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Pathophysiology of acute coronary syndromes in the elderly
IJCA-23172; No of Pages 5 International Journal of Cardiology xxx (2016) xxx–xxx
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Review
Pathophysiology of acute coronary syndromes in the elderly Lina Badimon a,b,⁎, Raffaele Bugiardini c, Judit Cubedo a a b c
Cardiovascular Research Center (CSIC-ICCC) and Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain Cardiovascular Research Chair UAB, Barcelona, Spain Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
a r t i c l e
i n f o
Article history: Received 21 July 2016 Accepted 28 July 2016 Available online xxxx Keywords: Ageing Elderly Acute coronary syndrome Cardiovascular disease
a b s t r a c t Elderly patients represent an important proportion of the acute coronary syndrome (ACS) population. Furthermore, this group of ACS patients is continuously growing because of the progressive ageing of the population. The ageing process implies marked changes in patient physiology that directly impact in their risk. However, there is a differential distribution in the risk of elderly patients, revealing the existence of a discrepancy between the chronological and the “biological age”. This discrepancy has highlighted the need of performing individual risk assessment in order to identify those patients at higher risk. In addition, the lack of representation of elderly patients in clinical trials leads to the underutilization of evidence-based therapies in this group of patients. All these factors influence not only the high prevalence of ACS presentation in the elderly but also their worse prognosis after suffering an ischaemic event. Herein we will explore the pathophysiological mechanisms behind the age-related changes at the vascular and the cardiac level that explain the high risk of elderly subjects of suffering ACS and their worse prognosis. © 2016 Published by Elsevier Ireland Ltd.
1. Introduction Several studies have demonstrated the link between ageing and atherothrombotic disease [1]. Indeed, the risk for cardiovascular atherothrombotic disease starts in the second decade of life and progresses over the years [2]. This association has an important social relevance given the progressive increase in life-expectancy in western societies. Specifically, European registries have revealed that elderly patients over 75 years old represent 27–34% of the whole acute coronary syndrome (ACS) population [3]. Moreover, epidemiological studies have highlighted that ageing patients are a growing cohort with over 85 year olds expected to triple by the year 2035 [4]. This changing epidemiology represents a great challenge for cardiovascular medicine as elderly patients are frequently underrepresented in clinical trials leading to uncertainty about the efficacy and safety of some treatments. Indeed, patients aged ≥75 years account for only 10% of patients enrolled in clinical trials [5]. As a result elderly patients are less likely to receive evidence-based therapies [6]. This fact, together with their higher baseline risk, contributes to the poorer outcome of elderly patients after suffering an ACS when compared to younger individuals [5]. Furthermore, it has been shown that ageing does not only increase the prevalence of clinically overt cardiovascular disease (CVD) but also that of subclinical cardiovascular disease such as silent coronary atherosclerosis. There
⁎ Corresponding author at: Cardiovascular Research Center, c/Sant Antoni MªClaret 167, 08025 Barcelona, Spain. E-mail address: [email protected] (L. Badimon).
are evidences of inducible ischaemia during combined thallium/ECG treadmill stress testing in an important percentage of healthy elderly volunteers with a poorer prognosis compared with their counterparts without subclinical coronary artery disease (CAD) [7]. Several hypotheses have been postulated to explain this progressive increase in the prevalence of CVD with ageing: 1) ageing itself is synonymous with disease state; 2) there is an increased prevalence of other cardiovascular risk factors and increased time of exposure to them in older persons; and 3) the ageing process implies changes in the structure and function of the cardiovascular system providing a different scenario in which specific pathophysiological mechanisms become superimposed [8]. What is true is that the interaction between age-related changes and pathophysiological disease mechanisms determines not only CVD presentation in the elderly, but also their prognosis after suffering an ischaemic event.
2. Pathophysiological mechanisms associated to ACS presentation in the elderly Independently of the existence of other co-morbidities such as the presence of additional risk factors, ageing is directly associated to changes at different levels (Fig. 1) that contribute to the higher risk of elderly patients of suffering ACS. The increase in CVD prevalence with ageing has been attributed to several age-related changes such as changes in the vascular wall elasticity, the coagulation and haemostatic system, endothelial dysfunction and an impaired regenerative capacity [9,10].
http://dx.doi.org/10.1016/j.ijcard.2016.07.205 0167-5273/© 2016 Published by Elsevier Ireland Ltd.
Please cite this article as: L. Badimon, et al., Pathophysiology of acute coronary syndromes in the elderly, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.07.205
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L. Badimon et al. / International Journal of Cardiology xxx (2016) xxx–xxx
Fig. 1. Pathophysiological mechanisms associated to the high cardiovascular risk in the elderly. The ageing process is associated to changes at different levels: increased low-density lipoprotein (LDL) oxidation and decreased atheroprotective properties of high-density lipoproteins (HDL); pro-inflammatory state; endothelial dysfunction; disequilibrium in extracellular matrix synthesis and degradation; enhanced coagulation and impaired fibrinolysis; changes in cardiac calcium (Ca2+) homeostasis; mitochondrial dysfunction with increased reactive oxygen species (ROS) generation and decreased ATP production; and impaired cardiac regenerative capacity.
2.1.1. Coagulation and haemostasis During last years several studies have been focused on the analysis of the coagulation system among older adults [1,11]. Indeed, increased plasma concentrations of several clotting factors have been found in elderly individuals such as fibrinogen [12], factors VII, VIII, IX, X and XII [13–15], von Willebrand factor [16], high molecular-weight kininogen, and prekallikrein [17]. This altered haemostatic system has not only a direct impact on cardiovascular risk but also on the cognitive status in the elderly. Thus, a link between an abnormal clotting system and cognitive deficits has been suggested in part due to the association between elevated fibrinogen levels with cognitive decline [18] and increased risk of Alzheimer's disease [19]. Fibrinogen levels had been also associated to the incidence of dementia in the Rotterdam study [19], and markers of thrombin generation have been associated to an increased risk of cognitive decline [20]. Coagulation factor VIII and plasminogen activator inhibitor 1 (PAI-1) levels were related to the age-related changes in the haemostatic system and microinfarct in vascular dementia [21]. Indeed, PAI-1 levels have been described as a key molecule linking fibrinolysis and ageing [22]. Furthermore, in a recent study, we have found that healthy octogenarian subjects (with preserved functional and cognitive status) without a previous manifestation of CVD have a coordinated decrease in two important anti-fibrinolytic proteins when compared to octogenarians with an un-healthy phenotype (functional and cognitive decline and malnutrition) including those with CVD [23]. Specifically, we have found that plasma levels of alpha-2-antiplasmin, main serine-protease inhibitor controlling the dissolution of fibrin polymers into soluble fragments by inhibiting plasmin activity [24], and coagulation factor XIII were lower in healthy octogenarians without a previous manifestation of CVD when compared to those with an un-healthy phenotype and CVD event presentation. Coagulation factor XIII is able to alter the rheological properties of fibrin by promoting intramolecular cross-links between fibrin strands stabilising fibrin clot and delaying the fibrinolytic process [25]. This antifibrinolytic activity of coagulation factor XIII is due, not only to its ability to cross-link alpha-2-antiplasmin into the fibrin network decreasing the proteolytic vulnerability of the fibrin clot, but also to its influence on fibrin formation leading to the formation of clots with
an increased fibre density [26]. It has been shown that depletion of coagulation factor XIII or alpha-2-antiplasmin results in the same increase in the thrombi lysis rate [27]. Importantly, we have described that the increased levels of antifibrinolytic proteins found in un-healthy octogenarians with a previous CVD event are associated with the formation of denser fibrin clots with a decreased fibrinolytic response. Moreover, coagulation factor XIII-B chain levels are associated with the nutritional state and the ability of performing daily life activities measured by the Lawton–Brody index, which has been reported to be an independent predictor of 3-year mortality in the Octabaix prospective study [28]. Changes in alpha-2-antiplasmin are more associated to CVD event presentation while changes in coagulation factor XIII are more significantly related to cognitive impairment. Therefore, the combination of both anti-fibrinolytic proteins could afford information about the global health status in the elderly in a specific time point explaining not only the risk of suffering both, atherothrombotic disease and cognitive decline, but probably also the worse prognosis of this subgroup of patients after suffering an ischaemic event. 2.2. Inflammation Several studies have reported a pro-inflammatory state in the elderly. In fact, increased levels of different inflammatory markers, such as Creactive protein (CRP) or interleukine-6 (IL-6) have been described in elderly subjects [29]. This enhanced inflammatory response has been related to a disproportional reactivity of senescent immune cells that release huge amounts of pro-inflammatory cytokines leading to an exaggerated immune response [30]. Furthermore, this pro-inflammatory state can contribute to alter the haemostatic equilibrium by affecting fibrinolysis. The association between increased CRP levels and cardiovascular risk has been extensively studied and demonstrated [31]. Even more, increased levels of CRP have been independently associated with unfavourable outcomes in ACS patients [32]. Therefore, the presence of a pro-inflammatory state in the elderly may contribute, not only to the higher prevalence of ACS in this group of patients, but also to a worse prognosis after suffering an acute event. Indeed, it has been shown that patients N 75 years that suffer a major bleeding event
Please cite this article as: L. Badimon, et al., Pathophysiology of acute coronary syndromes in the elderly, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.07.205
L. Badimon et al. / International Journal of Cardiology xxx (2016) xxx–xxx
following percutaneous coronary intervention (PCI) have higher CRP levels than patients without bleeding [33]. 2.3. Lipid profile Ageing has been associated with a decrease in the atheroprotective properties of high-density lipoprotein (HDL). Specifically, a reduced capacity of HDL from elderly patients to promote cholesterol efflux and to inhibit LDL oxidation has been described [34,35]. Moreover, proteomic and lipidomic analyses have revealed compositional changes in HDL from elderly subjects with enrichment in several acute-phase proteins and factors involved in complement activation [36]. Among them, elderly patients show an important increase in the HDL levels of serum amyloid A (SAA). Importantly, this protein has been directly related to the shift towards a pro-inflammatory profile of HDL in patients after suffering an acute myocardial infarction (MI) [37]. Thus, the increase in SAA levels in the elderly could exacerbate their pro-inflammatory profile. Additionally, elderly patients also show a decreased HDL content of paraoxonase-1 (PON1) when compared to younger individuals [35,38]. This is important, as the Caerphilly Prospective Study demonstrated that low PON1 levels predict the occurrence of ACS [39]. Therefore, the decrease in PON1 content in HDL of elderly subjects might contribute to the higher risk of suffering ACS in this group of patients.
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2.6. Impaired cardiac metabolism and regenerative capacity Together with changes in myocardial structure, ageing is also associated with an altered calcium homeostasis in cardiomyocytes. Specifically, there is impaired calcium recycling and reduced calcium sensitivity of myofilament proteins that can lead to impaired cardiomyocyte relaxation [56]. Moreover, ageing has been associated to an excessive formation of mitochondrial reactive oxygen species (ROS) and as a consequence to the damage of mitochondrial DNA and redox-sensitive mitochondrial proteins. This in turn contributes to mitochondrial dysfunction and further increases ROS production. Indeed, mitochondria in aged cardiomyocytes are usually enlarged with swelling, loss of cristae, and destruction of inner membranes [57]. But the key element in the age-related mitochondrial dysfunction is the decrease in ATP production [58] that severely hampers cardiac function because of the important energy demand of this organ. There are some studies suggesting that in the aged heart, cardiac stem cells may have impaired regenerative capacity, either by intrinsic senescence of stem cells or by the extrinsic hostile milieu associated to ageing [59]. Indeed, it has been shown that elderly hearts exhibit a reduced turnover rate of cardiomyocytes when compared to young adult hearts (0.45% and 1%, respectively) [60]. 3. Vascular and cardiac impact of ageing
2.4. Endothelial dysfunction Several clinical studies have demonstrated that ageing induces a progressive decrease in endothelium-dependent vasodilatation [40–42]. This decline is mainly due to ageing-associated changes in 3 main endothelium-derived vasodilators, NO, prostacyclin and the endothelium-derived hyperpolarizing factor (EDHF), and leads to an enhanced reactivity to vasoconstrictors [43,44]. However, despite the attenuated generation of endothelial NO, and excessive constitutive generation of NO by vascular smooth muscle cells (VSMC) has been also proposed to impact endothelial ageing. Indeed, an age-related increased expression of the inducible NO synthase (iNOS) has been reported [45]. This iNOS induction further promotes oxidative stress within the vascular wall [46]. In addition, ageing increases the release of endothelin-1 (ET-1), a potent vascular growth factor, from endothelial cells [47,48]. This increase in ET-1 levels with ageing could affect to the evolution of elderly patients after suffering an ACS as it has been shown that high ET-1 levels after MI are associated with the presence of microvascular obstruction and lower myocardial salvage index [49], probably contributing to the worse prognosis of elderly patients post-ACS. Indeed, it has been shown that the administration of an ET-1 receptor blocker during primary PCI in patients with a ST-elevation MI (STEMI) may improve tissue-level perfusion and left ventricular ejection fraction (LVEF) [50]. 2.5. Impaired extracellular matrix homeostasis The maintenance of a correct balance between extracellular matrix (ECM) synthesis and degradation is essential for normal cardiac structure and function. Age is related to a disequilibrium in this balance leading to changes in the amount and distribution of ECM components and thus to what is known as age-dependent myocardial remodelling [51]. Specifically, a study combining electron microscopy and histochemical analysis of human hearts revealed an increase in collagen types I and III with age [52]. This fact could favour the development of diastolic heart failure (HF) in the elderly [53]. Indeed, increasing age has been associated with a higher incidence of HF [54], probably due to, at least in part, this deregulation of ECM homeostasis. Furthermore this agerelated progressive alteration of myocardial structure is an important risk factor for cardiac morbidity and mortality [55], directly affecting the prognosis of elderly patients after suffering an ACS.
All these age-related changes dramatically alter the homeostatic balance favouring tissue damage and hampering tissue repair mainly affecting at a vascular and a cardiac level (Fig. 2) [55]. It is known that ageing is accompanied by changes in the vascular structure and function, especially in the large arteries, increasing the probability of suffering an ACS [61]. These changes include: phenotypic alterations in endothelial cells (EC) and VSMC, collagen deposition, and vascular wall thickening; and finally promoting arterial stiffness [62,63]. Interestingly, a similar age-associated vascular remodelling has been observed in large arteries of rodent and nonhuman primates [64,65]. Cross-sectional studies have demonstrated an increased wall thickening, dilatation and stiffness in large arteries with ageing [66], leading to an increase in arterial blood pressure [67]. Importantly, the presence of vascular abnormalities, at both micro and macrovascular level, evidenced by non-invasive tests of different organs such as the brain or the kidney, or in the carotid and peripheral arteries has been linked to functional decline, frailty, disability, and mortality in the elderly [68–71]. In the context of macrovascular abnormalities, coronary angiogram (CA), which is one of the most commonly used measurements, plays a key role for risk stratification in CAD [72]. Patients aged N 85 years have more complex vascular lesions with a higher rate of calcified, tortuous and ostial lesions, multi-vessel disease and left main stenosis [73]. It has been recently shown that CA has a prognostic value in patients aged ≥65 years [74]. Specifically, it has been shown that patients with a normal CA have a higher 5-year survival rate (96%) than patients with a CA showing b 30% diameter stenosis (85%). This is even apparent at long-term follow-up with 61% 15-year survival rate in patients with a normal CA and 55% in patients with b30% diameter stenosis. At the cardiac level, ageing is characterized by a loss of functional cells and a decline in the regenerative capacity of the myocardium leading to alterations in the structure and function of the heart [75]. These age-related cardiac changes induce an increase in left ventricular (LV) wall thickness, alterations in the diastolic filling pattern, impaired LV ejection and heart rate reserve capacity, and altered heart rhythm, leading to an increased prevalence of LV hypertrophy, HF, and atrial fibrillation in the elderly [55]. Specifically, changes in LV function are attributable to LV wall thickness and to the alterations in calcium homeostasis that induce a residual myofilament calcium-derived activation from the preceding systole. This ageing increase in LV hypertrophy contributes to the higher prevalence of ischaemic heart disease
Please cite this article as: L. Badimon, et al., Pathophysiology of acute coronary syndromes in the elderly, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.07.205
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Fig. 2. Impact of age-related changes at vascular and cardiac level. Ageing induces changes in the structure and function in the vasculature and the myocardium dramatically increasing the probability of suffering an ACS in the elderly and predisposing these patients to a worse prognosis after the event.
(IHD) in the elderly as it has been directly associated with an increased risk for coronary heart disease (CHD), sudden death, and overall CVD [76,77]. All these age-associated changes in vascular and cardiac structure and function have a direct impact on the occurrence, presentation, and manifestations of heart disease in the elderly. 4. Concluding remarks The cardiovascular system undergoes multiple changes with age. Despite the improvements in our understanding of the ageing process and in the management of elderly ACS patients, this growing subgroup still have lower rates of survival. Age-related decline in organ function increases cardiovascular risk. The unpredictable interaction between age-related changes in organ functions and pharmacokinetics and pharmacodynamics may result in untoward reactions to medications and poorer outcomes. There is a clear need to perform clinical trials designed to specifically study the elderly population, or at least to include all age ranges in the enrolment of clinical trials in order to obtain evidences of the suitability to translate the results into the clinical practice in this specific group of patients.
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[5]
[6]
[7]
[8]
[9] [10] [11]
[12]
Conflict of interest
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The authors report no relationships that could be construed as a conflict of interest.
[14] [15]
Acknowledgement [16]
This work has been supported by grants from the Spanish Ministry of Economy and Competitiveness of Science [SAF2013-42962-R to L.B.]; and Institute of Health Carlos III, ISCIII [TERCEL RD12/0019/0026 and RIC RD12/0042/0027 to L.B.] Spain. We thank FIC-Fundacion Jesús Serra, Barcelona, Spain, for their continuous support.
[17]
References
[19]
[1] G.H. Tofler, J. Massaro, D. Levy, M. Mittleman, P. Sutherland, I. Lipinska, et al., Relation of the prothrombotic state to increasing age (from the Framingham Offspring Study), Am. J. Cardiol. 96 (2005) 1280–1283. [2] G.S. Berenson, S.R. Srnivasan, Bogalusa Heart Study G, cardiovascular risk factors in youth with implications for aging: the Bogalusa Heart Study, Neurobiol. Aging 26 (2005) 303–307. [3] H. Wienbergen, A.K. Gitt, R. Schiele, C. Juenger, T. Heer, C. Vogel, et al., Different treatments and outcomes of consecutive patients with non-ST-elevation myocardial
[18]
[20]
[21]
infarction depending on initial electrocardiographic changes (results of the Acute Coronary Syndromes [ACOS] Registry), Am. J. Cardiol. 93 (2004) 1543–1546. C. McCune, P. McKavanagh, I.B. Menown, A review of current diagnosis, investigation, and management of acute coronary syndromes in elderly patients, Cardiol. Ther. 4 (2015) 95–116. K.P. Alexander, L.K. Newby, C.P. Cannon, P.W. Armstrong, W.B. Gibler, M.W. Rich, et al., Acute coronary care in the elderly, part I: non-ST-segment-elevation acute coronary syndromes: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology: in collaboration with the Society of Geriatric Cardiology, Circulation 115 (2007) 2549–2569. M.J. Zaman, S. Stirling, L. Shepstone, A. Ryding, M. Flather, M. Bachmann, et al., The association between older age and receipt of care and outcomes in patients with acute coronary syndromes: a cohort study of the Myocardial Ischaemia National Audit Project (MINAP), Eur. Heart J. 35 (2014) 1551–1558. J.L. Fleg, G. Gerstenblith, A.B. Zonderman, L.C. Becker, M.L. Weisfeldt, P.T. Costa Jr., et al., Prevalence and prognostic significance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardiography in asymptomatic volunteers, Circulation 81 (1990) 428–436. E.G. Lakatta, D. Levy, Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part I: aging arteries: a “set up” for vascular disease, Circulation 107 (2003) 139–146. R. Abbate, D. Prisco, C. Rostagno, M. Boddi, G.F. Gensini, Age-related changes in the hemostatic system, Int. J. Clin. Lab. Res. 23 (1993) 1–3. R.P. Brandes, I. Fleming, R. Busse, Endothelial aging, Cardiovasc. Res. 66 (2005) 286–294. H.J. Cohen, T. Harris, C.F. Pieper, Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly, Am. J. Med. 114 (2003) 180–187. W.B. Kannel, P.A. Wolf, W.P. Castelli, R.B. D'Agostino, Fibrinogen and risk of cardiovascular disease. The Framingham Study, JAMA 258 (1987) 1183–1186. L. Balleisen, J. Bailey, P.H. Epping, H. Schulte, J. van de Loo, Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population: I. Baseline data on the relation to age, gender, body-weight, smoking, alcohol, pill-using, and menopause, Thromb. Haemost. 54 (1985) 475–479. K.A. Bauer, B.L. Kass, H. ten Cate, J.J. Hawiger, R.D. Rosenberg, Factor IX is activated in vivo by the tissue factor mechanism, Blood 76 (1990) 731–736. R. Coppola, P. Cristilli, M. Cugno, R.A. Ariens, D. Mari, P.M. Mannucci, Measurement of activated factor XII in health and disease, Blood Coagul. Fibrinolysis 7 (1996) 530–535. M.G. Conlan, A.R. Folsom, A. Finch, C.E. Davis, P. Sorlie, G. Marcucci, et al., Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study, Thromb. Haemost. 70 (1993) 380–385. D. Mari, P.M. Mannucci, R. Coppola, B. Bottasso, K.A. Bauer, R.D. Rosenberg, Hypercoagulability in centenarians: the paradox of successful aging, Blood 85 (1995) 3144–3149. G. Xu, H. Zhang, S. Zhang, X. Fan, X. Liu, Plasma fibrinogen is associated with cognitive decline and risk for dementia in patients with mild cognitive impairment, Int. J. Clin. Pract. 62 (2008) 1070–1075. M. van Oijen, J.C. Witteman, A. Hofman, P.J. Koudstaal, M.M. Breteler, Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia, Stroke 36 (2005) 2637–2641. D.J. Stott, M. Robertson, A. Rumley, P. Welsh, N. Sattar, C.J. Packard, et al., Activation of hemostasis and decline in cognitive function in older people, Arterioscler. Thromb. Vasc. Biol. 30 (2010) 605–611. J. Gallacher, A. Bayer, G. Lowe, M. Fish, J. Pickering, S. Pedro, et al., Is sticky blood bad for the brain?: hemostatic and inflammatory systems and dementia in the Caerphilly Prospective Study, Arterioscler. Thromb. Vasc. Biol. 30 (2010) 599–604.
Please cite this article as: L. Badimon, et al., Pathophysiology of acute coronary syndromes in the elderly, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.07.205
L. Badimon et al. / International Journal of Cardiology xxx (2016) xxx–xxx [22] M. Cesari, M. Pahor, R.A. Incalzi, Plasminogen activator inhibitor-1 (PAI-1): a key factor linking fibrinolysis and age-related subclinical and clinical conditions, Cardiovasc. Ther. 28 (2010) e72–e91. [23] J. Cubedo, T. Padro, E. Pena, R. Aledo, F. Formiga, A. Ferrer, et al., High levels of antifibrinolytic proteins are found in plasma of older octogenarians with cardiovascular disease and cognitive decline, J. Am. Coll. Cardiol. 65 (2015) 2667–2669. [24] F.J. Castellino, V.A. Ploplis, Structure and function of the plasminogen/plasmin system, Thromb. Haemost. 93 (2005) 647–654. [25] L. Shen, L. Lorand, Contribution of fibrin stabilization to clot strength. Supplementation of factor XIII-deficient plasma with the purified zymogen, J. Clin. Invest. 71 (1983) 1336–1341. [26] E.L. Hethershaw, A.L.C. La Corte, C. Duval, M. Ali, P.J. Grant, R.A. Ariens, et al., The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis, J. Thromb. Haemost. 12 (2014) 197–205. [27] S.R. Fraser, N.A. Booth, N.J. Mutch, The antifibrinolytic function of factor XIII is exclusively expressed through alpha(2)-antiplasmin cross-linking, Blood 117 (2011) 6371–6374. [28] F. Formiga, A. Ferrer, D. Chivite, A. Montero, H. Sanz, R. Pujol, et al., Utility of geriatric assessment to predict mortality in the oldest old: the Octabaix study 3-year followup, Rejuvenation Res. 16 (2013) 279–284. [29] T. Berge, S.R. Ulimoen, S. Enger, H. Arnesen, I. Seljeflot, A. Tveit, Impact of atrial fibrillation on inflammatory and fibrinolytic variables in the elderly, Scand. J. Clin. Lab. Invest. (2013). [30] W.M. Freitas, L.S. Carvalho, F.A. Moura, A.C. Sposito, Atherosclerotic disease in octogenarians: a challenge for science and clinical practice, Atherosclerosis 225 (2012) 281–289. [31] K. Tuomisto, P. Jousilahti, J. Sundvall, P. Pajunen, V. Salomaa, C-reactive protein, interleukin-6 and tumor necrosis factor alpha as predictors of incident coronary and cardiovascular events and total mortality. A population-based, prospective study, Thromb. Haemost. 95 (2006) 511–518. [32] S.K. James, P. Armstrong, E. Barnathan, R. Califf, B. Lindahl, A. Siegbahn, et al., Troponin and C-reactive protein have different relations to subsequent mortality and myocardial infarction after acute coronary syndrome: a GUSTO-IV substudy, J. Am. Coll. Cardiol. 41 (2003) 916–924. [33] G. Ndrepepa, F.J. Neumann, S. Schulz, M. Fusaro, S. Cassese, R.A. Byrne, et al., Incidence and prognostic value of bleeding after percutaneous coronary intervention in patients older than 75 years of age, Catheter. Cardiovasc. Interv. 83 (2014) 182–189. [34] H. Berrougui, M. Isabelle, M. Cloutier, G. Grenier, A. Khalil, Age-related impairment of HDL-mediated cholesterol efflux, J. Lipid Res. 48 (2007) 328–336. [35] L. Jaouad, C. de Guise, H. Berrougui, M. Cloutier, M. Isabelle, T. Fulop, et al., Agerelated decrease in high-density lipoproteins antioxidant activity is due to an alteration in the PON1's free sulfhydryl groups, Atherosclerosis 185 (2006) 191–200. [36] M. Holzer, M. Trieb, V. Konya, C. Wadsack, A. Heinemann, G. Marsche, Aging affects high-density lipoprotein composition and function, Biochim. Biophys. Acta 1831 (2013) 1442–1448. [37] K. Alwaili, D. Bailey, Z. Awan, S.D. Bailey, I. Ruel, A. Hafiane, et al., The HDL proteome in acute coronary syndromes shifts to an inflammatory profile, Biochim. Biophys. Acta 1821 (2012) 405–415. [38] I. Seres, G. Paragh, E. Deschene, T. Fulop Jr., A. Khalil, Study of factors influencing the decreased HDL associated PON1 activity with aging, Exp. Gerontol. 39 (2004) 59–66. [39] B. Mackness, P. Durrington, P. McElduff, J. Yarnell, N. Azam, M. Watt, et al., Low paraoxonase activity predicts coronary events in the Caerphilly Prospective Study, Circulation 107 (2003) 2775–2779. [40] K. Egashira, T. Inou, Y. Hirooka, H. Kai, M. Sugimachi, S. Suzuki, et al., Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans, Circulation 88 (1993) 77–81. [41] N. Singh, S. Prasad, D.R. Singer, R.J. MacAllister, Ageing is associated with impairment of nitric oxide and prostanoid dilator pathways in the human forearm, Clin. Sci. (Lond.) 102 (2002) 595–600. [42] D. Lyons, S. Roy, M. Patel, N. Benjamin, C.G. Swift, Impaired nitric oxide-mediated vasodilatation and total body nitric oxide production in healthy old age, Clin. Sci. (Lond.) 93 (1997) 519–525. [43] Y. Shirasaki, C. Su, T.J. Lee, P. Kolm, W.H. Cline Jr., G.A. Nickols, Endothelial modulation of vascular relaxation to nitrovasodilators in aging and hypertension, J. Pharmacol. Exp. Ther. 239 (1986) 861–866. [44] R. Busse, I. Fleming, Regulation of endothelium-derived vasoactive autacoid production by hemodynamic forces, Trends Pharmacol. Sci. 24 (2003) 24–29. [45] A. Csiszar, Z. Ungvari, J.G. Edwards, P. Kaminski, M.S. Wolin, A. Koller, et al., Aginginduced phenotypic changes and oxidative stress impair coronary arteriolar function, Circ. Res. 90 (2002) 1159–1166. [46] Y. Xia, J.L. Zweier, Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages, Proc. Natl. Acad. Sci. U. S. A. 94 (1997) 6954–6958. [47] W. Goettsch, T. Lattmann, K. Amann, M. Szibor, H. Morawietz, K. Munter, et al., Increased expression of endothelin-1 and inducible nitric oxide synthase isoform II in aging arteries in vivo: implications for atherosclerosis, Biochem. Biophys. Res. Commun. 280 (2001) 908–913.
5
[48] T. Kumazaki, R. Wadhwa, S.C. Kaul, Y. Mitsui, Expression of endothelin, fibronectin, and mortalin as aging and mortality markers, Exp. Gerontol. 32 (1997) 95–103. [49] X. Freixa, M. Heras, J.T. Ortiz, S. Argiro, E. Guasch, A. Doltra, et al., Usefulness of endothelin-1 assessment in acute myocardial infarction, Rev. Esp. Cardiol. 64 (2011) 105–110. [50] C. Adlbrecht, M. Andreas, B. Redwan, K. Distelmaier, J. Mascherbauer, A. Kaider, et al., Systemic endothelin receptor blockade in ST-segment elevation acute coronary syndrome protects the microvasculature: a randomised pilot study, EuroIntervention 7 (2012) 1386–1395. [51] B. Swynghedauw, Molecular mechanisms of myocardial remodeling, Physiol. Rev. 79 (1999) 215–262. [52] A.B. Mendes, M. Ferro, B. Rodrigues, M.R. Souza, R.C. Araujo, R.R. Souza, Quantification of left ventricular myocardial collagen system in children, young adults, and the elderly, Med. B. Aires 72 (2012) 216–220. [53] R. Martos, J. Baugh, M. Ledwidge, C. O'Loughlin, C. Conlon, A. Patle, et al., Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction, Circulation 115 (2007) 888–895. [54] R.H. Mehta, S.S. Rathore, M.J. Radford, Y. Wang, Y. Wang, H.M. Krumholz, Acute myocardial infarction in the elderly: differences by age, J. Am. Coll. Cardiol. 38 (2001) 736–741. [55] E.G. Lakatta, D. Levy, Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part II: the aging heart in health: links to heart disease, Circulation 107 (2003) 346–354. [56] Y.A. Chiao, P.S. Rabinovitch, The aging heart, Cold Spring Harb. Perspect. Med. 5 (2015) a025148. [57] A. Terman, U.T. Brunk, Myocyte aging and mitochondrial turnover, Exp. Gerontol. 39 (2004) 701–705. [58] C. Mammucari, R. Rizzuto, Signaling pathways in mitochondrial dysfunction and aging, Mech. Ageing Dev. 131 (2010) 536–543. [59] V.L. Ballard, J.M. Edelberg, Stem cells and the regeneration of the aging cardiovascular system, Circ. Res. 100 (2007) 1116–1127. [60] O. Bergmann, R.D. Bhardwaj, S. Bernard, S. Zdunek, F. Barnabe-Heider, S. Walsh, et al., Evidence for cardiomyocyte renewal in humans, Science 324 (2009) 98–102. [61] M.E. Safar, Arterial aging–hemodynamic changes and therapeutic options, Nat. Rev. Cardiol. 7 (2010) 442–449. [62] M.G. Scioli, A. Bielli, G. Arcuri, A. Ferlosio, A. Orlandi, Ageing and microvasculature, Vasc. Cell. 6 (2014) 19. [63] H.Y. Lee, B.H. Oh, Aging and arterial stiffness, Circ. J. 74 (2010) 2257–2262. [64] Z. Li, J. Froehlich, Z.S. Galis, E.G. Lakatta, Increased expression of matrix metalloproteinase-2 in the thickened intima of aged rats, Hypertension 33 (1999) 116–123. [65] K. Asai, R.K. Kudej, Y.T. Shen, G.P. Yang, G. Takagi, A.B. Kudej, et al., Peripheral vascular endothelial dysfunction and apoptosis in old monkeys, Arterioscler. Thromb. Vasc. Biol. 20 (2000) 1493–1499. [66] E.G. Lakatta, Cardiovascular regulatory mechanisms in advanced age, Physiol. Rev. 73 (1993) 413–467. [67] J.D. Pearson, C.H. Morrell, L.J. Brant, P.K. Landis, J.L. Fleg, Age-associated changes in blood pressure in a longitudinal study of healthy men and women, J. Gerontol. A Biol. Sci. Med. Sci. 52 (1997) M177–M183. [68] D. Inzitari, G. Pracucci, A. Poggesi, G. Carlucci, F. Barkhof, H. Chabriat, et al., Changes in white matter as determinant of global functional decline in older independent outpatients: three year follow-up of LADIS (leukoaraiosis and disability) study cohort, BMJ 339 (2009) b2477. [69] D.H. Kim, A.B. Newman, I. Hajjar, E.S. Strotmeyer, R. Klein, E. Newton, et al., Retinal microvascular signs and functional loss in older persons: the cardiovascular health study, Stroke 42 (2011) 1589–1595. [70] M.J. Sarnak, R. Katz, L.F. Fried, D. Siscovick, B. Kestenbaum, S. Seliger, et al., Cystatin C and aging success, Arch. Intern. Med. 168 (2008) 147–153. [71] A.B. Newman, J.S. Gottdiener, M.A. McBurnie, C.H. Hirsch, W.J. Kop, R. Tracy, et al., Associations of subclinical cardiovascular disease with frailty, J. Gerontol. A Biol. Sci. Med. Sci. 56 (2001) M158–M166. [72] R. Bugiardini, O. Manfrini, G.M. De Ferrari, Unanswered questions for management of acute coronary syndrome: risk stratification of patients with minimal disease or normal findings on coronary angiography, Arch. Intern. Med. 166 (2006) 1391–1395. [73] V.B. Shanmugam, R. Harper, I. Meredith, Y. Malaiapan, P.J. Psaltis, An overview of PCI in the very elderly, J. Geriatr. Cardiol. 12 (2015) 174–184. [74] A.E. Moreyra, M. Charalambous, N.M. Cosgrove, S. Rajaei, K. Cullen, J.Q. Cheng, et al., Usefulness of a normal coronary angiogram in patients aged ≥65 years to foretell survival, Am. J. Cardiol. 116 (2015) 1487–1494. [75] D.F. Dai, T. Chen, S.C. Johnson, H. Szeto, P.S. Rabinovitch, Cardiac aging: from molecular mechanisms to significance in human health and disease, Antioxid. Redox Signal. 16 (2012) 1492–1526. [76] D. Levy, R.J. Garrison, D.D. Savage, W.B. Kannel, W.P. Castelli, Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study, N. Engl. J. Med. 322 (1990) 1561–1566. [77] A.W. Haider, M.G. Larson, E.J. Benjamin, D. Levy, Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death, J. Am. Coll. Cardiol. 32 (1998) 1454–1459.
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Review
Pathophysiology of acute coronary syndromes in the elderly Lina Badimon a,b,⁎, Raffaele Bugiardini c, Judit Cubedo a a b c
Cardiovascular Research Center (CSIC-ICCC) and Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain Cardiovascular Research Chair UAB, Barcelona, Spain Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
a r t i c l e
i n f o
Article history: Received 21 July 2016 Accepted 28 July 2016 Available online xxxx Keywords: Ageing Elderly Acute coronary syndrome Cardiovascular disease
a b s t r a c t Elderly patients represent an important proportion of the acute coronary syndrome (ACS) population. Furthermore, this group of ACS patients is continuously growing because of the progressive ageing of the population. The ageing process implies marked changes in patient physiology that directly impact in their risk. However, there is a differential distribution in the risk of elderly patients, revealing the existence of a discrepancy between the chronological and the “biological age”. This discrepancy has highlighted the need of performing individual risk assessment in order to identify those patients at higher risk. In addition, the lack of representation of elderly patients in clinical trials leads to the underutilization of evidence-based therapies in this group of patients. All these factors influence not only the high prevalence of ACS presentation in the elderly but also their worse prognosis after suffering an ischaemic event. Herein we will explore the pathophysiological mechanisms behind the age-related changes at the vascular and the cardiac level that explain the high risk of elderly subjects of suffering ACS and their worse prognosis. © 2016 Published by Elsevier Ireland Ltd.
1. Introduction Several studies have demonstrated the link between ageing and atherothrombotic disease [1]. Indeed, the risk for cardiovascular atherothrombotic disease starts in the second decade of life and progresses over the years [2]. This association has an important social relevance given the progressive increase in life-expectancy in western societies. Specifically, European registries have revealed that elderly patients over 75 years old represent 27–34% of the whole acute coronary syndrome (ACS) population [3]. Moreover, epidemiological studies have highlighted that ageing patients are a growing cohort with over 85 year olds expected to triple by the year 2035 [4]. This changing epidemiology represents a great challenge for cardiovascular medicine as elderly patients are frequently underrepresented in clinical trials leading to uncertainty about the efficacy and safety of some treatments. Indeed, patients aged ≥75 years account for only 10% of patients enrolled in clinical trials [5]. As a result elderly patients are less likely to receive evidence-based therapies [6]. This fact, together with their higher baseline risk, contributes to the poorer outcome of elderly patients after suffering an ACS when compared to younger individuals [5]. Furthermore, it has been shown that ageing does not only increase the prevalence of clinically overt cardiovascular disease (CVD) but also that of subclinical cardiovascular disease such as silent coronary atherosclerosis. There
⁎ Corresponding author at: Cardiovascular Research Center, c/Sant Antoni MªClaret 167, 08025 Barcelona, Spain. E-mail address: [email protected] (L. Badimon).
are evidences of inducible ischaemia during combined thallium/ECG treadmill stress testing in an important percentage of healthy elderly volunteers with a poorer prognosis compared with their counterparts without subclinical coronary artery disease (CAD) [7]. Several hypotheses have been postulated to explain this progressive increase in the prevalence of CVD with ageing: 1) ageing itself is synonymous with disease state; 2) there is an increased prevalence of other cardiovascular risk factors and increased time of exposure to them in older persons; and 3) the ageing process implies changes in the structure and function of the cardiovascular system providing a different scenario in which specific pathophysiological mechanisms become superimposed [8]. What is true is that the interaction between age-related changes and pathophysiological disease mechanisms determines not only CVD presentation in the elderly, but also their prognosis after suffering an ischaemic event.
2. Pathophysiological mechanisms associated to ACS presentation in the elderly Independently of the existence of other co-morbidities such as the presence of additional risk factors, ageing is directly associated to changes at different levels (Fig. 1) that contribute to the higher risk of elderly patients of suffering ACS. The increase in CVD prevalence with ageing has been attributed to several age-related changes such as changes in the vascular wall elasticity, the coagulation and haemostatic system, endothelial dysfunction and an impaired regenerative capacity [9,10].
http://dx.doi.org/10.1016/j.ijcard.2016.07.205 0167-5273/© 2016 Published by Elsevier Ireland Ltd.
Please cite this article as: L. Badimon, et al., Pathophysiology of acute coronary syndromes in the elderly, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.07.205
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Fig. 1. Pathophysiological mechanisms associated to the high cardiovascular risk in the elderly. The ageing process is associated to changes at different levels: increased low-density lipoprotein (LDL) oxidation and decreased atheroprotective properties of high-density lipoproteins (HDL); pro-inflammatory state; endothelial dysfunction; disequilibrium in extracellular matrix synthesis and degradation; enhanced coagulation and impaired fibrinolysis; changes in cardiac calcium (Ca2+) homeostasis; mitochondrial dysfunction with increased reactive oxygen species (ROS) generation and decreased ATP production; and impaired cardiac regenerative capacity.
2.1.1. Coagulation and haemostasis During last years several studies have been focused on the analysis of the coagulation system among older adults [1,11]. Indeed, increased plasma concentrations of several clotting factors have been found in elderly individuals such as fibrinogen [12], factors VII, VIII, IX, X and XII [13–15], von Willebrand factor [16], high molecular-weight kininogen, and prekallikrein [17]. This altered haemostatic system has not only a direct impact on cardiovascular risk but also on the cognitive status in the elderly. Thus, a link between an abnormal clotting system and cognitive deficits has been suggested in part due to the association between elevated fibrinogen levels with cognitive decline [18] and increased risk of Alzheimer's disease [19]. Fibrinogen levels had been also associated to the incidence of dementia in the Rotterdam study [19], and markers of thrombin generation have been associated to an increased risk of cognitive decline [20]. Coagulation factor VIII and plasminogen activator inhibitor 1 (PAI-1) levels were related to the age-related changes in the haemostatic system and microinfarct in vascular dementia [21]. Indeed, PAI-1 levels have been described as a key molecule linking fibrinolysis and ageing [22]. Furthermore, in a recent study, we have found that healthy octogenarian subjects (with preserved functional and cognitive status) without a previous manifestation of CVD have a coordinated decrease in two important anti-fibrinolytic proteins when compared to octogenarians with an un-healthy phenotype (functional and cognitive decline and malnutrition) including those with CVD [23]. Specifically, we have found that plasma levels of alpha-2-antiplasmin, main serine-protease inhibitor controlling the dissolution of fibrin polymers into soluble fragments by inhibiting plasmin activity [24], and coagulation factor XIII were lower in healthy octogenarians without a previous manifestation of CVD when compared to those with an un-healthy phenotype and CVD event presentation. Coagulation factor XIII is able to alter the rheological properties of fibrin by promoting intramolecular cross-links between fibrin strands stabilising fibrin clot and delaying the fibrinolytic process [25]. This antifibrinolytic activity of coagulation factor XIII is due, not only to its ability to cross-link alpha-2-antiplasmin into the fibrin network decreasing the proteolytic vulnerability of the fibrin clot, but also to its influence on fibrin formation leading to the formation of clots with
an increased fibre density [26]. It has been shown that depletion of coagulation factor XIII or alpha-2-antiplasmin results in the same increase in the thrombi lysis rate [27]. Importantly, we have described that the increased levels of antifibrinolytic proteins found in un-healthy octogenarians with a previous CVD event are associated with the formation of denser fibrin clots with a decreased fibrinolytic response. Moreover, coagulation factor XIII-B chain levels are associated with the nutritional state and the ability of performing daily life activities measured by the Lawton–Brody index, which has been reported to be an independent predictor of 3-year mortality in the Octabaix prospective study [28]. Changes in alpha-2-antiplasmin are more associated to CVD event presentation while changes in coagulation factor XIII are more significantly related to cognitive impairment. Therefore, the combination of both anti-fibrinolytic proteins could afford information about the global health status in the elderly in a specific time point explaining not only the risk of suffering both, atherothrombotic disease and cognitive decline, but probably also the worse prognosis of this subgroup of patients after suffering an ischaemic event. 2.2. Inflammation Several studies have reported a pro-inflammatory state in the elderly. In fact, increased levels of different inflammatory markers, such as Creactive protein (CRP) or interleukine-6 (IL-6) have been described in elderly subjects [29]. This enhanced inflammatory response has been related to a disproportional reactivity of senescent immune cells that release huge amounts of pro-inflammatory cytokines leading to an exaggerated immune response [30]. Furthermore, this pro-inflammatory state can contribute to alter the haemostatic equilibrium by affecting fibrinolysis. The association between increased CRP levels and cardiovascular risk has been extensively studied and demonstrated [31]. Even more, increased levels of CRP have been independently associated with unfavourable outcomes in ACS patients [32]. Therefore, the presence of a pro-inflammatory state in the elderly may contribute, not only to the higher prevalence of ACS in this group of patients, but also to a worse prognosis after suffering an acute event. Indeed, it has been shown that patients N 75 years that suffer a major bleeding event
Please cite this article as: L. Badimon, et al., Pathophysiology of acute coronary syndromes in the elderly, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.07.205
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following percutaneous coronary intervention (PCI) have higher CRP levels than patients without bleeding [33]. 2.3. Lipid profile Ageing has been associated with a decrease in the atheroprotective properties of high-density lipoprotein (HDL). Specifically, a reduced capacity of HDL from elderly patients to promote cholesterol efflux and to inhibit LDL oxidation has been described [34,35]. Moreover, proteomic and lipidomic analyses have revealed compositional changes in HDL from elderly subjects with enrichment in several acute-phase proteins and factors involved in complement activation [36]. Among them, elderly patients show an important increase in the HDL levels of serum amyloid A (SAA). Importantly, this protein has been directly related to the shift towards a pro-inflammatory profile of HDL in patients after suffering an acute myocardial infarction (MI) [37]. Thus, the increase in SAA levels in the elderly could exacerbate their pro-inflammatory profile. Additionally, elderly patients also show a decreased HDL content of paraoxonase-1 (PON1) when compared to younger individuals [35,38]. This is important, as the Caerphilly Prospective Study demonstrated that low PON1 levels predict the occurrence of ACS [39]. Therefore, the decrease in PON1 content in HDL of elderly subjects might contribute to the higher risk of suffering ACS in this group of patients.
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2.6. Impaired cardiac metabolism and regenerative capacity Together with changes in myocardial structure, ageing is also associated with an altered calcium homeostasis in cardiomyocytes. Specifically, there is impaired calcium recycling and reduced calcium sensitivity of myofilament proteins that can lead to impaired cardiomyocyte relaxation [56]. Moreover, ageing has been associated to an excessive formation of mitochondrial reactive oxygen species (ROS) and as a consequence to the damage of mitochondrial DNA and redox-sensitive mitochondrial proteins. This in turn contributes to mitochondrial dysfunction and further increases ROS production. Indeed, mitochondria in aged cardiomyocytes are usually enlarged with swelling, loss of cristae, and destruction of inner membranes [57]. But the key element in the age-related mitochondrial dysfunction is the decrease in ATP production [58] that severely hampers cardiac function because of the important energy demand of this organ. There are some studies suggesting that in the aged heart, cardiac stem cells may have impaired regenerative capacity, either by intrinsic senescence of stem cells or by the extrinsic hostile milieu associated to ageing [59]. Indeed, it has been shown that elderly hearts exhibit a reduced turnover rate of cardiomyocytes when compared to young adult hearts (0.45% and 1%, respectively) [60]. 3. Vascular and cardiac impact of ageing
2.4. Endothelial dysfunction Several clinical studies have demonstrated that ageing induces a progressive decrease in endothelium-dependent vasodilatation [40–42]. This decline is mainly due to ageing-associated changes in 3 main endothelium-derived vasodilators, NO, prostacyclin and the endothelium-derived hyperpolarizing factor (EDHF), and leads to an enhanced reactivity to vasoconstrictors [43,44]. However, despite the attenuated generation of endothelial NO, and excessive constitutive generation of NO by vascular smooth muscle cells (VSMC) has been also proposed to impact endothelial ageing. Indeed, an age-related increased expression of the inducible NO synthase (iNOS) has been reported [45]. This iNOS induction further promotes oxidative stress within the vascular wall [46]. In addition, ageing increases the release of endothelin-1 (ET-1), a potent vascular growth factor, from endothelial cells [47,48]. This increase in ET-1 levels with ageing could affect to the evolution of elderly patients after suffering an ACS as it has been shown that high ET-1 levels after MI are associated with the presence of microvascular obstruction and lower myocardial salvage index [49], probably contributing to the worse prognosis of elderly patients post-ACS. Indeed, it has been shown that the administration of an ET-1 receptor blocker during primary PCI in patients with a ST-elevation MI (STEMI) may improve tissue-level perfusion and left ventricular ejection fraction (LVEF) [50]. 2.5. Impaired extracellular matrix homeostasis The maintenance of a correct balance between extracellular matrix (ECM) synthesis and degradation is essential for normal cardiac structure and function. Age is related to a disequilibrium in this balance leading to changes in the amount and distribution of ECM components and thus to what is known as age-dependent myocardial remodelling [51]. Specifically, a study combining electron microscopy and histochemical analysis of human hearts revealed an increase in collagen types I and III with age [52]. This fact could favour the development of diastolic heart failure (HF) in the elderly [53]. Indeed, increasing age has been associated with a higher incidence of HF [54], probably due to, at least in part, this deregulation of ECM homeostasis. Furthermore this agerelated progressive alteration of myocardial structure is an important risk factor for cardiac morbidity and mortality [55], directly affecting the prognosis of elderly patients after suffering an ACS.
All these age-related changes dramatically alter the homeostatic balance favouring tissue damage and hampering tissue repair mainly affecting at a vascular and a cardiac level (Fig. 2) [55]. It is known that ageing is accompanied by changes in the vascular structure and function, especially in the large arteries, increasing the probability of suffering an ACS [61]. These changes include: phenotypic alterations in endothelial cells (EC) and VSMC, collagen deposition, and vascular wall thickening; and finally promoting arterial stiffness [62,63]. Interestingly, a similar age-associated vascular remodelling has been observed in large arteries of rodent and nonhuman primates [64,65]. Cross-sectional studies have demonstrated an increased wall thickening, dilatation and stiffness in large arteries with ageing [66], leading to an increase in arterial blood pressure [67]. Importantly, the presence of vascular abnormalities, at both micro and macrovascular level, evidenced by non-invasive tests of different organs such as the brain or the kidney, or in the carotid and peripheral arteries has been linked to functional decline, frailty, disability, and mortality in the elderly [68–71]. In the context of macrovascular abnormalities, coronary angiogram (CA), which is one of the most commonly used measurements, plays a key role for risk stratification in CAD [72]. Patients aged N 85 years have more complex vascular lesions with a higher rate of calcified, tortuous and ostial lesions, multi-vessel disease and left main stenosis [73]. It has been recently shown that CA has a prognostic value in patients aged ≥65 years [74]. Specifically, it has been shown that patients with a normal CA have a higher 5-year survival rate (96%) than patients with a CA showing b 30% diameter stenosis (85%). This is even apparent at long-term follow-up with 61% 15-year survival rate in patients with a normal CA and 55% in patients with b30% diameter stenosis. At the cardiac level, ageing is characterized by a loss of functional cells and a decline in the regenerative capacity of the myocardium leading to alterations in the structure and function of the heart [75]. These age-related cardiac changes induce an increase in left ventricular (LV) wall thickness, alterations in the diastolic filling pattern, impaired LV ejection and heart rate reserve capacity, and altered heart rhythm, leading to an increased prevalence of LV hypertrophy, HF, and atrial fibrillation in the elderly [55]. Specifically, changes in LV function are attributable to LV wall thickness and to the alterations in calcium homeostasis that induce a residual myofilament calcium-derived activation from the preceding systole. This ageing increase in LV hypertrophy contributes to the higher prevalence of ischaemic heart disease
Please cite this article as: L. Badimon, et al., Pathophysiology of acute coronary syndromes in the elderly, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.07.205
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Fig. 2. Impact of age-related changes at vascular and cardiac level. Ageing induces changes in the structure and function in the vasculature and the myocardium dramatically increasing the probability of suffering an ACS in the elderly and predisposing these patients to a worse prognosis after the event.
(IHD) in the elderly as it has been directly associated with an increased risk for coronary heart disease (CHD), sudden death, and overall CVD [76,77]. All these age-associated changes in vascular and cardiac structure and function have a direct impact on the occurrence, presentation, and manifestations of heart disease in the elderly. 4. Concluding remarks The cardiovascular system undergoes multiple changes with age. Despite the improvements in our understanding of the ageing process and in the management of elderly ACS patients, this growing subgroup still have lower rates of survival. Age-related decline in organ function increases cardiovascular risk. The unpredictable interaction between age-related changes in organ functions and pharmacokinetics and pharmacodynamics may result in untoward reactions to medications and poorer outcomes. There is a clear need to perform clinical trials designed to specifically study the elderly population, or at least to include all age ranges in the enrolment of clinical trials in order to obtain evidences of the suitability to translate the results into the clinical practice in this specific group of patients.
[4]
[5]
[6]
[7]
[8]
[9] [10] [11]
[12]
Conflict of interest
[13]
The authors report no relationships that could be construed as a conflict of interest.
[14] [15]
Acknowledgement [16]
This work has been supported by grants from the Spanish Ministry of Economy and Competitiveness of Science [SAF2013-42962-R to L.B.]; and Institute of Health Carlos III, ISCIII [TERCEL RD12/0019/0026 and RIC RD12/0042/0027 to L.B.] Spain. We thank FIC-Fundacion Jesús Serra, Barcelona, Spain, for their continuous support.
[17]
References
[19]
[1] G.H. Tofler, J. Massaro, D. Levy, M. Mittleman, P. Sutherland, I. Lipinska, et al., Relation of the prothrombotic state to increasing age (from the Framingham Offspring Study), Am. J. Cardiol. 96 (2005) 1280–1283. [2] G.S. Berenson, S.R. Srnivasan, Bogalusa Heart Study G, cardiovascular risk factors in youth with implications for aging: the Bogalusa Heart Study, Neurobiol. Aging 26 (2005) 303–307. [3] H. Wienbergen, A.K. Gitt, R. Schiele, C. Juenger, T. Heer, C. Vogel, et al., Different treatments and outcomes of consecutive patients with non-ST-elevation myocardial
[18]
[20]
[21]
infarction depending on initial electrocardiographic changes (results of the Acute Coronary Syndromes [ACOS] Registry), Am. J. Cardiol. 93 (2004) 1543–1546. C. McCune, P. McKavanagh, I.B. Menown, A review of current diagnosis, investigation, and management of acute coronary syndromes in elderly patients, Cardiol. Ther. 4 (2015) 95–116. K.P. Alexander, L.K. Newby, C.P. Cannon, P.W. Armstrong, W.B. Gibler, M.W. Rich, et al., Acute coronary care in the elderly, part I: non-ST-segment-elevation acute coronary syndromes: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology: in collaboration with the Society of Geriatric Cardiology, Circulation 115 (2007) 2549–2569. M.J. Zaman, S. Stirling, L. Shepstone, A. Ryding, M. Flather, M. Bachmann, et al., The association between older age and receipt of care and outcomes in patients with acute coronary syndromes: a cohort study of the Myocardial Ischaemia National Audit Project (MINAP), Eur. Heart J. 35 (2014) 1551–1558. J.L. Fleg, G. Gerstenblith, A.B. Zonderman, L.C. Becker, M.L. Weisfeldt, P.T. Costa Jr., et al., Prevalence and prognostic significance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardiography in asymptomatic volunteers, Circulation 81 (1990) 428–436. E.G. Lakatta, D. Levy, Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part I: aging arteries: a “set up” for vascular disease, Circulation 107 (2003) 139–146. R. Abbate, D. Prisco, C. Rostagno, M. Boddi, G.F. Gensini, Age-related changes in the hemostatic system, Int. J. Clin. Lab. Res. 23 (1993) 1–3. R.P. Brandes, I. Fleming, R. Busse, Endothelial aging, Cardiovasc. Res. 66 (2005) 286–294. H.J. Cohen, T. Harris, C.F. Pieper, Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly, Am. J. Med. 114 (2003) 180–187. W.B. Kannel, P.A. Wolf, W.P. Castelli, R.B. D'Agostino, Fibrinogen and risk of cardiovascular disease. The Framingham Study, JAMA 258 (1987) 1183–1186. L. Balleisen, J. Bailey, P.H. Epping, H. Schulte, J. van de Loo, Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population: I. Baseline data on the relation to age, gender, body-weight, smoking, alcohol, pill-using, and menopause, Thromb. Haemost. 54 (1985) 475–479. K.A. Bauer, B.L. Kass, H. ten Cate, J.J. Hawiger, R.D. Rosenberg, Factor IX is activated in vivo by the tissue factor mechanism, Blood 76 (1990) 731–736. R. Coppola, P. Cristilli, M. Cugno, R.A. Ariens, D. Mari, P.M. Mannucci, Measurement of activated factor XII in health and disease, Blood Coagul. Fibrinolysis 7 (1996) 530–535. M.G. Conlan, A.R. Folsom, A. Finch, C.E. Davis, P. Sorlie, G. Marcucci, et al., Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study, Thromb. Haemost. 70 (1993) 380–385. D. Mari, P.M. Mannucci, R. Coppola, B. Bottasso, K.A. Bauer, R.D. Rosenberg, Hypercoagulability in centenarians: the paradox of successful aging, Blood 85 (1995) 3144–3149. G. Xu, H. Zhang, S. Zhang, X. Fan, X. Liu, Plasma fibrinogen is associated with cognitive decline and risk for dementia in patients with mild cognitive impairment, Int. J. Clin. Pract. 62 (2008) 1070–1075. M. van Oijen, J.C. Witteman, A. Hofman, P.J. Koudstaal, M.M. Breteler, Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia, Stroke 36 (2005) 2637–2641. D.J. Stott, M. Robertson, A. Rumley, P. Welsh, N. Sattar, C.J. Packard, et al., Activation of hemostasis and decline in cognitive function in older people, Arterioscler. Thromb. Vasc. Biol. 30 (2010) 605–611. J. Gallacher, A. Bayer, G. Lowe, M. Fish, J. Pickering, S. Pedro, et al., Is sticky blood bad for the brain?: hemostatic and inflammatory systems and dementia in the Caerphilly Prospective Study, Arterioscler. Thromb. Vasc. Biol. 30 (2010) 599–604.
Please cite this article as: L. Badimon, et al., Pathophysiology of acute coronary syndromes in the elderly, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.07.205
L. Badimon et al. / International Journal of Cardiology xxx (2016) xxx–xxx [22] M. Cesari, M. Pahor, R.A. Incalzi, Plasminogen activator inhibitor-1 (PAI-1): a key factor linking fibrinolysis and age-related subclinical and clinical conditions, Cardiovasc. Ther. 28 (2010) e72–e91. [23] J. Cubedo, T. Padro, E. Pena, R. Aledo, F. Formiga, A. Ferrer, et al., High levels of antifibrinolytic proteins are found in plasma of older octogenarians with cardiovascular disease and cognitive decline, J. Am. Coll. Cardiol. 65 (2015) 2667–2669. [24] F.J. Castellino, V.A. Ploplis, Structure and function of the plasminogen/plasmin system, Thromb. Haemost. 93 (2005) 647–654. [25] L. Shen, L. Lorand, Contribution of fibrin stabilization to clot strength. Supplementation of factor XIII-deficient plasma with the purified zymogen, J. Clin. Invest. 71 (1983) 1336–1341. [26] E.L. Hethershaw, A.L.C. La Corte, C. Duval, M. Ali, P.J. Grant, R.A. Ariens, et al., The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis, J. Thromb. Haemost. 12 (2014) 197–205. [27] S.R. Fraser, N.A. Booth, N.J. Mutch, The antifibrinolytic function of factor XIII is exclusively expressed through alpha(2)-antiplasmin cross-linking, Blood 117 (2011) 6371–6374. [28] F. Formiga, A. Ferrer, D. Chivite, A. Montero, H. Sanz, R. Pujol, et al., Utility of geriatric assessment to predict mortality in the oldest old: the Octabaix study 3-year followup, Rejuvenation Res. 16 (2013) 279–284. [29] T. Berge, S.R. Ulimoen, S. Enger, H. Arnesen, I. Seljeflot, A. Tveit, Impact of atrial fibrillation on inflammatory and fibrinolytic variables in the elderly, Scand. J. Clin. Lab. Invest. (2013). [30] W.M. Freitas, L.S. Carvalho, F.A. Moura, A.C. Sposito, Atherosclerotic disease in octogenarians: a challenge for science and clinical practice, Atherosclerosis 225 (2012) 281–289. [31] K. Tuomisto, P. Jousilahti, J. Sundvall, P. Pajunen, V. Salomaa, C-reactive protein, interleukin-6 and tumor necrosis factor alpha as predictors of incident coronary and cardiovascular events and total mortality. A population-based, prospective study, Thromb. Haemost. 95 (2006) 511–518. [32] S.K. James, P. Armstrong, E. Barnathan, R. Califf, B. Lindahl, A. Siegbahn, et al., Troponin and C-reactive protein have different relations to subsequent mortality and myocardial infarction after acute coronary syndrome: a GUSTO-IV substudy, J. Am. Coll. Cardiol. 41 (2003) 916–924. [33] G. Ndrepepa, F.J. Neumann, S. Schulz, M. Fusaro, S. Cassese, R.A. Byrne, et al., Incidence and prognostic value of bleeding after percutaneous coronary intervention in patients older than 75 years of age, Catheter. Cardiovasc. Interv. 83 (2014) 182–189. [34] H. Berrougui, M. Isabelle, M. Cloutier, G. Grenier, A. Khalil, Age-related impairment of HDL-mediated cholesterol efflux, J. Lipid Res. 48 (2007) 328–336. [35] L. Jaouad, C. de Guise, H. Berrougui, M. Cloutier, M. Isabelle, T. Fulop, et al., Agerelated decrease in high-density lipoproteins antioxidant activity is due to an alteration in the PON1's free sulfhydryl groups, Atherosclerosis 185 (2006) 191–200. [36] M. Holzer, M. Trieb, V. Konya, C. Wadsack, A. Heinemann, G. Marsche, Aging affects high-density lipoprotein composition and function, Biochim. Biophys. Acta 1831 (2013) 1442–1448. [37] K. Alwaili, D. Bailey, Z. Awan, S.D. Bailey, I. Ruel, A. Hafiane, et al., The HDL proteome in acute coronary syndromes shifts to an inflammatory profile, Biochim. Biophys. Acta 1821 (2012) 405–415. [38] I. Seres, G. Paragh, E. Deschene, T. Fulop Jr., A. Khalil, Study of factors influencing the decreased HDL associated PON1 activity with aging, Exp. Gerontol. 39 (2004) 59–66. [39] B. Mackness, P. Durrington, P. McElduff, J. Yarnell, N. Azam, M. Watt, et al., Low paraoxonase activity predicts coronary events in the Caerphilly Prospective Study, Circulation 107 (2003) 2775–2779. [40] K. Egashira, T. Inou, Y. Hirooka, H. Kai, M. Sugimachi, S. Suzuki, et al., Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans, Circulation 88 (1993) 77–81. [41] N. Singh, S. Prasad, D.R. Singer, R.J. MacAllister, Ageing is associated with impairment of nitric oxide and prostanoid dilator pathways in the human forearm, Clin. Sci. (Lond.) 102 (2002) 595–600. [42] D. Lyons, S. Roy, M. Patel, N. Benjamin, C.G. Swift, Impaired nitric oxide-mediated vasodilatation and total body nitric oxide production in healthy old age, Clin. Sci. (Lond.) 93 (1997) 519–525. [43] Y. Shirasaki, C. Su, T.J. Lee, P. Kolm, W.H. Cline Jr., G.A. Nickols, Endothelial modulation of vascular relaxation to nitrovasodilators in aging and hypertension, J. Pharmacol. Exp. Ther. 239 (1986) 861–866. [44] R. Busse, I. Fleming, Regulation of endothelium-derived vasoactive autacoid production by hemodynamic forces, Trends Pharmacol. Sci. 24 (2003) 24–29. [45] A. Csiszar, Z. Ungvari, J.G. Edwards, P. Kaminski, M.S. Wolin, A. Koller, et al., Aginginduced phenotypic changes and oxidative stress impair coronary arteriolar function, Circ. Res. 90 (2002) 1159–1166. [46] Y. Xia, J.L. Zweier, Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages, Proc. Natl. Acad. Sci. U. S. A. 94 (1997) 6954–6958. [47] W. Goettsch, T. Lattmann, K. Amann, M. Szibor, H. Morawietz, K. Munter, et al., Increased expression of endothelin-1 and inducible nitric oxide synthase isoform II in aging arteries in vivo: implications for atherosclerosis, Biochem. Biophys. Res. Commun. 280 (2001) 908–913.
5
[48] T. Kumazaki, R. Wadhwa, S.C. Kaul, Y. Mitsui, Expression of endothelin, fibronectin, and mortalin as aging and mortality markers, Exp. Gerontol. 32 (1997) 95–103. [49] X. Freixa, M. Heras, J.T. Ortiz, S. Argiro, E. Guasch, A. Doltra, et al., Usefulness of endothelin-1 assessment in acute myocardial infarction, Rev. Esp. Cardiol. 64 (2011) 105–110. [50] C. Adlbrecht, M. Andreas, B. Redwan, K. Distelmaier, J. Mascherbauer, A. Kaider, et al., Systemic endothelin receptor blockade in ST-segment elevation acute coronary syndrome protects the microvasculature: a randomised pilot study, EuroIntervention 7 (2012) 1386–1395. [51] B. Swynghedauw, Molecular mechanisms of myocardial remodeling, Physiol. Rev. 79 (1999) 215–262. [52] A.B. Mendes, M. Ferro, B. Rodrigues, M.R. Souza, R.C. Araujo, R.R. Souza, Quantification of left ventricular myocardial collagen system in children, young adults, and the elderly, Med. B. Aires 72 (2012) 216–220. [53] R. Martos, J. Baugh, M. Ledwidge, C. O'Loughlin, C. Conlon, A. Patle, et al., Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction, Circulation 115 (2007) 888–895. [54] R.H. Mehta, S.S. Rathore, M.J. Radford, Y. Wang, Y. Wang, H.M. Krumholz, Acute myocardial infarction in the elderly: differences by age, J. Am. Coll. Cardiol. 38 (2001) 736–741. [55] E.G. Lakatta, D. Levy, Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part II: the aging heart in health: links to heart disease, Circulation 107 (2003) 346–354. [56] Y.A. Chiao, P.S. Rabinovitch, The aging heart, Cold Spring Harb. Perspect. Med. 5 (2015) a025148. [57] A. Terman, U.T. Brunk, Myocyte aging and mitochondrial turnover, Exp. Gerontol. 39 (2004) 701–705. [58] C. Mammucari, R. Rizzuto, Signaling pathways in mitochondrial dysfunction and aging, Mech. Ageing Dev. 131 (2010) 536–543. [59] V.L. Ballard, J.M. Edelberg, Stem cells and the regeneration of the aging cardiovascular system, Circ. Res. 100 (2007) 1116–1127. [60] O. Bergmann, R.D. Bhardwaj, S. Bernard, S. Zdunek, F. Barnabe-Heider, S. Walsh, et al., Evidence for cardiomyocyte renewal in humans, Science 324 (2009) 98–102. [61] M.E. Safar, Arterial aging–hemodynamic changes and therapeutic options, Nat. Rev. Cardiol. 7 (2010) 442–449. [62] M.G. Scioli, A. Bielli, G. Arcuri, A. Ferlosio, A. Orlandi, Ageing and microvasculature, Vasc. Cell. 6 (2014) 19. [63] H.Y. Lee, B.H. Oh, Aging and arterial stiffness, Circ. J. 74 (2010) 2257–2262. [64] Z. Li, J. Froehlich, Z.S. Galis, E.G. Lakatta, Increased expression of matrix metalloproteinase-2 in the thickened intima of aged rats, Hypertension 33 (1999) 116–123. [65] K. Asai, R.K. Kudej, Y.T. Shen, G.P. Yang, G. Takagi, A.B. Kudej, et al., Peripheral vascular endothelial dysfunction and apoptosis in old monkeys, Arterioscler. Thromb. Vasc. Biol. 20 (2000) 1493–1499. [66] E.G. Lakatta, Cardiovascular regulatory mechanisms in advanced age, Physiol. Rev. 73 (1993) 413–467. [67] J.D. Pearson, C.H. Morrell, L.J. Brant, P.K. Landis, J.L. Fleg, Age-associated changes in blood pressure in a longitudinal study of healthy men and women, J. Gerontol. A Biol. Sci. Med. Sci. 52 (1997) M177–M183. [68] D. Inzitari, G. Pracucci, A. Poggesi, G. Carlucci, F. Barkhof, H. Chabriat, et al., Changes in white matter as determinant of global functional decline in older independent outpatients: three year follow-up of LADIS (leukoaraiosis and disability) study cohort, BMJ 339 (2009) b2477. [69] D.H. Kim, A.B. Newman, I. Hajjar, E.S. Strotmeyer, R. Klein, E. Newton, et al., Retinal microvascular signs and functional loss in older persons: the cardiovascular health study, Stroke 42 (2011) 1589–1595. [70] M.J. Sarnak, R. Katz, L.F. Fried, D. Siscovick, B. Kestenbaum, S. Seliger, et al., Cystatin C and aging success, Arch. Intern. Med. 168 (2008) 147–153. [71] A.B. Newman, J.S. Gottdiener, M.A. McBurnie, C.H. Hirsch, W.J. Kop, R. Tracy, et al., Associations of subclinical cardiovascular disease with frailty, J. Gerontol. A Biol. Sci. Med. Sci. 56 (2001) M158–M166. [72] R. Bugiardini, O. Manfrini, G.M. De Ferrari, Unanswered questions for management of acute coronary syndrome: risk stratification of patients with minimal disease or normal findings on coronary angiography, Arch. Intern. Med. 166 (2006) 1391–1395. [73] V.B. Shanmugam, R. Harper, I. Meredith, Y. Malaiapan, P.J. Psaltis, An overview of PCI in the very elderly, J. Geriatr. Cardiol. 12 (2015) 174–184. [74] A.E. Moreyra, M. Charalambous, N.M. Cosgrove, S. Rajaei, K. Cullen, J.Q. Cheng, et al., Usefulness of a normal coronary angiogram in patients aged ≥65 years to foretell survival, Am. J. Cardiol. 116 (2015) 1487–1494. [75] D.F. Dai, T. Chen, S.C. Johnson, H. Szeto, P.S. Rabinovitch, Cardiac aging: from molecular mechanisms to significance in human health and disease, Antioxid. Redox Signal. 16 (2012) 1492–1526. [76] D. Levy, R.J. Garrison, D.D. Savage, W.B. Kannel, W.P. Castelli, Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study, N. Engl. J. Med. 322 (1990) 1561–1566. [77] A.W. Haider, M.G. Larson, E.J. Benjamin, D. Levy, Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death, J. Am. Coll. Cardiol. 32 (1998) 1454–1459.
Please cite this article as: L. Badimon, et al., Pathophysiology of acute coronary syndromes in the elderly, Int J Cardiol (2016), http://dx.doi.org/ 10.1016/j.ijcard.2016.07.205