Showing papers by "Edward G. Lakatta published in 2003"
TL;DR: Burt et al. as mentioned in this paper showed that a substantial percentage of older, community-dwelling, otherwise healthy volunteers have evidence of inducible ischemia during combined thallium/ECG treadmill stress testing, and their prognosis is poor compared with their counterparts without subclinical coronary disease.
Abstract: Our population is aging; in the United States today there are 35 million people 65 years of age or older. That number will double by the year 2030 (Figure 1). Although epidemiological studies have discovered that lipid levels, diabetes, sedentary lifestyle, and genetic factors are risk factors for coronary disease, hypertension, congestive heart failure, and stroke, the quintessential cardiovascular diseases within our society, advancing age unequivocally confers the major risk. The incidence and prevalence of these diseases increase steeply with advancing age (Figure 2). Not only does clinically overt cardiovascular disease increase dramatically with aging, but so do subclinical or occult diseases, such as silent coronary atherosclerosis. Figure 3 (top) shows that a substantial percentage of older, community-dwelling, otherwise healthy volunteers have evidence of inducible ischemia during combined thallium/ECG treadmill stress testing, and their prognosis is poor compared with their counterparts without subclinical coronary disease (Figure 3, bottom).
Figure 1. The demographic imperative. Numbers of persons 65 years of age or older (light bars) and 85 years of age or older in the United States from 1900 through 2030. Data taken from the US Census Bureau data with projections for 2030.
Figure 2. A, Prevalence of hypertension, defined as systolic blood pressure ≥140, diastolic blood pressure ≥90, or current use of medication for purposes of treating high blood pressure. Data are based on National Health and Nutrition Examination Survey III (1988–1991) (Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension . 1995;25:305–313). B, Incidence of atherothrombotic stroke (per 1000 subjects per year) by age in men (light bars) and women (dark bars) from the Framingham Heart Study. Data from Wolf PA. Lewis A. Conner lecture: contributions of epidemiology to the …
1,842 citations
TL;DR: In this paper, the potential link between age-associated changes in the heart and clinical cardiac disease outcomes was discussed, and it was shown that left ventricular hypertrophy is associated with increased risk for coronary heart disease, sudden death, stroke, and overall cardiovascular disease.
Abstract: The preceding article in this series1 reviewed evidence as to why age-associated changes in the central arterial system are risky with respect to vascular disease. In a similar vane, the focus of this article is on the potential link between age-associated changes in the heart and clinical cardiac disease outcomes.
Left ventricular hypertrophy, heart failure, and atrial fibrillation increase dramatically with age (Figure 1). The prevalence of left ventricular hypertrophy (LVH) also increases with rising blood pressure and body mass index, a measure of obesity.2–4 Whether identified by electrocardiography or echocardiography, left ventricular hypertrophy has been shown to be associated with increased risk for coronary heart disease, sudden death, stroke, and overall cardiovascular disease.4,5
Figure 1. A, Prevalence of echocardiographic left ventricular hypertrophy (LVH) in women according to baseline age and systolic blood pressure. B, Prevalence of echocardiographic LVH in men according to baseline age and systolic blood pressure. Both A and B are reprinted from Levy D, Anderson KM, Savage DD, et al. Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors: the Framingham Heart Study. Ann Intern Med . 1988;108:7–13. C, Prevalence of heart failure by age in Framingham Heart Study men (light bars) and women (dark bars). Reprinted from Ho KK, Pinsky JL, Kannel WB, et al. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 1993;22:6A–13A. D, Prevalence of AF by age in subjects from the Framingham Heart Study. Reprinted from Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke . 1991;22:983–988.
It has been increasingly appreciated that the development of heart failure with apparently preserved systolic function, as evidenced by a “normal” ejection fraction, occurs in about one-third to one-half of older patients with heart failure.6–9 In a …
1,155 citations
TL;DR: In this article, the authors presented evidence supporting the hypothesis that age-associated changes in cardiovascular structure/function are implicated in the markedly increased risk for cardiovascular disease in older persons has been presented in the preceding 2 articles in this series.
Abstract: Evidence supporting the hypothesis that age-associated changes in cardiovascular structure/function are implicated in the markedly increased risk for cardiovascular disease in older persons has been presented in the preceding 2 articles in this series.1,2 It follows that therapies to prevent or delay cardiovascular changes that accompany aging may reduce the risk for age-associated cardiovascular diseases. Understanding the nature and effectiveness of such therapies, however, requires an understanding of heart and arterial aging at the cellular and molecular levels. Fortunately, many of the age-associated changes in cardiac and arterial structure or function that have been observed in humans also occur across a wide range of other species. Insights gained from cellular and molecular studies in these animal models may hold clues that will assist in directing future efforts toward developing novel therapies for age-associated arterial and cardiac structural and functional remodeling in humans.
Age-associated remodeling of the walls of large arteries of rodents (Table 1) and nonhuman primates is quite similar to that observed in humans and includes luminal dilation, intimal and medial thickening (Figure 1), vascular stiffening, and endothelial dysfunction.3–7
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TABLE 1. Age-Associated Aortic Changes in Rodents
Figure 1. A, Morphometric changes in the aortic wall of rats showing significant aortic intimal thickening in old rats (upper), as compared with young rats (lower). m indicates media; a, adventitia. Arrows show the internal elastic lamina. Reprinted from reference 4. B, Representative aortic sections from 2-month, 8-month, and 30-month-old rats stained with an antibody against MMP-2 and MT1-MMP, a tissue activator for MMP-2. The antibody stains brown. L indicates lumen, m, media. Reprinted from reference 7. C, Representative examples of in vivo zymography in aortae of 2-month, 8-month, and 30-month-old rats. Control (left) reactive zymograms (right) and reactive zymograms after coincubation with a reactive buffer. Inset in lower …
1,026 citations
TL;DR: A single dose of rhEPO administered around the time of acute, sustained coronary insufficiency merits consideration with respect to its therapeutic potential to limit the extent of resultant MI and contractile dysfunction.
Abstract: Erythropoietin (EPO), well known for its role in stimulation of erythropoiesis, has recently been shown to have a dramatic neuroprotective effect in animal models of cerebral ischemia, mechanical trauma of the nervous system, and excitotoxins, mainly by reducing apoptosis. We studied the effect of single systemic administration of recombinant human EPO (rhEPO) on left ventricular (LV) size and function in rats during 8 weeks after the induction of a myocardial infarction (MI) by permanent ligation of the left descending coronary artery. We found that an i.p. injection of 3,000 units/kg of rhEPO immediately after the coronary artery ligation resulted, 24 h later, in a 50% reduction of apoptosis in the myocardial area at risk. Eight weeks after the induction of MI, rats treated with rhEPO had an infarct size 15–25% of the size of that in untreated animals. The reduction in myocardial damage was accompanied by reductions in LV size and functional decline as measured by repeated echocardiography. Thus, a single dose of rhEPO administered around the time of acute, sustained coronary insufficiency merits consideration with respect to its therapeutic potential to limit the extent of resultant MI and contractile dysfunction.
314 citations
TL;DR: Age‐associated arterial remodeling and the development and progression of experimental atherosclerosis in young animals share common mechanisms, ie, MMP‐2 activation and increased Ang II signaling, which might explain, in part, the dramatically exaggerated prevalence and severity of vascular diseases with aging.
Abstract: To seek evidence that the nonhuman primate arterial wall, as it ages in the absence of atherosclerosis, exhibits alterations in pathways that are involved in the pathogenesis of experimental atherosclerosis, we assessed aortic matrix metalloproteinase-2 (MMP-2) and its regulators, ie, membrane type-1 of matrix metalloproteinase (MT1-MMP) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), and the expression of angiotensin II (Ang II), angiotensin-converting enzyme (ACE), and chymase in young (6.4+/-0.7 years) and old (20.0+/-1.9 years) male monkeys. With advancing age, (1) the intimal thickness increased 3-fold and contained numerous vascular smooth muscle cells and matrix, but no inflammatory cells; (2) the intimal MMP-2 antibody-staining fraction increased by 80% (P<0.01); (3) in situ zymography showed that MMP-2 activity, mainly confined to the intima, increased 3-fold (P<0.01); (4) the MT1-MMP antibody-staining fraction increased by 150% (P<0.001), but the TIMP-2 antibody-staining fraction did not significantly change; (5) steady levels of the mRNA-staining fraction (via in situ hybridization) for MMP-2 increased 7-fold, for MT1-MMP increased 9-fold, and for TIMP-2 increased 2-fold (all P<0.001); and (6) intimal Ang II and ACE immunofluorescence were increased 5-fold and 5.6-fold, respectively, and colocalized with MMP-2. Thus, age-associated arterial remodeling and the development and progression of experimental atherosclerosis in young animals share common mechanisms, ie, MMP-2 activation and increased Ang II signaling. This might explain, in part, the dramatically exaggerated prevalence and severity of vascular diseases with aging.
215 citations
TL;DR: It is suggested that the components of MS interact to synergistically impact vascular thickness and stiffness and that the excess cardiovascular risk associated with MS is partly mediated through the amplified alterations in these vascular properties.
137 citations
TL;DR: It is concluded that enhanced Gi signaling is selectively involved in the dysfunction of &bgr;2- but not &b gr;1-AR in failing SHR hearts and that disruption of Gi signaling by PTX or selective activation of & bgr; 2-AR/Gs signaling by fenoterol restores the blunted &b Gr;2;-AR contractile response in the failing heart.
Abstract: Background— Myocardial contractile response to β1- and β2-adrenergic receptor (AR) stimulation is severely impaired in chronic heart failure, in which Gi signaling and the ratio of β2/β1 are often increased. Because β2-AR but not β1-AR couples to Gs and Gi with the Gi coupling negating the Gs-mediated contractile response, we determined whether the heart failure–associated augmentation of Gi signaling contributes differentially to the defects of these β-AR subtypes and, if so, whether inhibition of Gi or selective activation of β2-AR/Gs by ligands restores β2-AR contractile response in the failing heart. Methods and Results— Cardiomyocytes were isolated from 18- to 24-month-old failing spontaneously hypertensive (SHR) or age-matched Wistar-Kyoto (WKY) rat hearts. In SHR cardiomyocytes, either β-AR subtype–mediated inotropic effect was markedly diminished, whereas Gi proteins and the β2/β1 ratio were increased. Disruption of Gi signaling by pertussis toxin (PTX) enabled β2- but not β1-AR to induce a full p...
125 citations
TL;DR: In future investigation of pacemaker functioning in health, disease, and disease therapies the “bar ought to be raised” to embrace the impact of cyclic variation in submembrane [Ca2+] on pacemaker function.
Abstract: While a diversity of cell types and distribution within the sinoatrial node and cell-cell interactions add complexity to a complete elucidation of the heart's pacemaker function, it has become clear that cyclic variation of submembrane [Ca2+] and activation of the Na+-Ca2+ exchanger during diastolic depolarization (DD) act in concert with ion channels to confer on sinoatrial node cells (SANCs) their status of dominance with respect to pacemaker function. Studies using confocal microscopy indicate that subsarcolemmal Ca2+ release via ryanodine receptors occurs not only in response to the action potential (AP) upstroke, but also during the DD, and this is augmented by beta-adrenergic receptor (beta-AR) stimulation. Spontaneous APs simulated by mathematical SANC models beat at a faster rate when this subsarcolemmal Ca2+ waveform measured under beta-AR stimulation is introduced into the modeling scheme. Thus, in future investigation of pacemaker functioning in health, disease, and disease therapies the "bar ought to be raised" to embrace the impact of cyclic variation in submembrane [Ca2+] on pacemaker function. The full text of this article is available at http://www.circresaha.org.
98 citations
TL;DR: The results emphasize the need to account for biological variables (HF, sex and age interactions) to elucidate genomic correlates that trigger molecular pathways responsible for the progression of HF syndromes.
Abstract: Heart failure (HF) is the end result of progressive and diverse biological adaptations within the diseased myocardium We used cDNA microarrays and quantitative PCR to examine the transcriptomes of 38 left ventricles from failing and nonfailing human myocardium After identification of a pool of putative HF-responsive candidate genes by microarrays on seven nonfailing and eight failing hearts, we used quantitative PCR and a general linear statistical model in a larger sample set (n = 34) to validate and examine the role of contributing biological variables (age and sex) We find that most HF-candidate genes (transcription factors, Cebpb, Npat; signaling molecules, Map2k3, Map4k5; extracellular matrix proteins, Lum, Cola1; and metabolic enzymes, Mars) demonstrated significant changes in gene expression; however, the majority of differences among samples depended on variables such as sex and age, and not on HF alone Some HF-responsive gene products also demonstrated highly significant changes in expression as a function of age and/or sex, but independent of HF (Ngp1, Cd163, and Npat) These results emphasize the need to account for biological variables (HF, sex and age interactions) to elucidate genomic correlates that trigger molecular pathways responsible for the progression of HF syndromes
96 citations
TL;DR: Inhibition of NO bioavailability by ADMA and a subsequent reduction in EDD contribute to the increase in BP during high-salt intake in normotensive postmenopausal PMW not receiving estrogen.
Abstract: ObjectivesAsymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO), which plays an important role in natriuresis. We determined whether changes in endothelium-dependent vasodilation (EDD) and plasma ADMA predict changes in blood pressure (BP) after salt loading in normotens
73 citations
TL;DR: An in vitro model of cultured cardiac fibroblasts from aged rats was established to examine if the response of these cells to ANG II is modified in the aged heart, to counteract the effects of augmented intracardiac ANG II production in the senescent heart, limiting fibrogenesis.
Abstract: The intracardiac ANG II-forming pathway is activated in the senescent myocardium, raising the possibility of enhanced ANG II effects on cardiac fibroblasts. This study established an in vitro model...
TL;DR: It was determined that expression of the truncated polycystin-1 fusion protein introduced, or activated, an ATP-induced Ca2+ entry pathway that was undetectable in transfection control cell lines, indicating that dysregulated Ca2- entry might promote Cl- secretion and cyst expansion in ADPKD.
Abstract: The precise steps leading from mutation of the polycystic kidney disease (PKD1) gene to the autosomal dominant polycystic kidney disease (ADPKD) phenotype remain to be established. Fluid accumulation is a requirement for cyst expansion in ADPKD, suggesting that abnormal fluid secretion into the cyst lumen might play a role in disease. In this study, we sought to establish a link between polycystin-1 (the PKD1 gene product) and ATP-stimulated Cl- secretion in renal tubule cells. To do this, we performed a whole cell patch-clamp analysis of the effects of expression of the isolated cytoplasmic COOH-terminus of polycystin-1 in stably transfected mouse cortical collecting duct cells. The truncated polycystin-1 fusion protein prolonged the duration of ATP-stimulated Cl- conductance and intracellular Ca2+ responses. Both effects were dependent on extracellular Ca2+. It was determined that expression of the truncated polycystin-1 fusion protein introduced, or activated, an ATP-induced Ca2+ entry pathway that was undetectable in transfection control cell lines. Our findings are concordant with increasing evidence for a role of polycystin-1 in cell Ca2+ homeostasis and indicate that dysregulated Ca2+ entry might promote Cl- secretion and cyst expansion in ADPKD.
TL;DR: In vitro cicletanine treatment of sarcolemma from vehicle-treated rats also desensitized Na/K-ATPase to MBG, indicating that this effect was not solely attributable to a reduction in blood pressure, and PKC-induced phosphorylation of cardiac &agr;-1 Na-K- ATPase is a likely target for cicleTanine treatment.
Abstract: Marinobufagenin (MBG), an endogenous ligand of α-1 Na/K-ATPase, becomes elevated and contributes to hypertension in NaCl-loaded Dahl-S rats (DS). Protein kinase C (PKC) phosphorylates α-1 Na/K-ATPase and increases its MBG sensitivity. Cicletanine, an antihypertensive compound with PKC-inhibitory activity, reverses MBG-induced Na/K-ATPase inhibition and vasoconstriction. We hypothesized that increased PKC levels in sodium-loaded hypertensive DS would sensitize α-1 Na/K-ATPase to MBG and that PKC inhibition by cicletanine would produce an opposite effect. We studied the effects of cicletanine on systolic blood pressure, left ventricular PKC isoforms, cardiac α-1 Na/K-ATPase levels, and sensitivity to MBG in hypertensive DS. Seven DS received 50 mg · kg −1 · d −1 cicletanine, and 7 DS received vehicle during 4 weeks of an 8% NaCl diet. Vehicle-treated rats exhibited an increase in blood pressure, left ventricular mass, MBG excretion (74±11 vs 9±1 pmol/24 h, P 50 , 0.8 vs 4.4 nmol/L, P P 50 =20 μmol/L), and phorbol diacetate–induced α-1 Na/K-ATPase phosphorylation was reduced versus vehicle-treated rats. In vitro cicletanine treatment of sarcolemma from vehicle-treated rats also desensitized Na/K-ATPase to MBG, indicating that this effect was not solely attributable to a reduction in blood pressure. Thus, PKC-induced phosphorylation of cardiac α-1 Na/K-ATPase is a likely target for cicletanine treatment.
TL;DR: Moderate or greater physical activity, exercise, and fitness variables were independently associated with less vascular stiffness, even after inclusion of heart rate, visceral fat, and other correlates of APWV.
Abstract: Although it is well established that stiff blood vessels contribute to systolic hypertension and increased cardiovascular disease with aging, risk factors for vascular stiffness are still being defined. The Health, Aging, and Body Composition study is a longitudinal investigation of the determinants of physical-functional decline in a well-functioning biracial cohort of 3,075 men and women, age 70–79, in Pittsburgh, PA, and Memphis, TN. Aortic pulse-wave velocity (APWV), an index of vascular stiffness, was measured in 2,488 participants. Self-reported physical activity and exercise habits and fitness/walking endurance were also assessed. Moderate or greater physical activity, exercise, and fitness variables were independently associated with less vascular stiffness, even after inclusion of heart rate, visceral fat, and other correlates of APWV. Physical activity’s association with APWV was particularly strong when levels of physical activity were quite low, suggesting that a minimal amount of physical act...
TL;DR: Would oestrogen replacement potentially reverse this deleterious effect of inhibition of nitric oxide bioavailability by asymmetric dimethylarginine?
Abstract: We recently published a study showing that inhibition of nitric oxide (NO) bioavailability by asymmetric dimethylarginine (ADMA), and a subsequent reduction in endothelium-dependent vasodilation (EDD), contribute to the increase in blood pressure during high-salt intake in normotensive postmenopausal women not receiving oestrogen [1]. The logical subsequent question, as outlined in the Editorial Comment to that study, is ‘would oestrogen replacement potentially reverse this deleterious effect?’ [2].
TL;DR: The bioenergetic differences are consistent with access to an additional substrate pool during &bgr;1-AR stimulation, facilitating increased energy production by oxidative phosphorylation, and under flow-limiting conditions, anaerobic glycolysis.
Abstract: Background— In the heart, striking functional differences exist after stimulation of the β1- and β2-adrenergic receptor (AR) subtypes. These may be linked to differences in metabolic response during β1- and β2-AR stimulation. Methods and Results— The relation between work and metabolism was examined during selective β1- and β2-AR stimulation (β1 and β2 groups, respectively) in the isolated perfused rat heart. Measurements were made of rate-pressure product (RPP=LV developed pressure × heart rate), phosphorus-containing metabolites, and pH by 31P nuclear magnetic resonance spectroscopy and of O2 consumption by fiber-optic oximetry. Experiments were performed under high constant flow (HCF) and under flow-limiting conditions (constant pressure, CP). Despite substantially greater RPP increases relative to baseline during β1-AR (HCF, 475%; CP, 150%) than β2-AR (HCF, 90%; CP, 72%) stimulation, the relative decrease in the intracellular energy charge relative to baseline was similar for the β1 (HCF, 49%; CP, 64%...
TL;DR: The complimentary beneficial effects of the β1AR blockers and β2AR agonists on the LV and arterial system provides rationale for their combined usage, at least with respect to amelioration of dilated ischemic cardiomyopathy.