrast, the mechanisms that regulate heart rate during early cardiac development are poorly understood. Embryonic stem (ES) cells can differentiate into spontaneously contracting myocytes whose beating rate increases with differentiation time. These cells thus offer an opportunity to determine the mechanisms that regulate heart rate during development. Here we show that the increase in heart rate with differentiation is markedly depressed in ES cell-derived cardiomyocytes with a functional knockout (KO) of the cardiac ryanodine receptor (RyR2). KO myocytes show a slowing of the rate of spontaneous diastolic depolarization and an absence of calcium sparks. The depressed rate of pacemaker potential can be mimicked in wild-type myocytes by ryanodine, and rescued in KO myocytes with herpes simplex virus (HSV)-1 amplicons containing full-length RyR2. We conclude that a functional RyR2 is crucial to the progressive increase in heart rate during differentiation of ES cell-derived cardiomyocytes, consistent with a mechanism that couples Ca2+ release via RyR before an action potential with activation of an inward current that accelerates membrane depolarization.
120 citations
TL;DR: Understanding the adaptive mechanisms of Ca(2+) regulation in hibernating mammals may suggest new strategies to protect nonhibernator cells, including those of humans, from Ca( 2+)-induced dysfunction.
Abstract: Intracellular Ca(2+) homeostasis is a prerequisite for a healthy cell life. While cells from some mammals may suffer dysregulation of intracellular Ca(2+) levels under certain deleterious and stressful conditions, including hypothermia and ischemia, cells from mammalian hibernators exhibit a remarkable ability to maintain a homeostatic intracellular Ca(2+) environment. Compared with cells from non-hibernators, hibernator cells are characterized by downregulation of the activity of Ca(2+) channels in the cell membrane, which helps to prevent excessive Ca(2+) entry. Concomitantly, sequestration of Ca(2+) by intracellular Ca(2+) stores, especially the sarcoplasmic/endoplasmic reticulum, is enhanced to keep the resting levels of intracellular Ca(2+) stable. An increase in stored Ca(2+) in heart cells during hibernation ensures that the levels of Ca(2+) messenger are sufficient for forceful cell contraction under conditions of hypothermia. Maintenance of Na(+) gradients, via Na(+)-Ca(2+) exchangers, is also important in the Ca(2+) homeostasis of hibernator cells. Understanding the adaptive mechanisms of Ca(2+) regulation in hibernating mammals may suggest new strategies to protect nonhibernator cells, including those of humans, from Ca(2+)-induced dysfunction.
107 citations
TL;DR: In CHF, marinobufagenin, a specific ligand of the α-1 subunit of Na/K ATPase and a vasoconstrictor, MBG, potentiate each other's natriuretic effects, but may offset their vasoactive actions.
Abstract: Background A reduced cardiac output in chronic heart failure (CHF) evokes renal NaCl and water retention, and, therefore, activates mechanisms promoting natriuresis. Atrial natriuretic peptide (ANP) is one such factor. We hypothesized that another NaCl sensitive endogenous natriuretic factor, i.e.,
TL;DR: Janczewski et al. as discussed by the authors showed that the effects of an application of a shorter AP to OR myocytes to reduce +dCa2+i/dtmax and the Ca2+ transient amplitude are attributable to a reduction in SR Ca2+, presumably due to a reduced ICaL integral and likely also to an increased Ca 2+ extrusion via sarcolemmal Na+-CA2+ exchanger.
TL;DR: In spite of the modest cardiac hypertrophy, the overexpressed LCCs form functional coupling with RyRs, preserving both orthograde and retrograde Ca2+ signaling between L CCs and RyRs.
Abstract: Voltage-gated L-type Ca 2+ channels (LCCs) provide Ca 2+ ingress into cardiac myocytes and play a key role in intracellular Ca 2+ homeostasis and excitation-contraction coupling. We investigated the effects of a constitutive increase of LCC density on Ca 2+ signaling in ventricular myocytes from 4-month-old transgenic (Tg) mice overexpressing the α 1 subunit of LCC in the heart. At this age, cells were somewhat hypertrophic as reflected by a 20% increase in cell capacitance relative to those from nontransgenic (Ntg) littermates. Whole cell I Ca density in Tg myocytes was elevated by 48% at 0 mV compared with the Ntg group. Single-channel analysis detected an increase in LCC density with similar conductance and gating properties. Although the overexpressed LCCs triggered an augmented SR Ca 2+ release, the “gain” function of EC coupling was uncompromised, and SR Ca 2+ content, diastolic cytosolic Ca 2+ , and unitary properties of Ca 2+ sparks were unchanged. Importantly, the enhanced I Ca entry and SR Ca 2+ release were associated with an upregulation of the Na + -Ca 2+ exchange activity (indexed by the half decay time of caffeine-elicited Ca 2+ transient) by 27% and SR Ca 2+ recycling by ≈35%. Western analysis detected a 53% increase in the Na + -Ca 2+ exchanger expression but no change in the abundance of ryanodine receptor (RyR), SERCA2, and phospholamban. Analysis of I Ca kinetics suggested that SR Ca 2+ release-dependent inactivation of LCCs remains intact in Tg cells. Thus, in spite of the modest cardiac hypertrophy, the overexpressed LCCs form functional coupling with RyRs, preserving both orthograde and retrograde Ca 2+ signaling between LCCs and RyRs. These results also suggest that a modest but sustained increase in Ca 2+ influx triggers a coordinated remodeling of Ca 2+ handling to maintain Ca 2+ homeostasis.
TL;DR: This work reports that the peak ensemble-averaged single Ca channel currents from aging heart were enhanced compared to those from young adult, or adult hearts, and suggests that the compensatory increase in the L-type Ca currents during aging is a consequence of an apparent increase in both the number, and the activity of individual L- type Ca channels.
TL;DR: The results indicate that, regardless of whether Ca(2+) sparks are single-channel or multi-channel in origin, they are generated by thermodynamically irreversible stochastic processes.
TL;DR: Age-associated deficits in chronotropic and LV systolic reserve performance occur during prolonged submaximal upright cycle ergometry, analogous to those observed during graded maximal exercise.
TL;DR: These SAGE results represent the first quantitative expression profile of AMH and serve as a reliable transcriptome reference to identify dynamic changes in cardiac gene expression and carry out quantitative PCR analyses as an independent test of transcript abundance.
TL;DR: Some aspects of the current understanding of ageing of the heart and blood vessels in the absence of apparent disease are the focus of this review.
Abstract: The incidence and prevalence of coronary disease, hypertension, heart failure and stroke increase exponentially with advancing age. While epidemiologic studies have discovered that aspects of lifestyle and genetics are risk factors for these diseases, age, per se, confers the major risk. Thus, it is reasonable to hypothesise that specific pathophysiological mechanisms that underlie these diseases become superimposed on cardiac and vascular substrates that have been modified by an ‘ageing process’, and that the latter modulates disease occurrence and severity. In order to unravel this age-disease interaction, the nature of the ageing process in the heart and vasculature requires elucidation. Some aspects of the current understanding of ageing of the heart and blood vessels in the absence of apparent disease are the focus of this review.
TL;DR: The hypothesis that multiple aspects of single L-type Ca(2+) channel behavior are interrelated and are modulated by the magnitude of the conditioning depolarization and the nature and concentration of the ions permeating the channel is supported.
TL;DR: The results suggest that &agr;1-isoform–specific NKA inhibition by the endogenous digitalis-like ligand, MBG, is substantially enhanced via NKA phosphorylation by protein kinase C.
Abstract: Several vasoconstrictor agents can regulate the phosphorylation status of the Na + -K + ATPase (NKA). We have recently demonstrated that mammalian tissues contain an endogenous bufadienolide, digitalis-like α 1 -NKA–selective ligand, marinobufagenin (MBG). Protein kinase C induces phosphorylation of the α 1 -NKA isoform, the major isoform in vascular smooth muscle, kidney, and heart cells. We hypothesized that protein kinase C–induced phosphorylation of NKA can potentiate the effect of endogenous digitalis-like ligands, and that such potentiation can occur in an NKA isoform–specific fashion. A protein kinase C activator, phorbol 12,13-diacetate (PDA, 50 nmol/L), induced phosphorylation of the α 1 -NKA from human mesenteric artery (HMA) sarcolemma and rat kidney but not that of the α 3 -NKA from rat fetal brain. In HMA sarcolemma, which predominantly contains α 1 -NKA, PDA (50 nmol/L) potentiated the NKA-inhibitory effect of MBG at the level of high-affinity binding sites (0.05±0.03 nmol/L versus 4.0±1.7 nmol/L, P 3 -NKA ligand. In isolated endothelium-denuded HMA artery rings, 50 nmol/L PDA potentiated the MBG-induced vasoconstriction (EC 50 , 17±6 nmol/L versus 150±40 nmol/L; P 1 -isoform–specific NKA inhibition by the endogenous digitalis-like ligand, MBG, is substantially enhanced via NKA phosphorylation by protein kinase C. Thus, an interaction of protein kinase C–dependent phosphorylation and MBG on NKA activity may underlie the synergistic vasoactive effects of MBG and other endogenous vasoconstrictors in hypertension.
TL;DR: A beating rate is a result of synchronization of two “ionic generators”: a set of sarcolemmal ionic channels and an array of RyRs, which, when activated, can generate rhythmic oscillations of intracellular [Ca2+].
Abstract: To the Editor:
Recent studies1–3⇓⇓ have demonstrated that local Ca2+ release during the later part of diastolic depolarization (DD) via ryanodine receptors (RyRs) in the sinoatrial nodal cells (SANCs) activates the electrogenic Na+-Ca2+ exchanger (NCX). The resultant inward current enhances the rate of DD, leading to an earlier occurrence of the subsequent action potential, ie, to an increase in the beating rate.3 Thus, a beating rate is a result of synchronization of two “ionic generators”: (1) a set of sarcolemmal ionic channels and (2) an array of RyRs, which, when activated, can generate rhythmic oscillations of intracellular [Ca2+].
Other recent studies indicate that the effect β-adrenergic receptor (β-AR) stimulation to enhance the rate of DD and to increase the beating rate requires intact RyR function.4,5⇓ Specifically, β-AR stimulation by isoproterenol recruits additional RyRs to release Ca2+ during DD; this activates …
TL;DR: It is estimated that by the year 2035, nearly one in four individuals will be 65 years of age or older, and chronic heart failure is considered the cardiovascular epidemic of the new millennium, and has been designated a national research priority.
Abstract: It is estimated that by the year 2035, nearly one in four individuals will be 65 years of age or older. Cardiovascular diseases, such as coronary artery atherosclerosis and hypertension, and resultant chronic heart failure (CHF) reach epidemic proportions among older persons and are the leading cause of mortality in the United States, accounting for over 40 percent of deaths in those aged 65 years and above. The incidence of CHF increases 9-fold in men and 11-fold in women annually between the sixth and ninth decades of life, and in persons aged 80–89 years the annual incidence of CHF is 27 per 1000 in men and 22 per 1000 in women. Prevalence rates are similar to those of those incidence. Thus, age, per se is a major risk factor, if not the major risk factor, for chronic heart failure. The clinical manifestations and prognosis of heart failure also worsen with increasing age. Heart failure accounts for more hospital admissions in the older population, than any other single condition: about 50% are readmitted within 6 months. Longterm survival is very poor with a minority surviving 5 years after diagnosis. The changing population demographic in the US virtually ensures that these numbers will become more remarkable in the coming years. In fact, CHF is the only major cardiovascular syndrome that is increasing, and it is considered the cardiovascular epidemic of the new millennium, and as a result, has been designated a national research priority.
01 Jan 2002
TL;DR: This review will present a summary of a description of apoptotic pathways in the heart, followed by ways to measure it and the experimental and clinical evidence for the role of apoptosis in cardiac disease.
Abstract: Summary. This review will present a summary of a description of apoptotic pathways in the heart, followed by ways to measure it and the experimental and clinical evidence for the role of apoptosis in cardiac disease. An evaluation of the effectiveness of pharmacological and other therapeutic interventions in the prevention of apoptosis in the context of cardiac disease will also be presented.