International Journal of Cardiovascular Research Research ...1)-101.pdffemale sex is important risk...

International Journal of Cardiovascular Research

Research Article

Yasser Mohammed Hassanain Elsayed

Critical Care Unit, Fraskour Central Hospital, Damietta Health Affairs, Egyptian Ministry of Health (MOH), Egypt

Correspondence: Elsayed YMH, Critical Care Unit, Fraskour Central Hospital, Damietta Health Affairs, Egyptian Ministry of Health (MOH), Egypt. E-mail: [email protected]

Received: 25 February, 2019 ; Accepted: 6 April, 2019; Published: 18 April, 2019

Copyright: © 2019 Elsayed YMH, Atypical Presentations of Acute Coronary Syndrome in Elderly, Women, and Diabetic Patients-Updating Review. int j cardiol res; 1(1): 1-26.

Abstract

Introduction: Coronary heart disease is one of the leading causes of death worldwide. Chest pain is the cornerstone symptom of acute coronary syndrome. Atypical presentation of symptoms are the most significant reasons for the delay in seeking treatment for symptoms of the acute coronary syndrome.

The absent or atypical clinical signs in the elder, women and diabetic patients hinder the management of coronary artery disease especially using thrombolytic therapy. Lack of chest pain

Atypical Presentations of Acute Coronary Syndrome in

Elderly, Women, and Diabetic Patients-Updating Review

mailto:[email protected]

Elsayed YMH (2019) Atypical Presentations of Acute Coronary Syndrome in Elderly, Women, and Diabetic Patients-Updating Review. int j cardiol res; 1(1): 1-26. during acute coronary syndrome has been correlated to higher mortality rates. The elder, women and diabetic patients are the most important subgroups in an atypical presentation of acute coronary syndrome.

Objective: To explore the clinical presentations with outcome in acute coronary syndrome in the elderly, women, and diabetic patients were the purpose of this study.

Methods: Narrative literature focused atypical presentation in the elderly, women, and diabetic patients and its management.

Conclusion: Early and rapid diagnosis for atypical presentations of an acute coronary syndrome in the elderly, women and diabetic patients hurry the management and delay the mortality.

Introduction

Historical bit

Discovery history of coronary artery disease and its research for optimal diagnostic tools are quite longstanding [1]. Probably, the earliest description of ischemic chest pain was formulated around the 1550 BC, when Egyptians reported a realistic description of heart ischemia in the Ebers Papyrus, “if thou examines a man for illness in his cardiac and he has pains in his arms, and in his breast and in one side of his cardiac…it is death threatening him.” [2]. It is worth mentioning that the Russian clinicians and pathologists Obrastzov and Straschesko described in 1910 five patients presenting myocardial infarction, which was subsequently confirmed at autopsy [3]. Silent myocardial ischemia (SMI) was recognized as early as the beginning of the 20th century [4-5]. Since its original description in the 1970s, it has undergone intensive investigation, and its clinical significance is now well established [6].

Scoping, Definition and Clinical Significance

of Silent Myocardial Ischemia

Coronary heart disease (CHD) is one of the most common leading causes of death worldwide. About 3.8 million men and 3.4 million women die each year due to CHD [7]. Chest pain is the cornerstone symptom of acute coronary syndrome [8]. Despite chest pain is the most common symptom of coronary heart disease [9] but it is the last

manifestation of ischemic heart disease [10]. So, most episodes of acute coronary syndrome are characterized predominantly by chest pain [11]. Silent myocardial ischemia (SMI) is an important public health issue, and its early detection may prevent many episodes of sudden cardiac death annually [12]. Notably, in a significant percentage of patients, the cause of chest pain is never found [13]. According to the World Health Organization (WHO), one of the cornerstone features in the diagnosis of acute coronary syndrome (ACS) is the presence of chest pain; however, not all patients with myocardial ischemia present with chest pain. The extent to which this phenomenon occurs is largely unknown [14]. However, a proportion of patients may have atypical, minimal, or no symptoms (Table 1). Chest pain, however, is grounded on a wide spectrum of causes, ranging from totally harmless to immediately life-threatening [13]. In the Framingham study, approximately 25% of patients were found to have ST-segment elevation myocardial infarction (STEMI) on routine annual Electrocardiography (ECG), in absence of any previous clinical manifestation, so exhibiting truly silent infarctions [11,13]. An incidence of unrecognized non-ST-segment elevation myocardial infarction (NSTEMI) approaching a 3-fold higher frequency than unrecognized STEMI ones [13].

The acute coronary syndrome is defined as a spectrum of clinical presentations ranging from those for STEMI to presentations found in NSTEMI or in

Elsayed YMH (2019) Atypical Presentations of Acute Coronary Syndrome in Elderly, Women, and Diabetic Patients-Updating Review. int j cardiol res; 1(1): 1-26. unstable angina [15]. The acute coronary syndrome encompasses a spectrum of unstable coronary artery disease from unstable angina to ST-segment elevation myocardial infarction [16].

Silent myocardial ischemia (SMI) is defined as an objective documentation of myocardial ischemia in the absence of angina or anginal equivalents (e.g. dyspnea, diaphoresis, nausea vomiting.. etc) [5,6]. SMI is characterized by lack of unequivocal objective signs of myocardial infarction and minimal, atypical, or no symptoms at all [17]. Patients with atypical presentations were more likely to be elder, women, and diabetic. Approximately 1% to 4% of patients who present to an emergency department with acute myocardial infarction, atypical symptoms, and those without chest pain are most likely to be mistakenly discharged [18].

Patients with ST-segment elevation myocardial infarction are significantly less likely to receive reperfusion therapy [11]. The absence of ischemic chest pain at presentation was among the most significant risk factors predicting lower use of thrombolytic therapy among a subset of acute myocardial infarction patients. So, lack of chest pain during acute myocardial infarction has been correlated to higher mortality rates [19]. The mortality can be decreased significantly due to early thrombolysis or primary angioplasty [7].

Silent Myocardial Ischemia and Unstable

Angina

Gottlieb, Weisfeldt, et al. [20] studied patients with unstable angina whose symptomatic ischemia had been nearly eliminated with therapy.

Table (1): Typical versus atypical symptoms in elder, women and diabetics presenting with ACS [17,19,38,118,164-169]

Typical Versus Atypical Symptoms Percent %

• Typical Symptoms

48.3-84.1

• Chest pain/discomfort

• Pressure, tightness, squeezing

• Radiated to: Jaw, neck, shoulders, arm, back, epigastrium

• Associated with: Dyspnea, nausea, vomiting, lightheadedness, diaphoresis

• Atypical Symptoms 12.5-29.6

• Chest pain: Sharp, pleuritic, burning, aching, soreness, reproducible

• Symptoms other than chest pain (no chest pain) 3.5-21.8

• Sweating 46.5-46.8

• Shortness of breath 16.1- 40.5

• Nausea and vomiting 13.3-37.4

• Palpitations 5 -12.4

• Syncope 5 -12.4

• Dizziness or giddiness 10.7-24.9

• Abdominal pain 0-4.68

• Altered sensorium 5.3-6.2

• focal neurodeficit 1.5-1.7

• Epigastric pain 0-10

Elsayed YMH (2019) Atypical Presentations of Acute Coronary Syndrome in Elderly, Women, and Diabetic Patients-Updating Review. int j cardiol res; 1(1): 1-26.

• Dental pain 0-1.87

• Back pain 0-9.8

• Generalized weakness 0-1.3

• Myalgia 0-1.3

• Leg edema 0.8-1

• Headache 0- 1.5

• Poor oral intake 0-1

• Indigestion 0.83- 3.47

• Neck pain 0- 1.2

• Flu-like symptoms 0- 1.2

• Hemoptysis 0- 1.2

• Arm numbness 0- 1.2

• Fatigue 27.08-27.78

• Acid reflux 0- 2.4

• Jaw/ Neck pain 6.74- 10.73

• Arm pain 17.17- 24.16

• Generalized scared/anxiety feeling UA

• Fits UA

In this population, persistent silent myocardial ischemia evident on Holter monitoring was associated with more severe CAD. Compared with patients in whom silent myocardial ischemia was absent, those with SMI were more likely to experience early (within 30 days) adverse outcomes of MI or recurrent symptoms requiring revascularization, as well as late (after 2 years) adverse outcomes including death or recurrent MI. Similar observations were evident in patients after recent angioplasty [20,21].

Silent Myocardial Ischemia Post-Myocardial

Infarction

Among patients about to be discharged following hospitalization for myocardial infarction, treadmill testing revealed that exercise-induced ischemia with or without angina was associated with increased risk of coronary events and cardiac death [22,23]. In addition, a prospective study by Narins and associates [24] that evaluated 500 patients who underwent ambulatory monitoring and stress thallium scintigraphy 1 to 6 months after an episode of unstable angina or MI

found that 75% of the patients had evidence of silent myocardial ischemia.

Epidemiology and Statistics

Chest pain accounts for about 5.6 million emergency department visits annually [18]. Almost 20% of ST-segment elevation myocardial infarction patients presenting without chest pain dying in the hospital [11]. Episodes of asymptomatic ischemia occur in approximately 25% to 50% of patients with coronary artery disease25. However, the absence of chest pain predicted a greater likelihood of in-hospital death across the spectrum of acute coronary syndrome [11]. In fact, 70% to 80% of transient ischemic episodes are not associated with anginal chest pain or any other symptoms (silent ischemia) [5]. A high incidence of unrecognized myocardial infarction may be due to an independent tendency towards the atypical clinical presentation of the infarction onset with increasing age [26]. About 60% of hospital admissions for acute coronary syndrome are for patients older than 65 years of age, and approximately 85% of acute coronary syndrome related deaths occur in this age group. Large registries show 32% to

Elsayed YMH (2019) Atypical Presentations of Acute Coronary Syndrome in Elderly, Women, and Diabetic Patients-Updating Review. int j cardiol res; 1(1): 1-26. 43% of Non-ST-segment elevation myocardial infarction-acute coronary syndrome, and about 24%-28% of ST-segment elevation myocardial infarction admissions were for patients aged ≥75 years [27]. Coronary heart disease is the most important cause of death and disability among older women [28]. Furthermore, in women, heart disease is too often a silent killer nearly two-thirds of women who died suddenly had no previous symptoms [29]. Approximately one-third (men) to half (women) of these events remained clinically unrecognized myocardial infarctions30. The incidence of myocardial infarction increased with age [30]. The prevalence of silent myocardial ischemia is higher than previously thought; in particular, it is 50% higher in diabetics [8,17]. However, not all patients with florid diabetic autonomic neuropathy have painless myocardial infarction [31]. About 90% of the published studies presenting data on the atypical presentation of chronic and acute ischemic heart disease are carried out in type 2 diabetics [8]. The Detection of Ischemia in Asymptomatic Diabetes study found that more than 20% of patients with asymptomatic type 2 diabetes (no angina or anginal equivalents) had silent myocardial ischemia [32]. Diabetic patients without clinical evidence of myocardial infarctions

have a high prevalence of myocardial scar consistent with myocardial infarctions detected by CMR that is associated with a significant risk of important cardiac events, including death [33].

Risk factors

Traditional risk factors have a significant impact on the symptomatology of acute coronary syndrome [8]. The symptomatology of acute coronary syndrome, which comprises both pain and non-pain symptoms may be affected by traditional risk factors such as age, gender, smoking, hypertension, diabetes, and dyslipidemia [8]. Diabetes, older age, female sex is important risk factors for atypical presentation [34]. Traditional Risk Factors Degree Classification versus Framingham Risk Score (FRS) Degree Classification is studied (Table 2). The most significant predictors of the absence of chest pain were age and diabetes [35]. Diabetes mellitus is the biggest factor related to asymptomatic ischemia in patients with stable coronary disease [36]. Advanced age is the single strongest risk factor for coronary artery disease and independent predictor for poor outcomes following an acute coronary syndrome [27].

Table (2): Traditional Risk Factors Degree Classification versus Framingham Risk Score (FRS) Degree Classification in women

Old Traditional Risk Factors Degree Classification170 Framingham Risk Score (FRS) Degree Classification171,172

• Major Risk Factors • Framingham Risk Factors and Risk Equivalents

• Diabetes • Hypertension

• Postmenopausal Without Hormone Replacement

• Hyperlipidemia

• Smoking

• Diabetes

• Peripheral Arterial Disease (PAD)

• Chronic Kidney Disease (CKD)

• Intermediate Risk Factors • Non-Framingham Risk Factors

• Hypertension • Overweight and Obesity

• Smoking • Family History of IHD

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987323/#r07https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987323/#r07


• Lipid abnormalities;especially low high-density lipoprotein and high triglyceride levels

• Metabolic Syndrome

• Polycystic Ovary Syndrome (PCOS)

• Adverse Pregnancy Outcomes • Systemic Autoimmune Disorders e.g., Systemic lupus

erythematosis (SLE) and rheumatoid arthritis

• Radiation Therapy • Obstructive Sleep Apnea (OSA)

• Osteopenia/Osteoporosis • Anemia • C-reactive protein • Lifestyle Factors: Alcohol, Physical inactivity, and Mediterranean

diet

• Psychosocial Variables; Acute mental stress, Depression, Anxiety, Anger, Marital status, and Socioeconomic Status (SES)

• Hormones and CVD Risk; Oral Contraceptives (OCPs), enopause and menopausal hormone therapy (MHT)

• MINOR Risk Factors

• Family history • Obesity • Age > 65 years • Sedentary lifestyle

However, several studies indicate that the only independent factor for silent ischemia is advanced age [36]. According to several studies, atypical presentations were found in approximately 20% of elderly patients in the Emergency Department [119]. Elderly patients with myocardial ischemia often have atypical clinical manifestations, due to comorbidities as diabetes mellitus, women, heart failure, nociceptive changes, depression, and dementia. Memory disorder causes the elderly to have memorization difficulty and describe the pain resulting from myocardial ischemia. Depression and fibromyalgia are neuropsychiatric disorders that interfere with the painful sensation. Sometimes, elderly persons complain of precordial pain, with the rejected diagnosis of myocardial ischemia, improve with antidepressants. The opposite can also occur, with elderly people with atypical pain for myocardial ischemia, generally attributed to depression, having significant coronary disease. The relationship between depression and coronary atherosclerotic disease is well

defined. However, there are several reasons why depression increases the occurrence of coronary disease. Patients with depression have less treatment adherence to drug and lifestyle changes. Also, depression [36] can cause a change of endothelial function, deregulation of the hypothalamic-pituitary-adrenal axis, increased platelet reactivity and inflammatory markers with interleukin36.

The possible reason could be a loss of estrogen and its cardiovascular protective effects in the elderly females 37] ]. Ethnically diverse women present with their incident MI at a younger age than white women [38]. Black women also have a higher incidence of sudden cardiac death as the first manifestation of coronary heart disease than white women. Asian Indian women have a greater proportionate mortality burden from coronary heart disease compared with non-Hispanic white women [38]. Framingham Risk Score (FRS) Degree Classification are studied (Table 3).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987323/#r07


Table (3): Risk factors for coronary heart disease (CAD) in women

Risk factors Notes 1. Framingham Risk Factors • Diabetes and Prediabetes • Menopause

• High Blood Pressure • High Blood Cholesterol

• Active or Passive Smoking • Peripheral Arterial Disease (PAD) • Chronic Kidney Disease (CKD)

• Unfortunately, coronary artery disease remains understudied, underdiagnosed, and undertreated in women with diabetes are at greater risk of heart disease than are men with diabetes173,174. • Even without estrogen replacement175. Low levels of estrogen after menopause pose a significant risk factor for developing cardiovascular disease in the smaller blood vessels (coronary microvascular disease) 173,174. • Hypertension underdiagnosed and undertreated remains a major risk factor for CAD in women171,172. Lifetime risk of developing hypertension is at least 90%172,176. • Elevated serum lipid levels are the greatest contributor to development of coronary heart disease worldwide 172. • Tobacco use increases coronary heart disease risk, including progression of atherosclerosis, myocardial infarction, and sudden cardiac death172. • PAD is a risk equivalent for CAD, and both share risk factors such as hypertension, diabetes and smoking172. • CKD is associated with coronary artery calcification independent of traditional risk factors172.

2. Non-Framingham Risk Factors

• Age • Being overweight or obese • Being physically inactive

• Having a family history of early heart disease • Having a history of preeclampsia during pregnancy • Unhealthy diet

• Pregnancy complications • Broken heart syndrome • Drugs and radiation-induced • Birth control bills

• 55 or older for women173,175 • By ≥ 20 Ibs., a BMI of 25 or higher can be associated with an increased risk of heart disease 173, 175,177. • Physical inactivity is higher among women than men, especially in non-Hispanic black and Hispanic adults173. Aim for 300 minutes of moderate aerobic activity or 150 minutes of vigorous aerobic activity a week. That's about 60 minutes a day, five days a week. In addition, aim to do strength training exercises two or more days a week)173,174. • Gender differences in the impact of family history on CAD risk have been controversial174, 177. • Pre-eclampsia, eclampsia, and pre-term delivery, all associated with increased future heart disease risk 178,179. • The Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major CV events by ~30% in people at high CV risk. Adherence to the DASH diet appears to lower blood pressure and risk of heart failure, but does not reduce the risk of sudden cardiac death in postmenopausal women28. • High blood pressure or diabetes during pregnancy can increase women's long-term risk of high blood pressure and diabetes and increase the risk of development of heart disease in the mothers174. • This condition often brought on by stressful situations that can cause severe, but usually temporary, heart muscle failure occurs more commonly in women after menopause. This condition may also be called takotsubo cardiomyopathy, apical


• Sedentary lifestyle

• Polycystic Ovary Syndrome (PCOS)

• Anemia

• Metabolic syndrome • Obstructive Sleep Apnea (OSA) • Osteopenia/Osteoporosis • Autoimmune disease • Psychosocial variables Systemic lupus erythematosis (SLE) Rheumatoid arthritis • Abnormal heart beats178 • Past history of any variant of acute coronary syndrome178

ballooning syndrome or stress cardiomyopathy175. • Chest wall radiation is associated with coronary atherosclerosis and CAD28,175. Some chemotherapy drugs and radiation therapies may increase the risk of cardiovascular disease174. • In combination with smoking175, 177. • Excessive alcohol consumption is associated with hyperlipidemia, hypertension, vasoconstriction, hypercoagulability, and a lower ventricular fibrillation threshold 127,173, 177, • Cardiac risk factors such as diabetes, obesity, hypertension, and metabolic syndrome are prevalent in women with PCOS28. • In the WISE study, 21% of women were anemic (Hg < 12 g/dL); anemia was not associated with severity of CAD or ejection fraction, but associated with higher risk of adverse outcomes; women with anemia were more likely to have renal dysfunction, diabetes, hypertension, and be non-white 28. • The metabolic syndrome is a clustering of risk factors that increases risk of CAD 73. • OSA in women as they may present atypical complaints of morning headaches, insomnia, and depression28. • Severity of osteoporosis is associated with cardiac events. Women have lower vitamin D levels compared to men, and a low vitamin D level is associated with hypertension, diabetes, and CAD28. • CAD is a leading cause of morbidity and mortality in SLE patients, and rheumatoid arthritis is associated with a two-to-threefold higher risk of MI and increased CVD mortality73. • Acute mental stress-related ischemia, infarction, and arrhythmias occur in both women and men as seen during disasters such as earthquakes and wars. A mental stress-associated acute syndrome, stress cardiomyopathy or Takotsubo-cardiomyopathy, is highly prevalent in post-menopausal women (80% of cases)28. - -

CAD; coronary heart disease, CVD; cardiovascular diseases

Cohn Classification of Silent

Myocardial Ischemia According to the Cohn classification [33,12] patients with silent ischemia are stratified into three types:

• Type I: This is the least common form of silent ischemia. It occurs in asymptomatic patients with obstructive CAD who do not experience anginal symptoms at any time.

• Type II: This type of ischemia occurs in patients with a documented previous myocardial infarction.

• Type III: This is the most common form; it occurs in patients with chronic stable angina, unstable angina, or variant angina.

Pathogenesis of SMI or Atypical

Presentations of ACS in Elderly,

Women, and Diabetes Indeed, pathogenesis in silent myocardial ischemia or atypical presentations of the acute coronary syndrome is large vary from diabetic to elderly and women.

Elsayed YMH (2019) Atypical Presentations of Acute Coronary Syndrome in Elderly, Women, and Diabetic Patients-Updating Review. int j cardiol res; 1(1): 1-26. Cardiac Autonomic Neuropathy in Diabetes

Mellitus

Introduction and Mortality

Cardiovascular autonomic neuropathy (CAN) is one of the most clinically significant complications of diabetes mellitus [40]. Possible explanations for the dissimilar symptoms in patients with diabetes mellitus comprise central mechanisms such as altered thresholds of pain sensitivity, beta-endorphin levels, in addition to autonomic neuropathy resulting in sensory denervation8. Cardiac autonomic neuropathy (CAN) is a serious complication of diabetic patients that is strongly associated with approximately 5-fold increased risk of cardiovascular mortality [41]. Cardiac autonomic neuropathy is strongly associated with increased both mortality [42-44], and in some studies with morbidities, such as stroke, coronary artery disease, and silent myocardial ischemia [41].

Pathogenesis, Risk Markers, and Risk Factors

Silent myocardial ischemia may be induced by different combinations of decreased sensitivity to painful stimuli and coronary micro vascular dysfunction [45]. The cases of silent myocardial ischemia have been shown to have a higher threshold for other forms of pain, such as that resulting from an electric shock, limb ischemia, and cutaneous application of heat or balloon inflation in the coronary artery [46]. Silent ischemia may be due to cerebral cortical dysfunction, rather than the peripheral nerve dysfunction. Frontal cortical stimulation appears to be necessary to experience cardiac pain, and some evidence indicates that in patients with silent ischemia, afferent pain impulses from the heart are subject to abnormal neural processing [47]. Patients with asymptomatic coronary heart disease had markedly less cortical activation than those who experienced angina. Extra cardiac factors may exert a critical impact on the central processing of afferent stimuli.

Amplifying and abating influences may include analgesic effects arising from concurrent exercise or vagal stimulation, emotional status and personality characteristics [48]. Mental stress can act as an inducer for ischemia in 40% to 70% of patients with CAD and has been reported to be a frequent trigger for the development of silent ischemia, acute myocardial infarction, and sudden cardiac death [49,50]. The development of silent ischemia in response to mental stress in the laboratory is independently associated with higher rates of fatal and nonfatal cardiac events and predicts events over and above exercise-induced ischemia [51]. Increased levels of beta-endorphin, an endogenous opiate, have been noted in patients with asymptomatic myocardial ischemia during exercise [52]. The expression of peripheral benzodiazepine receptors is higher in patients with SMI than in symptomatic patients [53]. Significantly elevated levels of anti-inflammatory cytokines (interleukin-4 and -10, transforming growth factor-beta), together with a decrease in leukocyte adhesion molecule expression (CD11b), may help identify some of the mechanisms of silent ischemia [54]. The association between diabetics and silent coronary heart disease has been attributed to autonomic neuropathy [12,55].

Clinical correlates or risk markers for cardiac autonomic neuropathy are age, diabetic duration, glycemic control, hypertension, and dyslipidemia, development of other micro vascular complications [41].

Established risk factors for cardiac autonomic neuropathy are poor glycemic control in type1 diabetes mellitus and a combination of hypertension, dyslipidemia, obesity, and unsatisfactory glycemic control in type 2 diabetes mellitus [41]. Silent myocardial ischemia is also recognized as a common manifestation of percutaneous coronary intervention, possibly due to the induction of coronary vasopasm [56].

Elsayed YMH (2019) Atypical Presentations of Acute Coronary Syndrome in Elderly, Women, and Diabetic Patients-Updating Review. int j cardiol res; 1(1): 1-26. Cardiovascular Associations with Cardiac Autonomic Neuropathy

The development of cardiac autonomic neuropathy is associated with the following; Postprandial hypotension, orthostatic hypotension, perioperative instability, resting tachycardia, silent myocardial ischemia, QT interval prolongation, sudden death syndrome, exercise intolerance, increased peripheral blood flow and warm skin, increased arteriovenous shunting with swollen veins, loss of reflex heart rate variations, increased venous pressure, hypertension, leg and foot edema, loss of protective cutaneous vasomotor reflexes, loss of venoarteriolar reflex with micro vascular damage, increased transcapillary leakage of macromolecules, increased medial arterial calcification, left ventricular dysfunction and hypertrophy, impaired baroreflex sensitivity, non-dipping, reverse dipping, sympathovagal imbalance, dysregulation of cerebral circulation, decreased sympathetically mediated vasodilation of coronary vessels, and increased arterial stiffness [41,42,57-62].

Clinical manifestations of Cardiac Autonomic Neuropathy

Cardiac autonomic neuropathy manifests in a spectrum of things, ranging from resting tachycardia and fixed heart rate to development of silent myocardial infarction [41]. Clinical manifestations of cardiac autonomic neuropathy include sinus tachycardia, exercise intolerance, postural hypotension in 6%- 32% of patients with DM [42,60,61]. Dizziness, light-headedness, fainting, blurred vision was found out in 4%-18% of diabetic patients [42,62]. Abnormal blood pressure regulation, dizziness, presyncope and syncope, intraoperative cardiovascular instability, asymptomatic coronary heart disease [41]. Orthostatic intolerance symptoms may be worse in the early morning, during prolonged standing, after meals, or physical activity [42,63,64]. Light-headedness, palpitations, weakness, faintness, and syncope are the most common

symptoms of CAN, that occurs upon standing [43,62].

Indication for Screening for cardiac autonomic neuropathy

Screening should be performed in the following:

Type 2 diabetic patients at the time of diagnosis.

Type 1 diabetic patients after 5 years of disease, in particular, those at greater risk for CAN due to a history of poor glycemic control (HbA1c > 7%), or the presence of one major CVD risk factor, or other chronic complications of Diabetes (level B).

Cardiac autonomic neuropathy screening may be also required in asymptomatic patients for pre-operative risk assessment before major surgical procedures (level C) [41,42].

Grades of Cardiac Autonomic Neuropathy

Cardiac autonomic neuropathy classified into three stages [5]:

Subclinical phase: Decreased heart rate variability.

Early phase: Resting tachycardia. Advanced stage: Exercise intolerance,

cardiomyopathy with left ventricular dysfunction, orthostatic hypotension, and silent myocardial ischemia.

Cardiac Autonomic Neuropathy Assessment

Methods of cardiac autonomic neuropathy assessment in clinical practice include: assessment of symptoms and signs, cardiovascular reflex tests based on heart rate and blood pressure, short-term electrocardiography, QT interval prolongation, heart rate variability (classic 24 hour Holter ECG), ambulatory blood pressure monitoring, heart rate turbulence, baroreflex sensitivity, muscle sympathetic nerve activity, catecholamine assessment and

Elsayed YMH (2019) Atypical Presentations of Acute Coronary Syndrome in Elderly, Women, and Diabetic Patients-Updating Review. int j cardiol res; 1(1): 1-26. cardiovascular sympathetic tests, heart sympathetic imaging [41,42,62-77].

Prevention and Treatment of Cardiac Autonomic Neuropathy

Prevention of cardiac autonomic neuropathies focuses on lifestyle modifications and tight glucose control. Early optimization of glucose control in patients with type 1 diabetes (class A) and a multifactorial approach targeting glycemia among other cardiovascular risk factors in patients with type 2 diabetes (class C) was considered for prevention or delay of CAN development79. Intensive glucose control reduced the risk of CAN development by 31%-45% [78,79]. Treatment of cardiac autonomic neuropathy is a complex process, that includes: Balanced diet and physical activity; early optimization of glycemic control; treatment of DLP; antioxidants, first of all α lipoic acid (ALA), aldose reductase inhibitors, acetyl L-carnitine; vitamins, first of all fat-soluble vitamin B1; correction of vascular endothelial dysfunction; prevention and treatment of thrombosis; in severe cases-treatment of OH [41] The promising methods include; the prescription of prostacyclin analogues, thromboxane A2 blockers and drugs that contribute into strengthening and/or normalization of Na+, K+-ATPase (phosphodiesterase inhibitor), ALA, dihomo-γ-linolenic acid (DGLA), ω-3 polyunsaturated fatty acids (ω-3 PUFAs), and the simultaneous prescription of ALA, ω-3 PUFAs and DGLA [41,80].

Pathophysiology in Women

Indeed, Plaque rupture, spontaneous coronary artery dissection, and coronary artery spasm are the target for pathogenic changes in silent myocardial ischemia or atypical presentations in women. However, there are essential differences in underlying pathophysiology importantly contribute to another clinical presentation of an acute coronary syndrome in women if comparable to men. When vascular dysfunction/ spasm is considered an important component of an

acute coronary syndrome, especially in younger women (

Elsayed YMH (2019) Atypical Presentations of Acute Coronary Syndrome in Elderly, Women, and Diabetic Patients-Updating Review. int j cardiol res; 1(1): 1-26. formation of occlusive atherothrombosis. Plaque erosion is another mechanism for coronary thrombosis without plaque rupture [88,89]. Erosions are distinguished by an absent or denuded endothelium overlying a plaque that is characterized by abundant proteoglycans and greater proliferation of smooth muscle than inflammatory cells. Coronary obstruction is precipitated largely by the thrombi that develop on the dysfunctional intima of plaque erosions. Downstream microembolization is more commonly associated with plaque erosion than with plaque rupture, resulting in focal myocardial necrosis [90,91]. About 2% to 7% of coronary thrombosis in ST-elevation myocardial infarction might originate from calcific nodules, seen more frequently in the right coronary artery [89]. Autopsy studies have shown an increased prevalence of plaque erosion in women compared with men, particularly in younger women [92]. Myocardial infarction without obstructive coronary artery disease is more common at younger ages and among women [93,94]. Plaque rupture is especially rare in premenopausal women, perhaps suggesting a protective effect of estrogen [95].

Spontaneous Coronary Artery Dissection

Spontaneous coronary artery dissection (SCAD) is a very rare cause of acute myocardial infarction that occurs more frequently in Women [85] should be suspected in any young woman who presents with an ACS without typical atherosclerotic risk factors [96]. The actual prevalence of Spontaneous coronary artery dissection is unknown, but current data suggest a prevalence of 0.2% to 4% [97-99] of patients undergoing cardiac catheterization, and it is reported to occur in 10.8% of women

Elsayed YMH (2019) Atypical Presentations of Acute Coronary Syndrome in Elderly, Women, and Diabetic Patients-Updating Review. int j cardiol res; 1(1): 1-26. associated with age-related physiological changes and multiple pathologies [118]. The higher prevalence of asymptomatic myocardial ischemia or with atypical symptoms in elderly is explained by increased pain threshold related to nociceptive changes and by the great prevalence of diseases such as depression and diabetes mellitus. Increased beta-endorphins levels have also been described in patients with asymptomatic myocardial ischemia [119]. In fact, the progressive increase occurs in the interval between the beginning of ST-segment depression and the onset of angina with increased age [120], indicating increased pain threshold among elderly [10]. A period of 1-hour interval or less from the angina attack is not usually enough to produce such histological findings, commonly known as classic morphologic alterations of the MI [121]. Elderly patients have changes in pain perception and altered ischemic thresholds [122], but the exact explanation for atypical pain syndromes is not known [123]. Autopsy studies have shown that more than 50% of the people older than 60 years have significant CAD, with an increasing prevalence of left main and/or triple-vessel CAD with older age [124]. Subclinical vascular disease, i.e. abnormal echocardiograms, increased carotid intima-media thickness or an abnormal ankle-brachial index, is common in elderly people with electrocardiographic evidence of myocardial infarction [123].

Prognosis and Mortality

Coronary heart disease is the leading cause of death among elderly patients [ 13] , in the developed world [27]. Advanced age is the single strongest risk factor for coronary artery disease and independent predictor for poor outcomes following an acute coronary syndrome [27].

Mortality is at least three-fold higher in patients older than 85 years compared with the younger than 65 years of age group [27]. The mortality rate after a first non-ST

segment elevation myocardial infarction in very elderly patients is very high [125]. The Framingham risk score underestimates risk stratification in women and classified greater than 90% women as low risk [126] (Table 3). Despite the women confer poorer outcomes than men but, diabetes has the greatest risk for coronary heart disease in women [127]. Coronary heart disease mortality rates three times is higher in diabetic women than in non-diabetic women [128]. Diabetic women have a more diffuse and non-obstructive pattern of coronary artery disease [129]. Cardiovascular disease is the principal cause of mortality and chest pain is the most frequent symptom in acute coronary artery disease with diabetes mellitus [8]. Coronary artery disease confers the foremost source of morbidity and mortality in diabetic patients with higher mortality after an acute cardiac event compared to non-diabetic [8]. Atypical symptoms go unrecognized in diabetes patients with non-cardiac chest pain, were associated with an increased risk of non-fatal and fatal coronary events [130].

Diagnosis and Clinical Presentation

Both efficacy and speed are necessary for effective management of acute coronary syndrome [131].

A high index of suspicion for an acute coronary syndrome is a pivotal, especially when evaluating women, diabetes, and older patients [132]. Atypical presentation of the acute coronary syndrome can range from a wide spectrum non-chest pain symptoms of silent myocardial ischemia to an epileptic seizures [7,8]. Presenting symptoms are classified as typical and all other symptoms as atypical, while asymptomatic was classified as silent [33]. Although, chest pain is the most common presentation of acute coronary syndrome [9] in elderly, women, and diabetic patients, they are also known to present with atypical symptoms such as either non-specific chest pain, particularly localized in the neck, back, jaw, and head or non-specific symptoms. The other non-specific symptoms

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Elsayed YMH (2019) Atypical Presentations of Acute Coronary Syndrome in Elderly, Women, and Diabetic Patients-Updating Review. int j cardiol res; 1(1): 1-26. of atypical presentation of the acute coronary syndrome such as weakness, fatigue, syncope, profuse sweating, nausea, vomiting, wheezing, dyspnoea, or cough, anxiety, rapid or irregular heart rate, and fullness, indigestion, or choking feeling [25,26,41,81]. (Table 1).

The spectrum of presentation changed significantly with increasing age [133]. Presenting symptoms of acute myocardial infarction differ in the elderly from those in younger patients [123]. Presenting symptoms of chest pain in elder were classified as typical and all other symptoms as atypical, while asymptomatic was classified as silent [39]. Atypical presentation of myocardial infarction is most commonly seen in individuals older than 75 years and in women [123].

Unfortunately, coronary artery disease remains understudied, underdiagnosed, and undertreated in women [12]. However, totally asymptomatic women are still considered at low risk for coronary disease unless they have diabetes or peripheral arterial disease [134].

Atypical presenting symptoms were recorded twice as frequently in diabetic patients diagnosed with angina compared with non-diabetic. The clinical history is the cornerstone of diagnosis in patients presenting with stable chest pain [130]. The cost of routine screening for CHD in patients with asymptomatic diabetes would be enormous and unnecessary because the presence of diabetes is a CHD equivalent [135]. Silent myocardial ischemia, infarction, and sudden cardiac death occur most often in patients who also have autonomic dysfunction [31]. Silent myocardial infarction is most often diagnosed using the 12-lead electrocardiogram for screening purposes [136]. With a high index of suspicion, early acquisition and interpretation of ECG, with subsequent serial tracings are critical for early diagnosis of ACS in the elderly person [27]. However, Dynamic ST segment and T

wave changes provide high sensitivity for detecting ischemia [27]. Newer imaging techniques such as; myocardial perfusion, single photon emission computed tomography, myocardial perfusion SPECT, and cardiac magnetic resonance offer better diagnostic capability [137]. The objective evidence for silent myocardial ischemia includes ST-segment shifts (usually depression), reversible regional wall motion abnormalities, and perfusion defects on scintigraphic studies [138]. Patients suffering from silent ischemia have central nervous activation different from those with angina when subjected to ischemic dobutamine stress, predominating the frontal cortex and ventral temporal Activation [139]. Interestingly, the thalamic area, which is responsible for the recognition of pain, had similar activation in patients with and without angina [135]. Initial and serial cardiac enzymes, with the most sensitive biomarker cardiac troponin (cTn) levels, are sensitive and specific in diagnosing ACS [27].

Prevention and Management

The absent or atypical clinical signs in elderly persons hinder the management of coronary heart disease [36]. Therefore, in elderly patients, atypical symptoms of coronary insufficiency should be valued, and to confirm or not a diagnosis of myocardial ischemia, the search through additional tests should be more rigorous [36]. Aggressive lifestyle modification (e.g. smoking cessation, dietary intervention, weight control) and pharmacological secondary prevention (e.g. tight blood glucose and blood pressure control and statin therapy) are indicated for older adults treated for ACS [27]. Despite the known sex differences in clinical presentation, management and outcomes of patients with coronary heart disease, possible differences in primary and secondary prevention have received less attention [140]. Three categories emerged to explain why women delay in seeking treatment:

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Elsayed YMH (2019) Atypical Presentations of Acute Coronary Syndrome in Elderly, Women, and Diabetic Patients-Updating Review. int j cardiol res; 1(1): 1-26. 1. Clinical,

2. Psychosocial factors, and

3. Sociodemographic.

These factors are found to be multifaceted and complex. Effective treatment in women is time dependent as mortality and morbidity rise with each hour of delay [140]. Management of cardiovascular autonomic neuropathy (CAN) is a pivotal and essential step (see above). The effects of other conventional antianginal therapies, namely B-blockers and calcium antagonists, alone and in combination, on silent ischemia have been extensively investigated [6]. The logical progression of this idea was that silent ischemia would respond more favorably to treatment with calcium antagonists, which act as vasodilators, than to B-blockade. The theory was not supported, however, by the multiple studies that have unequivocally shown that B-blockers reduce the incidence, frequency, duration, and severity of silent ischemia in a dose-dependent manner [141-143]. Calcium antagonists, phenylalkylamine, benzothiazepine, and dihydropyridine derivatives, have demonstrated efficacy in reducing silent ischemia6. In fact, B-blockers are in most cases superior to calcium antagonists alone in the reduction of the total ischemic burden [144,145]. The addition of a calcium antagonist toblockade has been shown to improve objective measures of ischemia, [146,147] and the combination of both types of agents has been found to be superior to either type alone in reducing ischemia [144,148]. In both APSIS and TIBET trials; B-blockers or calcium antagonists or their combination who showed a significant reduction in the total ischemic burden [149, 150]. In ASIST study [151] (atenolol versus placebo) reports a treatment benefit favoring patients with the abolition of ischemia on ambulatory monitoring, but a substantial proportion of this benefit is yielded from the reduction in aggravation of angina rather than objective acute events. TIBBS trial [152] (a study of bisoprolol and nifedipine and their

combination) reported a significant prognostic advantage for 100% eradication of ischemia. This was, however, due to a significant reduction in angina requiring revascularization. In the 2-year follow-up of the ACIP trial, conducted in patients with ambulatory ischemia as a prerequisite for entry, revascularization, particularly surgery, was superior to pharmacological therapy in improving prognosis [153].

Statins have been shown to offer consistent benefit for secondary prevention of cardiovascular events among patients with diabetes, compared with placebo [154]. Trials of most guideline-indicated pharmacotherapy for patients with ACS and diabetes have demonstrated similar or greater risk reduction than for patients without diabetes [154]. There was a lower mortality rate with a blood glucose target of below < 180 mg/dL than with a target of 81–108 mg/dL [155]. Coronary artery bypass grafting is preferred to percutaneous coronary intervention for patients with diabetes and multivessel disease, although the latter is reasonable in single-vessel disease [154]. The recommendations of the ACCF/AHA are that for patients with diabetes and single-vessel disease in non-STEMI ACS [156] or acute coronary occlusion of the infarct-related vessel in STEMI should be managed with PCI, but CABG is preferred for the management of multivessel disease [157]. There is no clear evidence that the usual post-ACS medications are less efficacious in women than in men [154]. The available evidence shows equivalent efficacy for the post-ACS use of aspirin [158], clopidogrel [159] and ticagrelor [160], as well as the short- and long-term use of β-blockers [161], statin therapy [162] and angiotensin-converting enzyme inhibitors [163] after myocardial infarction.

Conclusion and Recommendations

A high index of suspicion for acute coronary syndrome should be maintained, especially when evaluating the older, women, and diabetes patients. Patients with atypical

Elsayed YMH (2019) Atypical Presentations of Acute Coronary Syndrome in Elderly, Women, and Diabetic Patients-Updating Review. int j cardiol res; 1(1): 1-26. presentations of silent myocardial ischemia and those without chest pain should be always in the physician mind especially in high-risk groups. Necessary lifesaving measures immediately should be taken for high-risk patients. Thus, the education is essential for health care professionals especially; the general practitioners, emergency physicians, cardiologists, and intensivists to able to recognize atypical symptoms of ACS.

Acknowledgement

I wish to thank Dr. Ameer Mekkawy; M.sc. for technical support.

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