Canadian Cardiovascular Society grading of angina pectoris.
\n\n
\n\nThe project work was funded by the European Commission (EC) 7th Framework Programme (FP7), under the 9th Call for projects on Information and Communication Technologies. The publishing of this book was funded by the EC FP7 Post-Grant Open Access Pilot programme. 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Nguyen received his M.A. in Mathematics, and his Ph.D. in Applied Mathematics from the Claremont Graduate University; M.S.E.E. in Communication Systems Theory from University of California San Diego; and B.S.E. in Electronics and M.S.E. in Electromagnetic Field Theory from California State University Fullerton (CSUF). He also completed all course requirements and passed the comprehensive exam for his M.S.E.E. in Digital Signal Processing from California State University Long Beach. Dr. Nguyen is an expert in Satellite Operations (SATOPS), Satellite Communications (SATCOMs), advanced mathematical modeling for complex systems-of-systems, sensing and communication networks.\nCurrently, he serves as Adjunct Research Professor at CSUF, Mathematics Dept. Concurrently, he is also with the Aerospace Corporation, serving as a Deputy Chief System Architect in Space Systems Architect, Global Partnerships Subdivision. He has more than 13-years of service at Aerospace, and prior to his current position; he has served as Sr. Engineering Specialist, Sr. Project Lead, Section Manager, Associate Director, Interim Director, and Principal Technical Staff (the highest technical level at the corporation). At Aerospace, he invented HPA linearizer, GMSK synchronizers and developed advanced optimization techniques using game theory for achieving affordable and low-risk acquisition strategy. Prior to CSUF, he had also held a Research Assistant Professor at the Catholic University of America in concurrent with The Aerospace Corporation positions. \nHe was a Engineering Fellow from Raytheon, where he had 10-year of services at Raytheon, serving as Program Area Chief Engineer, Program Chief Engineer, PI, Technical Director, Program Manager, Lead Architect and Lead System Engineer for many advanced programs and pursuits related to sensing and communication networks. At Raytheon, he invented radar-communication technology and gun barrel detector using millimeter-wave. Previous to Raytheon and Aerospace Corporation, Dr. Nguyen was with NASA/JPL for more than 11-years, where he served as the NASA delegate to the international Consultative Committee for Space Data System (CCSDS). Many of his works on RF and Modulation were adopted as the CCSDS standards for USB waveforms and space RF systems. At JPL he invented QPSK phase ambiguity resolver and developed innovative optimization technique for simultaneous range-command-telemetry operation. He built the first laser lab and automated manufacturing lab when he was with ITT Technical Services in the early ’80s. \nHe has published more than 250 technical reports and papers. His work has appeared in NASA TechBrief, textbook, Open Access Book, SIAM Publication, CCSDS Blue Book, and Wiley & Sons Encyclopedia of Electrical and Electronics Engineering. He was selected as a Vietnamese-American Role Model by KCSI-TV, Channel 18 in 2002, and Recognition Honoree at 50-Year Celebration of CSUF in 2007. He received numerous Raytheon, Aerospace and NASA awards, and Air Force commendations. He holds 16 patents and has 01 patent pending. His biography has been listed in Marquis Who’sWho in Science and Engineering in America.",institutionString:"The Aerospace Corporation",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"California State University, Fullerton",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:[{id:"72485",title:"Satellite Control System: Part I - Architecture and Main Components",slug:"satellite-control-system-part-i-architecture-and-main-components",totalDownloads:157,totalCrossrefCites:0,authors:[null]},{id:"72443",title:"Effective Algorithms for Detection Outliers and Cycle Slip Repair in GNSS Data Measurements",slug:"effective-algorithms-for-detection-outliers-and-cycle-slip-repair-in-gnss-data-measurements",totalDownloads:71,totalCrossrefCites:0,authors:[null]},{id:"72147",title:"Future Satellite System Architectures and Practical Design Issues: An Overview",slug:"future-satellite-system-architectures-and-practical-design-issues-an-overview",totalDownloads:132,totalCrossrefCites:0,authors:[{id:"210657",title:"Dr.",name:"Tien",surname:"Nguyen",slug:"tien-nguyen",fullName:"Tien Nguyen"}]},{id:"72340",title:"Game Theoretic Training Enabled Deep Learning Solutions for Rapid Discovery of Satellite Behaviors",slug:"game-theoretic-training-enabled-deep-learning-solutions-for-rapid-discovery-of-satellite-behaviors",totalDownloads:101,totalCrossrefCites:0,authors:[null]},{id:"72725",title:"Communication Subsystems for Satellite Design",slug:"communication-subsystems-for-satellite-design",totalDownloads:239,totalCrossrefCites:0,authors:[null]},{id:"72839",title:"Overview of Existing and Future Advanced Satellite Systems",slug:"overview-of-existing-and-future-advanced-satellite-systems",totalDownloads:58,totalCrossrefCites:0,authors:[null]},{id:"72620",title:"Dynamic Link from Liftoff to Final Orbital Insertion for a MEO Space Vehicle",slug:"dynamic-link-from-liftoff-to-final-orbital-insertion-for-a-meo-space-vehicle",totalDownloads:58,totalCrossrefCites:0,authors:[null]},{id:"72311",title:"System Designs of Microsatellites: A Review of Two Schools of Thoughts",slug:"system-designs-of-microsatellites-a-review-of-two-schools-of-thoughts",totalDownloads:154,totalCrossrefCites:0,authors:[null]},{id:"72742",title:"Design of Intelligent and Open Avionics System Onboard",slug:"design-of-intelligent-and-open-avionics-system-onboard",totalDownloads:48,totalCrossrefCites:0,authors:[null]},{id:"74274",title:"Analysis of Spatiotemporal Variability of Surface Temperature of Okhotsk Sea and Adjacent Waters Using Satellite Data",slug:"analysis-of-spatiotemporal-variability-of-surface-temperature-of-okhotsk-sea-and-adjacent-waters-usi",totalDownloads:35,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"205697",firstName:"Kristina",lastName:"Kardum Cvitan",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/205697/images/5186_n.jpg",email:"kristina.k@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Despite these shortcomings, it is important to determine the underlying etiology of cardiomyopathy, both for evidenced-based clinical practice and for research purposes. This chapter offers a definition of ischemic cardiomyopathy, the most common form of heart failure, as well as describes its epidemiology, pathophysiology, diagnosis, evaluation, and treatment. It aims to facilitate for clinicians who treat patients with ischemic cardiomyopathy, researchers, and other professionals with an interest in the field and also patients and their relatives.
\nThe term ischemic cardiomyopathy describes a state of left ventricular systolic dysfunction due to coronary artery disease [1]. However, both European and American guidelines refer to the concept of cardiomyopathy as a primary heart muscle disease rather than the acquired forms of heart disease [2, 3]. Clinically, and for definitions in numerous scientific studies, patients with heart failure attributed to ischemic etiology are labeled as having ischemic cardiomyopathy. Thus, a heart failure patient with a history of myocardial infarction and evidence of coronary artery disease from imaging tools or functional tests is said to have an ischemic etiology. In practice, the etiology in an individual patient is not always clearly discernable. Patients with heart failure and no coronary artery disease may have angina/wall motion abnormalities [4]. On the other hand, severe coronary artery disease does not necessarily imply symptoms, myocardial infarction, or heart failure [1]. Even with information from an invasive coronary angiography when evaluating heart failure, the etiology is not always unambiguous. In science, the same overlap between an ischemic cause and other contributing causes frequently occur; heart failure may be complicated by hypertension, diabetes mellitus, valvular disease, and other factors that may interplay [5]. Nevertheless, it is important to interpret subgroup analyses with this in mind as it may explain inconsistency between studies. It has been proposed that patients with single-vessel disease should be classified as having nonischemic cardiomyopathy [1]. Typically, patients with ischemic cardiomyopathy include those with reduced ejection fraction with a cutoff at 35–40%, although this is also somewhat arbitrary [1, 6]. The boundaries between ischemic, nonischemic, and mixed dilated cardiomyopathy are worth taking into account depending on the context [7].
\nIschemic cardiomyopathy is common, and it is increasing worldwide based on risk factors for coronary artery disease becoming more prevalent. According to the World Health Organization (WHO), ischemic heart disease is considered the most common cause of death worldwide, and cardiovascular heart disease, which is predominantly coronary artery disease, claims a global death toll of 17.7 million every year, comprising 31% of all deaths [8]. More than three quarters of cardiovascular deaths come from low- and middle-income countries [9]. Furthermore, coronary artery disease is considered the most common cause of heart failure which affects 1–2% of the general population and 10% of people aged 70 years or more [10]. The risk of having heart failure diagnosed during the remaining lifetime at an age of 55 years is higher for men (33%) than women (28%) [11]. Etiological causes of heart failure are diverse, but the ischemic component is considered to be the largest contributor. Ischemic heart disease includes myocardial scar, stunning/hibernating myocardium, epicardial coronary artery disease, abnormal coronary microcirculation, and endothelial dysfunction [6]. The incidence of ischemic cardiomyopathy is likely to increase globally over the coming decades.
\nThe pathophysiology consists of two major mechanisms: reversible and irreversible damage of the myocardium that results in reduced myocardial function and cardiac output, with progression into a dilated phase. This myocardial damage is typically caused mainly by atherosclerosis of coronary arteries that result in reduced perfusion of cardiac muscle tissue, which clinically presents as acute coronary syndromes: ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina pectoris. Both STEMI and NSTEMI are characterized by the presence of necrosis of the myocardium and elevated cardiac biomarkers, whereas unstable angina is characterized by myocardial ischemia without necrosis of myocardial cells; however, all forms of myocardial ischemia can cause impaired myocardial function and ischemic cardiomyopathy. Prompt revascularization restores parts of viable myocardium, whereas other parts undergo necrosis and are thus irreversibly damaged. The transient myocardial depression during acute coronary syndrome is referred as stunning. Long-lasting but potentially reversible ischemic depression is described as hibernating myocardium. Hibernation and stunning are interchangeable when it occurs from repetitive temporary ischemic triggers [12]. This is important to recognize as triggers may be managed, and successful revascularization in conjunction with an optimal pharmaceutical approach may improve ejection fraction. From this perspective ischemic cardiomyopathy is a dynamic disease. It does not necessarily lead to deterioration and clinical improvement is possible. Occlusion of a coronary artery causes a localized myocardial injury in areas of reduced perfusion, whereas global coronary artery disease may lead to diffuse myocardial injury. Both global and localized myocardial impairments constitute components of ischemic cardiomyopathy.
\nCoronary artery disease is a consequence of atherosclerosis, which is attributed to many risk factors. Increasing age and male sex independently imply higher risk. The majority of risk factors are modifiable. In the international study INTERHEART, several risk factors for myocardial infarction were identified [13]. In this study, moderate amount of alcohol was beneficial, especially in women, but these results should be interpreted with caution:
ApoB/ApoA1 ratio
Smoking
Diabetes mellitus
Physical inactivity
Psychosocial risk factors
Abdominal obesity
Hypertension
Diet (less fruit/vegetables)
There is a strong age-related increase of atherosclerosis and myocardial infarction. Approximately 4% of the population, aged 75–84 years, suffers from symptomatic coronary disease [14]. There is a strong link between angina and risk of coronary artery disease mortality on a group level [14, 15]. Hypertension has been demonstrated to be causally linked to coronary artery disease [16]. Hypercholesterolemia is a major pathway to manifest coronary disease, and clinical events have been shown in this group in several studies over decades [16, 17, 18, 19]. Diabetic patients have an approximately threefold risk of myocardial infarction based on increased risk of coronary artery disease [20]. Smoking is a risk factor because of its vascular damaging effects [21]. Obesity and lifestyle factors, such as physical inactivity, also constitute risk factors [22]. Family history is complex but is an independent risk factor for coronary artery disease [23]. These factors, often in combination, may lead to multivessel disease; ischemic cardiomyopathy patients have more proximal locations of stenoses, greater lumen loss lesions and thus more extensive ischemic burden, and severe clinical manifestation with reduced working capacity [24].
\nIschemic cardiomyopathy patients present with the same general symptoms that are common in heart failure regardless of etiology. Typical symptoms of ischemic cardiomyopathy are breathlessness, orthopnea, exercise intolerance, fatigue, ankle swelling, less typically nocturnal cough, wheezing, bloated feeling, loss of appetite, confusion, palpitations, dizziness, and syncope. Symptoms are often accompanied by signs such as elevated jugular venous pressure, hepatojugular reflux, third heart sound (gallop rhythm), and laterally apical chamber impulse. There may also be less specific signs: weight gain due to fluid retention but also weight loss and cachexia in advanced heart failure, hepatomegaly, ascites, cold extremities, oliguria, and crepitations at pulmonary auscultation [6]. The first presentation might be as acute coronary syndrome, arrhythmias (atrial/ventricular tachycardia or bradycardia), or thromboembolic complications of left ventricular thrombus/atrial fibrillation after myocardial infarction such as stroke or systemic thromboembolism. Psychiatric symptoms such as depression and anxiety are common as a consequence of the mentioned symptoms and signs [25].
\nThe New York Heart Association (NYHA) Functional Classification is frequently used to classify heart failure into four categories according to the severity of symptoms [26]:
NYHA Class I: asymptomatic.
No limitation in physical activity despite the presence of heart disease. This can be suspected only if there is a history of heart disease, which is confirmed by investigations, for example, echocardiography.
NYHA Class II: mild.
Slight limitation in physical activity, more strenuous activity, causes shortness of breath, for example, walking on steep inclines or several flights of steps. Patients in this group can continue to have an almost normal lifestyle and employment.
NYHA Class III: moderate.
More marked limitation of activity that interferes with work. Walking on flat ground produces symptoms.
NYHA Class IV: severe.
Unable to carry out any physical activity without symptoms, patients are breathless at rest and mostly housebound [26].
History taking and physical examination remain important, but laboratory tests and cardiac imaging are today a key part of diagnosis and management of ischemic cardiomyopathy.
\nAssessment of risk factors for atherosclerosis and cardiovascular disease is an important part of the history and can support clinicians by enabling the classification of patients into three categories, low-, intermediate-, and high-risk groups, and thus aid in the selection of appropriate testing and treatment to minimize risk. According to American guidelines for assessment of cardiovascular risk, global risk scores (such as the Framingham Risk Score) that use multiple traditional cardiovascular risk factors should be obtained for risk assessment in asymptomatic adults without a clinical history of cardiovascular disease. These scores are useful for combining individual risk factor measurements into a single quantitative estimate of risk that can be used to target preventive interventions [27, 28]. Framingham Risk Score is an algorithm used in assessment of 10-year cardiovascular risk and is based on data that was obtained from the Framingham Heart Study, which is a study on the residents of the city of Framingham, Massachusetts, that began in 1948 [27, 28]. The predictors used in the Framingham Heart study are age, sex, diabetes mellitus, smoking, treated and untreated systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, and body mass index (BMI) replacing lipids in a simplified model [30]. Moreover, familial history of coronary artery disease should be investigated to assess the risk of ischemic heart disease in asymptomatic individuals [27, 28]. This assessment of risk factors and classification of risk groups determine the next step of investigations and treatment; for example, low risk patients do not need further investigations for risk evaluation. On the other hand, intensive preventive interventions are already indicated in high-risk patients, and thus further testing or risk assessment would not give additional benefit [27]. Other manifestations of atherosclerosis such as stroke, carotid artery disease, and intermittent claudication are signs of increased risk for ischemic heart disease because atherosclerosis is generalized and can affect any part of the vasculature [29]. History taking should also include questions about symptoms that indicate the presence of ischemic heart disease, such as retrosternal chest pain or discomfort that indicates angina, and this is often described as squeezing, burning pain or as a pressure, tightness, fullness, or a heavy weight in the middle of the chest that extends to the neck, left arm, jaw, and back. These symptoms can be accompanied by sweating, nausea, and vomiting [30]. Angina itself can be stable or unstable angina, and unstable angina comes in many different forms according to the American Heart Association [31]:
Rest angina within 1 week of presentation.
New-onset angina of the Canadian Cardiovascular Society (CCS) classification grade III or IV within 2 months of presentation.
Angina increasing in CCS grade to at least grade III or IV.
Variant angina.
Non-Q-wave myocardial infarction.
Post-myocardial infarction angina (>24 hours).
Canadian Cardiovascular Society (CCS) grading of angina pectoris is a practical way to define severity of angina by the level of physical activity needed for symptoms to arise (Table 1) [30].
\nGrade | \nActivity evoking angina | \nLimits to normal activity | \n
---|---|---|
I | \nProlonged exertion | \nNone | \n
II | \nWalking >2 blocks | \nSlight | \n
III | \nWalking ≤2 blocks | \nMarked | \n
IV | \nMinimal or rest | \nSevere | \n
Canadian Cardiovascular Society grading of angina pectoris.
Physical examination is of value in the assessment of a patient with suspected ischemic cardiomyopathy and grants important information. Heart murmurs and sounds might indicate valvular disease or other hemodynamic defects. Swelling of the ankles, an enlarged liver, crepitations on lung auscultation, and tachycardia can be signs of congestive heart failure [32]. Signs of atherosclerosis risk factors can predict the presence of coronary artery disease, for example, abdominal obesity and xanthelasma that is often associated with hyperlipidemia.
\nBlood pressure might be elevated, which is a risk factor for atherosclerosis and myocardial infarction, or it might be low, which could indicate hemodynamic compromise because of decreased cardiac output in severe heart failure. According to the American College of Cardiology guidelines from 2017, blood pressure is classified as normal, elevated, stage 1, or stage 2 hypertension (Table 2) [31].
\nClassification | \nBlood pressure | \n
---|---|
Normal | \n<120/<80 mmHg | \n
Elevated | \n120–129/<80 mmHg | \n
Hypertension stage 1 | \n130–139 or 80–89 mmHg | \n
Hypertension stage 2 | \n≥140 or ≥90 mmHg | \n
Blood pressure classification according to ACC guidelines 2017.
A 12-lead electrocardiography (ECG) is simple, easily accessible, cheap, and noninvasive as well as an important tool in the management of ischemic cardiomyopathy. It is recommended that a 12-lead ECG is performed in patients with hypertension or diabetes mellitus even if no symptoms are present. Additionally, in patients without these risk factors and without symptoms, it may still be of value [27].
\nMyocardial ischemia may present with different changes on ECG, and these changes may appear temporarily during acute myocardial ischemia (e.g., ST-segment elevations) or remain permanently such as pathological Q-waves after a transmural infarction:
ST-segment morphology changes [33]. ST-segment elevation occurs in acute STEMI, whereas ST-segment depression occurs in NSTEMI or unstable angina.
T-wave morphology changes. The T-wave becomes upright and tall, coronary T-waves, in the first few minutes of myocardial infarction (STEMI) or may be become inverted/negative in NSTEMI and unstable angina.
Pathological Q-waves which are negative and deep appear on ECG in transmural myocardial infarction and remain as a sign of permanent damage [33].
Tachyarrhythmias such as ventricular tachycardia and ventricular fibrillation or bradyarrhythmia such as atrioventricular block degrees I–III.
New left bundle branch block and less commonly right bundle branch block.
ECG abnormities may provide clues for the diagnosis of ischemic cardiomyopathy but have low specificity [34]. ECG signs can guide therapy. If atrial fibrillation is present, lifelong oral anticoagulation is warranted since all patients with ischemic cardiomyopathy and atrial fibrillation are at risk of thromboembolism. Symptomatic sinus node dysfunction or high-degree atrioventricular block can necessitate permanent pacemaker, except for intermittently during the acute phase of STEMI/NSTEMI because bradyarrhythmia is often transient following myocardial infarction. In ischemic cardiomyopathy patients with bundle branch block, typically left, cardiac resynchronization therapy (CRT) can be an option to improve symptoms of heart failure and survival. A completely normal ECG makes ischemic cardiomyopathy unlikely.
\nLaboratory tests can reveal and quantify many risk factors for ischemic cardiomyopathy, such as diabetes mellitus, hypercholesterolemia, renal failure, and C-reactive protein (CRP) [35].
\nCreatine kinase-MB (CK-MB) is a myocardial enzyme that is elevated in blood in cardiac muscle damage and ischemia, but it is not a specific marker for myocardial ischemia and can be elevated in other conditions, for example, renal failure, rhabdomyolysis, heart failure, and hypothyroidism [36, 37].
\nCardiac troponins are proteins that regulate the contraction of striated muscles and include three subunits (troponin C, troponin T, and troponin I) [38]. Cardiac troponin T and troponin I are cardiac regulatory proteins that control the calcium-mediated interaction between actin and myosin [39]. Cardiac troponin C is also identified in skeletal muscles, and thus it is not specific for myocardial damage [37]. The elevation of serum levels of cardiac troponins (T, I) is used in the diagnosis of acute myocardial infarction as a biochemical marker [39, 40]. They are superior compared to CK-MB as biomarkers for detection of the myocardial damage that is associated with myocardial infarction, and moreover, while levels are affected by renal function, they still have a reliable predictive value in patients with acute coronary syndrome regardless of renal function [41]. The raised cardiac troponin in serum may not be detectable for up to 4 hours after myocardial infarction; therefore, repeated tests should be performed again, for example, after 3 and 9 hours, if troponins were not raised on admission in patients with suspected acute coronary syndrome [39, 42]. Troponin I has a high specificity for myocardial muscle injury. Troponin I has three isoforms: cardiac, skeletal slow twitch, and skeletal fast twitch [36, 37]. It does not increase in skeletal muscle diseases, after normal physical exercise or in hypothyroidism [36]. It is not detected in healthy individuals without acute coronary syndrome or another disease with damage to myocytes such as myocarditis [36, 43]. Raised cardiac troponins have an important diagnostic and prognostic value in acute coronary syndrome, caused by atherosclerosis and occlusion of coronary arteries (primary myocardial ischemia), but it can be detected in secondary myocardial ischemia associated with many other conditions such as cardiac arrhythmias, large pulmonary embolization, heart failure of other etiologies such as idiopathic dilated cardiomyopathy and hypertrophic cardiomyopathy, or after therapeutic procedures, for example, coronary intervention (angioplasty), vasospastic angina, electrophysiological ablations, or electrical cardioversions [38, 39]. Furthermore, raised cardiac troponins can be caused by nonischemic myocardial damage in conditions such as perimyocarditis, cardiac trauma, septicemia, and chemotherapy [39]. In addition, cardiac troponins are raised in patients with renal failure without acute coronary syndrome, and the exact mechanism of this increase of cardiac troponin levels is still unclear, although raised cardiac troponin I in individuals with renal failure is controversial [36, 37, 39]. It appears that elevated troponin in renal failure is not associated with myocardial infarction rather with chronic myocardial damage and depends upon the assay technology [42]. However, cardiac troponins remain of predictive value in individuals with chest pain and suspected acute coronary syndrome despite renal failure [39]. Cardiovascular death is common in end-stage renal disease, and both increased cardiac troponin I and T predict a two- to fivefold increase in mortality in these patients [41].
\nB-Type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) are secreted by ventricular cardiomyocytes as a result of stress and tension in the muscle fibers of the ventricular wall and by myocardial ischemia. They have a strong prognostic and diagnostic value in patients with heart failure. Both BNP and NT-proBNP are significantly elevated in individuals with systolic or diastolic myocardial dysfunction. High levels are predictive of worse prognosis and higher risk of cardiovascular death and readmission to hospital. Furthermore, BNP and NT-proBNP levels indicate the severity of heart failure [44]. Until recently, the clinical application of BNP and NT-proBNP measurement in patients with coronary artery disease has been unclear, but many recent studies have found that both BNP and NT-proBNP levels increase in myocardial ischemia and acute coronary syndromes. This has led to the suggestion that these biomarkers can be secreted by cardiomyocytes as a direct result of myocardial ischemia regardless of ventricular wall stress [44, 45]. In support of this, it has been found that transient myocardial ischemia that occurs due to coronary interventions (stent inflation) can lead to elevation of BNP levels [46]. However, the diagnostic and prognostic value of these biomarkers in coronary artery disease remains unclear, and further investigations are needed.
\nCardiac imaging is an essential tool in understanding heart failure and guiding treatment. Historically, X-ray played a role to show pulmonary congestion and may add other clues to a dyspnea investigation. Instead, today echocardiography is the cornerstone in management of heart failure. It provides information about the morphology of all four chambers, function of wall motion and valves, ejection fraction, pulmonary artery pressure, and pericardial effusion, and is available, noninvasive, and cheap. Other imaging methods are used in the evaluation and provide incremental value, some are an essential part of clinical practice, and others are mainly used in research, but this may change in the future.
\nTransthoracic echocardiography includes two- and three-dimensional techniques, pulsed and continuous Doppler, color Doppler, tissue Doppler imaging and contrast, and strain measurements. Assessment of ejection fraction is important as it guides therapeutic choices with regard to pharmaceutical agents and device therapy and provides information about prognosis. Therefore the method used to determine ejection fraction is crucial. According to ESC guidelines, Simpson’s rule is the preferred choice. It should be obtained from the apical four-chamber view and two-chamber view but requires accurate tracing of the endocardium. Echocardiography is the most common diagnostic investigation for coronary artery disease after ECG and chest X-ray [47] and can provide detailed information about left ventricular function, cardiac output, left ventricular ejection fraction, wall motion abnormalities in ischemic cardiomyopathy, and possible complications of acute coronary syndromes such as myocardial aneurysm [48], mitral regurgitation secondary to papillary muscle dysfunction or rupture [47, 49], intracardiac thrombus [50], ventricular free wall rupture, and pseudoaneurysm formation after myocardial infarction [47]. Transthoracic echocardiography is an important tool in the assessment of patients with acute chest pain, both for diagnosis of acute coronary syndromes and for exclusion of other causes of acute chest pain such as aortic dissection and pericardial effusion.
\nEchocardiogram findings in ischemic cardiomyopathy include:
Decreased left ventricular ejection fraction, which is one of the most important predictors of mortality [51, 52].
Left ventricular diastolic dysfunction [53]. The evaluation of left ventricular dysfunction and filling pressures is of great benefit to distinguish ischemic cardiomyopathy from other syndromes that cause dyspnea such as pulmonary diseases [54].
Mitral and tricuspid regurgitations [53].
Detection of both localization and size of myocardial infarction [47].
According to 2013 ESC guidelines on the management of stable coronary artery disease, resting echocardiography should be performed in all patients with the first presentation of coronary artery disease:
Exclusion of alternate causes of angina.
Identification of regional wall motion abnormalities suggestive of coronary artery disease.
Measurement of left ventricular ejection fraction for risk stratification and quantification of heart failure severity.
Evaluation of diastolic function [54].
The principle of stress echocardiography is the combination of physical (treadmill or bicycle), pharmacological (dobutamine, dipyridamole, or adenosine), or electrical stress (external pacing) with two-dimensional echocardiography [56]. The goal of this technique is the provocation of myocardial ischemia that can be detected with a two-dimensional echocardiogram. It is a noninvasive and easy test for both the patient and the physician and has accuracy in diagnosis of coronary artery disease comparable to that of radionuclide stress perfusion imaging or cardiac magnetic resonance, but it is ultimately less expensive [57].
\nThe response of the myocardium depending on regional wall function during stress echocardiography can be classified into four patterns: normal, ischemic, necrotic, and viable [57].
Normal response: normokinetic wall function at rest and normo- or hyperkinetic at stress.
Ischemic response: normokinetic regional wall function at rest and hypokinesia, akinesia, or dyskinesia at stress. Stress exacerbates wall dysfunction.
Necrotic response: an area with wall dysfunction at rest stays immobile at stress.
Viability response: an area with dysfunction at rest responds either with recovery and improvement at stress or with improvement at an early phase of stress and thereafter impairment (biphasic response); this indicates viability despite ischemia.
A common indication for stress echocardiography is the diagnosis of coronary artery disease in the group of patients in whom exercise ECG is contraindicated, unfeasible, or not diagnostic [57, 58]. It can also be used in the assessment of viability in ischemic cardiomyopathy before revascularization. In addition, stress echocardiography can be used in the assessment of a patient with established coronary artery disease after revascularization, but also to evaluate the preoperative risk in patients with coronary artery disease and too reveal the region of ischemia in the myocardium.
\nComputed tomography of the coronary arteries is an accurate noninvasive diagnostic test for coronary artery disease [59]. In addition, it provides information on cardiac valves and chambers [60]. The main practical application of computed tomography angiography has been in the outpatient setting in patients with suspected coronary artery disease, but many studies now examine its application in the setting of low-risk chest pain patients in the emergency department [60]. The advantage of computed tomography angiography is its negative predictive value, while the method is lacking in positive predictive value (i.e., it is good at ruling out, but less good at confirming coronary artery disease) [60]. It should be considered in patients with lower risk of coronary artery disease as an alternative to stress testing or when results have been inconclusive [55].
\nMyocardial scintigraphy, positron emission tomography (PET), and single photon emission computed tomography (SPECT) all utilize radioactive isotopes for imaging. Scintigraphy forms two-dimensional images, while images from PET and SPECT form images in three dimensions. Scintigraphy and SPECT utilize gamma cameras to detect gamma radiation, while PET simultaneously detects two gamma rays emitted at a 180° angle to each other. Cardiac nuclear imaging at rest gives information about areas damaged by myocardial infarction and myocardial viability by mapping metabolism and perfusion. Exercise or pharmacological (usually dobutamine) stress testing provides information on the presence of angina and low perfusion in coronary arteries resulting in ischemia. Importantly, measurement of perfusion by scintigraphy is relative (not absolute) to the area with the highest perfusion. Because of this relative expression of quantification, three-vessel coronary disease with equally reduced perfusion in the whole heart might appear to be well perfused. In cases where this relative perfusion will be misleading, PET should be performed instead. The SHIFT trial viability substudy indicated that viability or absence thereof did not identify patients with more benefit from coronary artery bypass grafting [61]. However, decision-making about revascularization based on viability using imaging could be considered in special cases. Sympathetic innervation imaging with specific tracers can be used in heart failure for risk stratification, although this is seldom used in clinical practice [62]. Stress testing is valuable in the evaluation of manifest or suspected coronary artery disease; however, it is mainly those who are unable to perform exercise testing (treadmill or bicycle) or those with defects on resting ECG that make exercise ECG difficult to interpret (pacemaker rhythm/bundle branch block) that are in need of radionuclide imaging. Scintigraphy should also be considered in patients with high pretest probability of coronary artery disease as an alternative to exercise ECG. All nuclear imaging modalities expose the patient to a small, but not negligible, amount of ionizing radiation. PET and SPECT are further limited by comparatively high cost and limited accessibility (especially of PET tracers because of short half-life time) and are not routinely used. PET can be used to measure regional myocardial blood flow, by comparing this at maximal hyperemia, and at resting flow, an estimation can be made of noninvasive fractional flow reserve. This otherwise requires an invasive coronary angiography to measure (decline in arterial pressure over a stenosis) [63].
\nThe main advantage of magnetic resonance in the evaluation of ischemic cardiomyopathy is the ability to visualize scar tissue, which is nonviable and the remaining contractile myocardial tissue which is viable. In this context, there are two modalities of cardiac magnetic resonance tomography: the modality first utilizes late gadolinium enhancement in the assessment of nonviable tissue, and the second modality uses low-dose dobutamine stress magnetic resonance in the assessment of viable tissue [64]. The method assesses ventricular volumes, functions in addition to scar tissue, and is free of ionizing radiation; complications are rare and almost exclusively related to stress testing [65, 66, 67]. For patients with suspected coronary artery disease, normal cardiac magnetic resonance tomography is a predictor of good prognosis with 1-year cumulative incidence of adverse events at 1.0% (all-cause mortality, aborted sudden cardiac death, myocardial infarction), which is comparable to the population at large [67]. Moreover, magnetic resonance has been shown to both detected ischemic cardiomyopathy that was not previously suspected and conversely to find an alternate diagnosis in previously suspected coronary artery disease [65, 66].
\nInvasive coronary angiography is a procedure where a catheter is inserted into the coronary arteries, usually through the radial artery. By using radiocontrast and X-ray images, coronary vasculature can be assessed. Coronary angiography retains the advantage that if a stenosis or culprit lesion requiring intervention is found, it can be treated by balloon angioplasty and the insertion of a stent. Fractional flow reserve is a way of determining the physiological significance of a stenosis and is the ratio of blood pressure measured distally to and proximally to the stenosis; this is usually considered to be significant at 0.8 [68]. The purpose should be to either perform coronary angiography to treat confirmed coronary artery disease (percutaneous coronary intervention) or to rule out stable coronary artery disease with noninvasive testing: Only if this has failed, a diagnostic coronary angiography should be considered [55]. Patients with severe angina (CCS 3) should perform coronary angiography, as well as patients with a clinical profile or noninvasive testing indicating high risk of cardiovascular death or myocardial infarction [55].
\nBroadly speaking, the treatment of ischemic cardiomyopathy could be said to consist of four strategies: the primary and secondary prevention of coronary artery disease, anti-ischemic treatment such as revascularization and antiplatelet therapy, treatment of heart failure with medications or cardiac devices, and the prevention and treatment of arrhythmia and sudden cardiac death that often accompany ischemic cardiomyopathy.
\nPhysical activity, weight loss in patients with the metabolic syndrome or obesity, cessation of smoking, and treatment of hypertension, diabetes mellitus, and hypercholesterolemia (especially lowering of LDL) prevent progression of coronary artery disease and thus the development or worsening of ischemic cardiomyopathy [69].
\nAll individuals with coronary artery disease have high risk of cardiovascular events and should be treated with statins according to the recommendations of the ESC/European Atherosclerosis Society guidelines for the management of dyslipidemia, regardless of low-density lipoprotein cholesterol (LDL-C) levels [70]. The goal of treatment is to reach LDL-C target <1.8 mmol/L and/or >50% reduction if it could not reach the target level [55]. Other medications (e.g., fibrates, resins, nicotinic acid, and ezetimibe) may reduce the LDL cholesterol level without any benefit on clinical outcomes [55].
\nIschemia is by definition the root cause of ischemic cardiomyopathy; thus, targeting this pathophysiological mechanism is of great importance for prevention and treatment. Revascularization should if possible be the first line of therapy in acute coronary syndrome. Antiplatelet therapy inhibits the formation of blood clots in coronary arteries, thereby decreasing risk of myocardial infarction, while other medications increase vasodilation and coronary blood flow or decrease heart rate and myocardial oxygen demand.
\nIn patients with ischemic cardiomyopathy, revascularization should always be considered in addition to optimal pharmacological treatment [71]. Revascularization can be performed as open heart surgery, coronary bypass grafting, or percutaneous coronary intervention. The choice of method should be discussed with expertise in revascularization preferably including cardiothoracic surgery and anesthesiology in selected cases. In one study, all-cause mortality after 9.8 years was significantly lower in the coronary artery bypass graft group compared with patients in the medical therapy group (59 versus 66% [359 versus 398 patients]; hazard ratio 0.84; 95% confidence interval 0.73–0.97). In the STICH trial, the following variables were associated with improved outcome after coronary artery bypass grafting: 6-minute walk test more than 300 m, three-vessel disease, mitral regurgitation, and ejection fraction less than 27% [72]. Median follow-up was 56 months, and it also significantly improved health-related quality of life (at 4, 12, 24, and 36 months as assessed by the Kansas City Cardiomyopathy Questionnaire) [73]. Most studies show improvement in both survival and ejection fraction after revascularization compared to optimal pharmacological therapy alone [74, 75, 76]. It seems like viable myocardium is a predictor of improved survival [75, 76]. Unfortunately, there are no randomized controlled trials comparing percutaneous coronary intervention and coronary artery bypass grafting in ischemic cardiomyopathy. In an observational study, death rates were similar at median follow-up of 2.9 years. Patients who underwent percutaneous coronary intervention had larger risk of myocardial infarction and repeated revascularization but lower risk of stroke [77].
\nAntiplatelet drugs prevent occlusion by inhibiting platelet adhesion and thus the formation of thrombi in coronary vessels [78]. Acetylsalicylic acid is well studied, it exerts its effect by inhibiting cyclooxygenase (COX-1 and COX-2) enzymes and reduces cardiovascular death by 15% in high-risk patients [79]. Low-dose acetylsalicylic acid therapy is essential in secondary prevention of cardiovascular events in coronary artery disease, and its benefit in this case is clear, but it is not recommended in the primary prevention of myocardial infarction [55, 79]. The P2Y12 receptor is a protein, which exists on the surface of platelets and plays an essential role in the aggregation process activated by adenosine diphosphate. In acute coronary syndrome, a P2Y12 antagonists such as clopidogrel, prasugrel, or ticagrelor is recommended in addition to acetylsalicylic acid; this treatment should be continued for up to 12 months in the case of revascularization with a stent [80]. A P2Y12 inhibitor can also be considered for secondary prevention when acetylsalicylic acid is unsuitable. In cases of primary percutaneous coronary intervention due to STEMI, dual antiplatelet therapy should be complemented with unfractionated heparin. A parenteral glycoprotein IIb/IIIa inhibitor, which inhibits platelet aggregation, may be considered as bailout therapy if thrombi or falling fractional flow reserve is seen during primary percutaneous coronary intervention [80]. In acute coronary syndrome without ST-segment elevation, a low-molecular-weight heparin, such as fondaparinux, should be administered subcutaneously [81].
\nBeta-blockers exert beneficial effects on the myocardium that decrease heart rate, contractility, atrioventricular conduction, and risk of arrhythmia. Beta-blockers reduce the risk for cardiovascular death and myocardial infarction by 30% in post-myocardial infarction patients and are useful in the management of effort-induced angina [55, 82]. In Europe, the most widely used beta-blockers provide predominantly β1-blockade, such as bisoprolol, metoprolol, atenolol, and nebivolol. Carvedilol, which is a nonselective β-blocker that targets the α1-receptor, is also used, especially in advanced heart failure. By decreasing heart rate and contractility, the oxygen demand of the heart muscle decreases, thus also decreasing ischemia and ventricular arrhythmia. However, beta-blockers might worsen prognosis in the context of bradycardia or circulatory shock, because of negative inotropic effects, and should be used with caution in heart failure with decompensation.
\nIvabradine is a blocker of the funny channel, If, which is found almost exclusively in the sinus node. By selective inhibition of the sinus node, reduction of heart rate and minimization of myocardial oxygen demand can be achieved, without negative inotropic effect that could result in lowered blood pressure [55]. Ivabradine has been shown to improve heart failure outcomes both in ischemic and unspecific etiologies. It is indicated in patients with sinus rhythm above 70 beats per minute [83, 84]. The combination of atenolol with ivabradine 7.5 mg twice daily gave better heart rate control and amelioration of angina symptoms [55].
\nCalcium channel blockers play a role in the management of coronary artery disease by its main effect on vessels with vasodilation and lowering of peripheral vascular resistance. Calcium channel blockers are classified into two main groups: the dihydropyridines that include amlodipine, nifedipine, felodipine, lacidipine, and lercanidipine and the non-dihydropyridines that include verapamil and diltiazem. Dihydropyridines have a greater vascular selectivity, whereas non-dihydropyridines have a property of nodal suppression and tendency of heart rate lowering, which is why the combination of beta-blockers and non-dihydropyridines (verapamil and diltiazem) must be avoided because of the risk of bradyarrhythmia or AV block [55]. By reducing heart rate and increasing dilation of coronary vessels, calcium channel blockers, like the beta-blockers, reduce the ischemic burden in coronary artery disease, although due to decreased contractility they should be avoided in heart failure [85]. Nitrates cause vasodilation of both coronary arteries and veins that gives symptomatic relief of angina due to its active component nitric oxide. There are two types of nitrates: short-acting nitrates (sublingual nitroglycerin 0.3–0.6 mg, tablet or spray form, and isosorbide dinitrate 5 mg sublingually) that is used for acute angina. Long-acting nitrates are used for angina prophylaxis: isosorbide dinitrate (oral preparation), mononitrates, and transdermal nitroglycerin patches [55].
\nTreatment of heart failure includes pharmaceutical agents, comorbidities like anemia, implantable cardioverter defibrillators, cardiac resynchronization therapy, and mechanical circulatory support and transplant.
\nRenin-angiotensin-aldosterone system (RAAS) inhibition that is achieved by either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is an essential component of heart failure management. Both European and American guidelines for the management of heart failure recommend inhibition of the renin-angiotensin system for patients with chronic heart failure to reduce mortality and morbidity [86]. ARNi is a combination of an angiotensin receptor blocker and an inhibitor of neprilysin, which is an enzyme that breaks down vasoactive peptides such as natriuretic peptides, adrenomedullin, and bradykinin and as a result brings about vasodilation. The first approved ARNi product was valsartan/sacubitril. ARNi should not be administered together with angiotensin-converting enzyme inhibitor, which has to be withdrawn [86].
\nBoth in coronary artery disease and in heart failure, beta-blockers are a crucial part of therapy. Beta-blockers are useful independent of blood pressure levels in patients with heart failure and improve survival. Bisoprolol was shown to reduce mortality of patients with heart failure in the CIBIS-II trial [87]. The CIBIS-III trial showed non-inferiority for titration of bisoprolol before enalapril as compared to the reverse order [88]. Considering the beneficial and well-documented effect of beta-blockers in coronary artery disease, in ischemic cardiomyopathy, titration of beta-blockers first should be considered in hemodynamically stable patients. Metoprolol is also beneficial in heart failure and was in the MERIT-HF trial shown to improve survival by both preventing worsening of heart failure and decreasing risk of sudden cardiac death [89]. In the US Carvedilol HF trial, decreased risk of death was seen for carvedilol as well [90].
\nThe selective aldosterone receptor antagonist group includes spironolactone and eplerenone. This class of medication exerts pharmacological effect by blocking the aldosterone receptor; therefore, sodium reabsorption and diuresis are decreased, while potassium retention is increased. Consequently, they cause water loss and lower blood pressure. Spironolactone has been shown to decrease morbidity and mortality in symptomatic heart failure but is associated with antiandrogen side effects such as gynecomastia and disadvantageous mineral corticoid steroid effects [91]. Eplerenone has milder side effects and has shown at least similar beneficial effect on prognosis [92]. In symptomatic heart failure, a selective aldosterone receptor antagonist should be administered in addition to baseline therapy, if tolerated by the patient [6].
\nDigoxin, first isolated from the digitalis plant, has inotropic properties; it increases contractility and decreases heart rate. It is most commonly used in rate control of atrial fibrillation preferably in addition to beta-blockers. The role of digitalis in the treatment of patients with chronic heart failure is controversial, and its long-term effect on mortality remains unclear. Studies indicate that digoxin decreases the frequency of hospitalization and relives symptoms of heart failure, but it has no effect on survival or mortality in individuals receiving angiotensin-converting enzyme inhibitors and diuretics [93].
\nBy far the most commonly used loop diuretic is furosemide; alternative substances are bumetanide and torsemide. Blockage of sodium-potassium-chloride cotransporters results in increased excretion of sodium, chloride, and potassium and thereby increased diuresis [94]. This decreases the congestion induced by heart failure and therefore it can be useful for symptomatic relief. High doses of loop diuretics have been linked to increased mortality; however, it is the patients with most severe heart failure and congestion that receive the highest doses. For stable patients enteral administration is used, while in cases of worsened heart failure with congestion, intravenous therapy is recommended [94].
\nLevosimendan is an inodilator, with both vasodilator and positive inotropic properties. It increases calcium sensitization of troponin C and thus increases cardiac contractility [95]. It can be indicated in acutely decompensated patients with chronic heart failure due to systolic dysfunction of the left ventricle [95, 96]. Levosimendan is well tolerated in general but might have adverse effects such as hypotension, tachycardia, atrial fibrillation, hypokalemia, and headache [95]. Levosimendan has an active metabolite (OR-1896); due to this, effects such as improved hemodynamics and contractility can last for over 1 week. Infusions are administered intermittently. Levosimendan infusions reduce symptoms, hospitalizations, and short-term mortality [95].
\nAnemia can mimic symptoms of heart failure such as dyspnea and tiredness. It also worsens prognosis and symptoms in heart failure. In the RED-HF trial darbepoetin alfa, an agent that binds to the erythropoietin receptor and thus stimulates formation of red blood cells did not decrease cardiovascular mortality in anemic heart failure patients; in fact it increased the risk of stroke [97]. Intravenous iron on the other hand has been shown to decrease symptoms and improve quality of life, and enteral iron substitution is associated with gastrointestinal side effects that might be exacerbated in heart failure where gastrointestinal swelling and malabsorption are common [98]. Anemia might worsen ischemia in coronary artery disease, the underlying cause of ischemic cardiomyopathy, and thus extra care is warranted in this group of patients.
\nImplantable cardioverter defibrillators (ICDs) effectively not only abort ventricular arrhythmias by either antitachycardia pacing or cardioversion but also provide protection against bradycardia. In heart failure, a major cause of death is due to sudden arrhythmic events. Notably, the proportion of sudden cardiac death is higher in patients with NYHA II than NYHA III. Therefore, even patients with mild heart failure symptoms need to be considered for an ICD as primary prevention. Antiarrhythmic drugs, including amiodarone, might reduce the risk of tachyarrhythmia, but they do not reduce overall mortality and may even increase it. In survivors of cardiac arrest, ICD is recommended as secondary prevention. Patients who have documented ventricular tachycardia with hemodynamic compromise have a secondary prevention indication for ICD for protection from sudden cardiac death [99, 100, 101, 102]. Primary prevention indication for ICD should be considered in patients who never experienced a ventricular arrhythmia, with ejection fraction below 35% despite at least 3 months of optimal pharmacological therapy, NYHA functional classes II–III, and at least an estimated survival above 1 year. Two randomized controlled trials showed no benefit in patients who had an ICD the first 40 days after myocardial infarction [103, 104]. If the patient is considered at high risk, during this period a wearable defibrillator is an option [105, 106]. Before offering the patient an ICD, the physician should integrate information about comorbidity and life expectancy; if it is estimated to be less than 1 year including patients with NYHA IV despite pharmacological optimization, ICD is not indicated, but the patient may be reevaluated if improvement occurs. For the group of patients with mild heart failure (NYHA II), an ICD saves one life per year for every 50 patients. Ischemic cardiomyopathy patients have higher risk of sudden death, and the benefit in that group is believed to be higher [107]. In elective replacement of an ischemic cardiomyopathy device, careful judgment is warranted including reevaluation of risk [108, 109, 110, 111, 112]. Subcutaneous ICD (S-ICD) is an alternative in selected cases where risk of infection is high or vascular access is difficult and when there is no need of pacing or expected need of antitachycardia pacing. In general 20% of ICD leads fail over a period of 10 years; therefore, S-ICD may be more advantageous in cases of long life expectancy [113, 114].
\nCardiac resynchronization therapy (CRT), which can be used either with a pacemaker (CRT-P) or with an ICD (CRT-D), reduces morbidity and mortality and improves health-related quality of life in selected patients who fulfill certain criteria [115]. The principle of these devices is to use a pacing system that is biventricular to decrease dyssynchrony and thus heart failure, in patients with heart failure, reduced ejection fraction, and a bundle branch block [116].
\nAccording to ESC guidelines from 2013 regarding the indications of CRT in patients with heart failure and sinus rhythm:
Left bundle branch block with QRS duration >150 ms. CRT is recommended in chronic heart failure patients with left ventricular ejection fraction ≤35% who remain in NYHA functional classes II, III, and ambulatory IV despite adequate medical treatment (recommendation class I, level of evidence A).
Left bundle branch block with QRS duration 120–150 ms. CRT is recommended in chronic heart failure patients with left ventricular ejection fraction ≤35% who remain in NYHA functional classes II, III, and ambulatory IV despite adequate medical treatment (recommendation class I, level of evidence B).
Non-left bundle branch block with QRS duration >150 ms. CRT should be considered in chronic heart failure patients with left ventricular ejection fraction ≤35% who remain in NYHA functional classes II, III, and ambulatory IV despite adequate medical treatment (recommendation class IIa, level of evidence B).
Non-left bundle branch block with QRS duration 120–150 ms. CRT may be considered in chronic heart failure patients with left ventricular ejection fraction ≤35% who remain in NYHA functional classes II, III, and ambulatory IV despite adequate medical treatment (recommendation class IIb, level of evidence B).
CRT in patients with chronic heart failure with QRS duration <120 ms is not recommended (recommendation class III, level of evidence B) [117].
In clinical practice it has been revealed that CRT in patients with severe heart failure has positive effects on symptoms and exercise tolerance. Furthermore, it improved quality of life and minimized the need for rehospitalization. However, some patients are nonresponders and receive little or no benefit from CRT. The level of ejection fraction in the trials varies: RAFT and MADIT-CRT used 30% as a cutoff [118, 119]. REVERSE used 40% and BLOCK-HF 50% [118, 120, 121, 122]. The QRS width is important in selecting patients. None of the landmark trial selected patients based on sex, QRS morphology, or ischemic vs. nonischemic subgroups. It is not clear if CRT itself reduces the need for ICD or if the improvement of heart failure may expose the patient to a longer period of risk for sudden death. Imaging tests with regard to dyssynchrony are not part of guidelines in selecting patients for CRT [123]. When there is an extensive myocardial scar, the improvement in ejection fraction will be less, and the optimal placement of the left ventricular lead will be more difficult to gain acceptable pacing thresholds without phrenic nerve stimulation.
\nIn patients who do not stabilize with optimal pharmacological therapy, the need for further therapeutic options including mechanical assists should be addressed. In cardiogenic shock, extracorporeal support like Impella™ can be used for temporary bridging. When long-term mechanical assist is indicated, left ventricular assist device can be used for recovery or more often as destination therapy if transplant is not possible. In the meantime, extracorporeal membrane oxygenation (ECMO) may be used to support patients with heart failure (left or biventricular failure) until a decision about a permanent solution is taken. In a randomized trial on high-risk percutaneous coronary intervention in patients with impaired left ventricular function, the 30-day cumulative incidence of major adverse events was not different for patients with intra-aortic balloon pump as compared to left ventricular assist device [124]. Due to lack of heart donors, the left ventricular assist device as a destination therapy has been advocated. The survival rates after 3 years in those receiving the latest continuous flow devices are at least as good as in transplanted patients, but long-term survival is unknown [125].
\nIschemic cardiomyopathy, which is commonly encountered as an underlying cause of heart failure, warrants qualified management to improve survival. This includes thorough evaluation and optimal pharmaceutical treatment, device therapy with cardiac resynchronization therapy with/without an implantable cardioverter defibrillator, and mechanical support as bridging or destination therapy in end-stage disease. From a general perspective, it is crucial to reduce risk factors for coronary artery disease to prevent ischemic cardiomyopathy.
\nStroke also known as cerebrovascular accidents is the world’s second death-perpetrating disease after cardiovascular diseases [1, 2], and it affects about 13.7 million people annually in the globe [3]. About one third of all strokes translate into fatalities, and another one third constitutes stroke survivors staying with residual disability that accounts as foremost noticeable root of long-term neurological disability in adults [4, 5] and third most common cause of all disabilities globally [6]. Stroke classically depicts a syndrome with sudden onset of acute focal injury of the central nervous system (CNS) of vascular origin that produces focal or global neurological deficit in accordance with affected area of blood supply [7]. Thus, based on the isolated territory of the brain involve, stroke can be cerebral stroke, brainstem stroke, cerebellar stroke, or thalamic stroke, while based on underline cause it can be ischemic stroke (thrombotic, embolic, lacunar, watershed, or cryptogenic) which results from brain vascular occlusion, or hemorrhagic stroke (intraparenchymal or subarachnoid) which is due to blood-related aberrations [8].
Cerebral stroke results in loss of cerebral cortex related functions that manifests as motor impairment [9, 10, 11], sensory impairment [12, 13, 14], cognitive impairment [15, 16, 17], balance impairment [18] among others. The motor function of the cerebral cortex is embedded in the motor cortex (primary motor area, premotor cortex, supplementary motor area, cingulate motor areas) located in the frontal lobe anterior to central sulcus, the motor cortex is responsible for planning, initiation, execution, and regulation of voluntary movement which is achieved through originating descending corticospinal tract and corticobulbar system to the spinal cord and brainstem respectively [19]. Cerebral cortex plays principal role in sensory/perceptual functions by providing meaning to all sensations (except sense of smell) through primary somatosensory cortex in the postcentral gyrus of the parietal lobe, and other primary cortical sensory areas such as auditory cortex in the temporal lobe and visual cortex in the occipital lobe. Cognitive function involves multifaceted domains of cognitive processes including memory, learning, attention, thought, comprehension, perception, language among others [20]. Each of these domains of cognition requires cerebral cortex, illustration can be seen in memory domain where memory acquisition involves sensory cortex, memory retrieval involves prefrontal cortex, and memory storage is distributed throughout the cortex [21]. Balance and coordination of movement involve integrated functioning of both pyramidal and extra-pyramidal systems, and the cerebral cortex is the main principal origin of pyramidal system.
The mechanism of cerebral damage after stroke determines the cerebral stroke impairments, and the mechanism of damage is relative to whether the type of stroke is ischemic or hemorrhagic. Ischemic stroke consists of five distinct pathophysiologic mechanism each of which has distinct time frame; these includes immediate (within minutes) peri-infarct depolarization and excitotoxicity, hours later by neuro-inflammation and oxidative stress, days later by apoptosis [8]. In addition to ischemia related cascade of events aforementioned, hemorrhagic stroke is associated with two additional unique pathophysiologic phases. The primary; acute phase which is due to physical effect of hematoma (mass effect) from the mass accumulated blood, and the secondary; subacute phase termed as cytotoxicity from secondary metabolites of blood components [22, 23, 24].
Recovery to some extent from post stroke impairments observed among stroke survivors was one of the early evidences that led to move away from outdated dogma widely misconceived previously that; there was no possibility for repair or change within the CNS after it had suffered a lesion; and that once there is damage such as stroke that leads to neuronal demise inadvertently, the brain structures and functions are lost forever [25, 26]. It is now well-established fact that CNS repair or change itself but it just that it relatively does not do well enough, and that functional recovery after damage relies on neuroplasticity [27, 28]. Neuroplasticity is life-long natural capability of the CNS to rearrange itself in both molecular form and function in response to new experience or stimulus. Brain plasticity is pivotal to functional recovery after cerebral stroke, and this spontaneous, endogenous and intrinsic capacity of the brain is what restorative rehabilitation approaches for stroke explore, promote and remodel in the right direction to achieve optimal functional recovery after stroke [29, 30].
There is exploding surge among scientists to pay more attention in searching for various therapeutic strategies that can enhance neuroplasticity to augment functional recovery with rehabilitation after stroke [31, 32, 33, 34]. Although this strategy is still in developmental stage but the reasons for this shift in attention are not far-fetched. Firstly, the thrombolytic/thrombectomy clinical treatment available for acute stroke has a very restrictive time window of administration of 4–5 hours of lesion onset [35]. This is in contrast to restorative/rehabilitative interventions that has unlimited therapeutic window of lifelong applicability [36]. Secondly, rehabilitation interventions are still far from sufficiency for optimal and ideal recovery from impairments after stroke [37], as about 50% of stroke survivors still leaves with residual disability and remain functionally dependent despite rehabilitative management [38]. Understanding the mechanisms of cerebral damage and their recovery after cerebral stroke is essential towards development of strategies that harness and enhance neuroplasticity in combination with rehabilitation processes [39]. This paper therefore discusses the mechanism of cerebral damage after stroke as well as elucidates the concept of neuroplasticity as key for recovery following stroke.
In ischemic stroke, irreversible cascade of damage to the brain tissue ensue once the cerebral blood flow (CBF) reduces to less than 12 ml/100 g/min of the normal range of 50–60 ml/100 g/min. Within seconds of this abrupt ischemic insult, neuronal cells in the center of ischemic region termed as ischemic prenumbra undergoes anoxic depolarization due to loss of ATP-dependent ionic pump homeostasis, and they never repolarize [40]. This necrotic core of ischemic prenumbra is enclosed by a zone of relatively lesser impacted tissue termed as ischemic penumbra, which is abridged functionally silent by the reduced blood flow but maintains metabolically active and therefore can repolarize at the expense of further energy consumption [41]. This repetitive depolarization and repolarization of ischemic penumbra are termed peri-infarct depolarization and the important period of time during which this volume of brain tissue is salvageable is referred to as the window of opportunity. The energy failure in the functioning of ATP dependent sodium potassium pump in the ischemic prenumbra results in massive uncontrolled anoxic depolarization that results in opening of voltage-gated calcium channels, mitochondrial dysfunction which further deplete energy required to maintain ion gradient, and abnormally extracellular buildup of excitatory amino acids [42, 43].
Consequently, excitatory glutamate and other excitatory amino acids such as aspartate becomes excessively released, and glutamate hyperexcitation of glutamate N-methyl-D-aspartate (NMDA) receptor, which is arguably the most calcium-influx allowing ionotropic glutamate receptor; results in massive influx of calcium ion (Ca++) into hypoxic neuron. Calcium ion triggers series of cascading events that ultimately lead to neuronal demise through activation of proteolytic enzymes, stimulation of pathogenic genes, lipid peroxidation and free radical generation [44]. For this; glutamate and other excitatory amino acids are cumulatively termed excitotoxins, and their accompanying neuronal damage termed excitotoxicity [45]. Calcium activates key number of disparaging intracellular enzymes such as proteases, kinases, lipases, and endonuclease that not only wildly permits release of cytokines and other mediators that result in the loss of cellular integrity but also orchestrated triggering of intrinsic apoptotic pathway of neuronal death. Specifically, calcium through mobilizing phospholipases hydrolyses membrane bound glycerophospholipids to yield free fatty acids, which enable free radical peroxidation of other membrane bound lipids. Calcium through mobilizing proteases lyses integral structural proteins and activates nitric oxide synthase enzyme that triggers free radical machinery [46].
Prior excitotoxicity activates microglia and astrocytes which are the brain resident innate immunity to reacts and release cytokines, chemokines (chemotaxis cytokines), and matrix metalloproteases (MMPs). This constitutes neuro-inflammation, and microglia activation institutes the initial vital neuro-inflammatory response in acute stroke, which together with blood-borne innate immune cells and later adaptive immune cells support the course. This neuro-inflammatory response supposedly aims to reduce injury processes but this response under stroke pathology develops improperly more reactive and aggressive to yield numerous inflammatory mediators that trigger apoptosis and orchestrate lethal neuronal injury [47, 48]. Activated microglia becomes phagocytes that can release plethora of substances, some of which are neuroprotective such as neurotropic factors; nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), insulin-like growth factor I (IGF-I), and growth associated protein (GAP-43/B-50), while some are neurotoxic such as tumor necrosis alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Blood–brain barrier (BBB) which confers brain with protection against systemic toxins is disrupted by matrix metalloproteinases (MMPs) with MMP-2 (gelatinase A) and MMP-9 (gelatinase B) being the leading concerns in cerebral ischemia [49]. MMP-2 that is normally expressed at low levels becomes increased during cerebral ischemia to galvanizes MMP-9, which abolishes components of the basement membrane in the vascular wall leading to BBB distraction, thus allowing further infiltration of inflammatory mediators and other potential toxins [50].
Oxidative stress signifies disparity in the high-level oxidants (free radicals) with respect to corresponding nonconforming low level of antioxidants. Long term cerebral hypo-perfusion produces abnormal proportions of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) oxidants through several mechanisms of injury, such as mitochondrial inhibition, calcium ions overload, ischemia–reperfusion injury, and neuroinflammation [51]. During cerebral ischemia, there is mitochondrial inhibition of oxidative phosphorylation due to the lack of sufficient oxygen, and the oxygen depleted cell shift to glycolytic pathway of ATP generation that results in lactate and hydrogen ion (H+) build-up in the mitochondria and the consequent reversal of the H+ uniporter on the mitochondrial membrane that results in superfluous cytosolic H+ buildup and acidosis [52]. Acidosis partly lead to oxidative stress by supplying excessive H+ for the successive progression in the generation of hydrogen peroxide (H2O2) and the final hydroxyl radicals (∙OH) either in the turnout of transition metal ions (Fenton reaction) or in the presence of superoxide radical (Haber-Weiss reaction), with this effect more pronounced in neurons due to inherently low anti-oxidant defense. In addition, the compelling protein and lipid oxidant peroxynitrite (OONO_) of RNS is favorably generated in the oxygen depleted cell by the reaction of nitric oxide (NO) and superoxide (O2∙−), thereby also contributing to oxidative stress.
Calcium overloads, as a result of glutamate mediated NMDA receptor excitotoxicity, also contributes in neuronal oxidative stress at cytosolic and mitochondrial level. At cytosolic level, excessive calcium ion activation of key intracellular enzymes such as neuronal nitric oxide synthase (nNOS) via Ca2+ binds calmodulin to induce subsequent downstream effect, as nNOS catalysis results in generation of nitric oxide (NO) free radical from L-arginine [53, 54]. At the mitochondrial level, excessive calcium ion influx into mitochondrial matrix leads to the inner mitochondrial accumulation of momentous level of Ca2+ via mitochondrial calcium uniporter (MCU) which proliferates disturbance of usual bio-energetic, mitochondrial ROS, and membrane permeability [55].
Apoptosis is a physiological mechanism of cell death through programmed cellular machinery of either extrinsic or intrinsic pathways [56]. Under stroke pathology, neuronal demise by necrosis preponderance in the ischemic prenumbra is marked by excitotoxicity, while additional process of neuronal demise by apoptosis which is more delayed and predominant in the ischemic penumbra occur in a fashion where apoptosis becomes dysregulated [57]. Thus, while the neurons within the core infarct die by immediate necrosis due to insufficient ATP, the penumbra die by ATP requiring process of apoptosis, supporting the established evidence that cellular demise after cerebral ischemia transpires through both necrosis and apoptosis [58]. Multiple pre-existing pathophysiologic mechanisms that can induce apoptosis after cerebral ischemia includes pro- calcium influx, pro-inflammatory cytokines and oxidative stress [59]. Apoptosis can be caspase-dependent or caspase-independent, and the most common is caspase-dependent which is initiated and triggered through distinctively intrinsic (or mitochondrial) pathway or extrinsic (or death receptor) pathway. Both intrinsic and extrinsic pathways share similar terminal phase termed execution phase where caspase 3 leads to the destruction of cellular components and cell death [60].
In hemorrhagic stroke, the mechanism of damage begins with additional process of mass effect from the mass accumulated blood, and cytotoxicity from the secondary metabolites of blood components, in addition to shared common damaging caused by ischemia such as excitotoxicity, neuroinflammation, oxidative/nitrosative stress, and apoptosis. The initial bleed from the cerebral hemorrhage causes immediate physical disruption of the cellular cytoarchitecture of the brain and increases local pressure which can cause compressions, hypothetically disrupting blood flow and principally causing brain herniation [61]. The subsequent expansion of hematoma causes mass effect of hematoma growth leading to further rise in intracranial pressure, brain herniation, and impacted blood flow that is correlated with neurologic deterioration and degraded clinical outcomes. Depending on the dynamic of hematoma expansion (growth), the primary damage ensues within minutes to hours subsequent to the onset of bleeding and is basically due to mechanical damage associated with the mass effect [62].
Secondary injury after cerebral hemorrhage termed as cytotoxicity occurs due to series of events initiated by the prior primary injury mechanism (mass effect), that is specifically due to body response to the hematoma for instance inflammatory response, and from the multiple blood components released from hematoma [61]. The extravasated blood components released from hematoma being implicated to cumulatively imposed cellular toxicity includes; majorly the erythrocytes and plasma proteins, and the damage-associated molecular patterns (DAMPs) which are nucleic acids, extracellular matrix components, proteins, lipid mediators, ATP and uric acid released from necrotic tissues [63]. At the early stage of cytotoxicity, the toxicity of extravasated blood plasma components such as coagulation factors, complement components, and immunoglobulins are known to be the main contributing factor of cellular damage. Subsequently, erythrocytes lysis leads to release of its major intracellular component hemoglobin (Hb), which when metabolize via hemoglobin metabolic pathway release degradation products; heme and iron (Fe). Both Hb and its degradation products are potent cytotoxic chemicals capable of causing death to many brain cells through mechanism of free radical generation with substantial increase oxidative stress and subsequent damage to DNA [62].
The ultimate goal of stroke management is to promote optimal recovery of lost functions and reduce further injury. This recovery depends majorly on brain plasticity; a spontaneous regeneration process that encompasses neural plastic changes in the lesioned hemisphere to reestablish its structural and functional reorganization. Brain plasticity under pathological condition completely differs from plasticity under properly functioning brain. For instance, plasticity in normally functioning brain is a prerequisite basis of learning and memory that involves plastic adaptation such as long-term potentiation (LTP). This is opposed to plastic changes observed using MRI in cerebral stroke pathology, that involves modification in intracortical myelin, augmented neurogenesis, improved spine density in neuronal dendrites and alterations in astrocyte volume [64].
Stroke recovery to certain extent also depends on severity extent of the initial injury deficit as the severity of the damage is inversely related to the prognosis for recovery [65]. But it was also observed that recovery differs even among post stroke patients with similar clinically assessed severity. This apparently stress the recovery role of other brain endogenous survival mechanism such as extent to which collateral circulation bypass to supply blood to the perilesional neurons, angiogenesis, inhibitory neurotransmitters that counteract excitotoxicity, and multiple representations of the same function in different cortical areas [66]. Appropriate rehabilitation and drug treatment that target underline cause of stroke are also critical to recovery after post stroke cerebral damage. Rehabilitation aims to maximize optimum recovery of lost functions as a result of impairments deficit after stroke but overall, brain plasticity underlies recovery promoted by rehabilitation [67, 68, 69].
Recovery from stroke has also been attributed to be dependent on resolution of early local processes in the brain that includes resolve of perilesional edema, re-emergence of circulation within the ischemic penumbra, resolution of remote functional depression of neurological function induced by process of diaschisis [70]. As previously stated stroke recovery majorly depends on brain reorganization process of plasticity which in turn dictates recovery promoted by rehabilitation. Mechanism through which rehabilitation mediates brain plasticity to promote recovery has been studied and explained. Rehabilitation such as physical therapists stroke interventions modifies neurotrophic factor expression in the CNS especially brain derived neurotrophic factor (BDNF), which in turn upon binding with its tyrosine kinase B (TrkB) cognate receptor recruits a cascade of signaling pathways that ultimately mediates activity-associated plasticity of neurons [71, 72]. Activity-associated plasticity signifies a means of functional and structural neuroplasticity that is tailored by the depolarizing behavior of neurons, and the mechanisms governing activity-associated plasticity includes LTP and activity-associated development of corticospinal circuitry among others [72]. Therefore, through brain plasticity after cerebral stroke, reorganization by recruiting cortical or subcortical structures to adopt the function of the injured tissue, reinforcement of remaining synaptic pathways and then creating new connections, recruitment of other pathways that are functionally alike the damaged tissue but anatomically distinct, strengthening of existing but weaker and functionally silent connections, can all be achieved to recover lost cerebral functions [73].
Neuroplasticity is a general term that covers all available processes of neuronal reorganization possible [66], such as neurogenesis, synaptogenesis, dendritic arborization, axonal sprouting, LTP, recruitment of other pathways, reinforcement of functionally silent synapses. Neurogenesis is the process of generating of neurons of neural cell types from precursors neural stem cells and/or neural progenitor cells (NPCs) [74]. Synaptogenesis is a broad term that encompasses the complex process of synaptic contacts formation, maturation and maintenance which form the basis for establishing neural circuits [75]. Dendritic arborization describes a process of neuronal dendrites tree-like branching out to make new synaptic connection through mechanisms of dendrite morphogenesis [76]. Sprouting is a form of plastic changes in the synapses in which there is axonal synaptic reorganization to modify the efficacy of synapses [77]. LTP is the fundamental form of synaptic plasticity where synapses become strengthened and this forms the cellular basis of learning and memory [78].
Neuroplasticity is regulated by the corresponding cascade of intracellular events that translates into plastic changes. However, the plastic changes may either be adaptive, where it is related with an upsurge in function or maladaptive where it is linked with adverse consequences such as loss of function or augmented damage [79, 80]. This brings about the concept that not all plasticity effect positively on clinical status, that maladaptive plastic changes from dysregulated neuroplasticity result in an aberrant neural organization [79]. Typical example of situation where neuroplasticity becomes maladaptive can be seen in new onset of seizures after long period of cerebral trauma, where aberrant progressive plastic changes in the brain in the form of inappropriate synaptogenesis and axonal sprouting accounts for this late development. Neuroplasticity can also be seen as structural where the plastic changes involves the organization and number of synapses such as synaptogenesis, axonal sprouting and dendritic arborization, or functional where the plastic changes involves the efficacy and strength of synaptic connections such as LTP.
The basis of plastic changes that allows for neuroplasticity to become realistic depend upon factors such as neuronal excitability, which define the ability of a nerve to produce an action potential and in turn depends on the permeability, electrical and chemical state of the neuron [81]. This is then followed by adaptive changes termed plasticity, in which there are stable functional transformations that occur in specific neuronal systems as a result of specific stimuli or the combination of stimuli [82]. Furthermore, it has been revealed that effective and repeated action potentials are required from the presynaptic neuron to stimulate the postsynaptic to cause a change in the strength of an interneuron connection [83]. Cumulatively, the aforementioned process leads to biochemical changes, and anatomical adaptations which reinforce the connections between neighboring neurons, thus accounting for molecular, cellular, systems, and behavioral perspectives of explaining neuroplasticity [84].
The strength of the excitation impulse must exceed the threshold value to increase the synaptic efficacy and the stability of the connections between neurons. Nevertheless, when neurons are stimulated only with subthreshold stimuli, the overall activity of the synapse may decrease [85]. Studies conducted on unilateral lesion of the hippocampus results in the formation of new synapses (synaptogenesis) by the axons from the remaining contra-lateral hippocampal system [86]. Thus, the postsynaptic portion of a synapse continues to function properly despite the degeneration of the presynaptic region, and the surviving axons form new synapses. The fibers that form the (new) synapses are homologous to the damaged synapses, which may significantly facilitate the restoration of normal function.
Table 1 summarized various strategies that were found to enhance neuroplasticity and the mechanism through which modulate neuroplasticity.
Strategy | Proposed mechanism reported to modulate and promote neuroplasticity | References |
---|---|---|
Transcranial direct current stimulation (noninvasive) | Modification of neuronal membrane potentials, consequently persuading neuronal excitability which form part of the basis of neuroplasticity. | [87, 88] |
Deep brain stimulation (invasive) | This by stimulating neuronal network connected to the stimulated region, the pathological neuronal network becomes altered by changes in the neurochemical components thereby inducing morphological changes in both the dendrites (dendritic arborization) and axons (axonal sprouting). | [89] |
Functional Electrical Stimulation (FES noninvasive) | Hypothesized to modulate neuroplasticity through repeated generation of neurons synaptic activity that might facilitate synaptic remodeling, leading to neural reorganization. | [90] |
Aerobic Exercise | Aerobic exercise is linked with surge in neurogenesis and angiogenesis, together with rise in neurotrophic molecules especially BDNF and other growth factors implicated in neurite outgrowth and synaptic plasticity | [91, 92] |
Brain-derived neurotropic factor (BDNF) therapy | By binding of BDNF to its TrkB cognate receptor, two distinctive intracellular signaling pathways namely phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) becomes initiated, thereby regulating transcriptional gene activity of neurite outgrowth and neurogenesis. | [93, 94] |
Statins | Proposed mechanism by which statins modulates neuroplasticity involves indirect effect through statin-mediated increase in proteins such as endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), tissue plasminogen activator (tPA), and brain-derived neurotropic factor (BDNF) among others. | [95] |
Erythropoietin (EPO) therapy | EPO and EPO receptor (EPOR) that both becomes upregulated in response to cerebral ischemia, when supplemented act to indirectly augment neurogenesis through EPO-mediated increase in the expression vascular endothelial growth factor (VEGF) and brain-derived neurotropic factor (BDNF). | [96] |
Phosphodiesterase type 5 inhibitors (PDE-5 inhibitors) | PDE-5 inhibitors competitively inhibit phosphodiesterase enzymes responsible for converting cyclic guanylyl monophosphate (cGMP) back to GMP, thus fostering cGMP accumulation which has diverse cellular effect in the brain including angiogenesis, and neurogenesis which are requirements of neuroplasticity | [97] |
Vascular endothelial growth factor (VEGF) therapy. | Proposed mechanism through which VEGF modulates neuroplasticity involves mediating the PI3K–AKT–nuclear factor kappa B signaling pathway; an intracellular pathway that regulate transcriptional factors involves in neurogenesis | [98, 99] |
Various strategies that were found to enhance neuroplasticity.
Advancement in the understanding of mechanism of cerebral damage after stroke and brain neuroplasticity have continue to be a cutting-edge landmark information towards reducing human disability as a result of stroke. Strategies aimed at harnessing and augmenting neuroplasticity in complement with neurorehabilitation offers reasonable level of hope to maximize stroke recovery and diminish cerebral stroke induced neurological impairments. Although these strategies are rapidly evolving towards achieving clinical viability and success, more is needed to be done especially pertaining to outcome measures of neuroplasticity that rely on biomarkers of neuroplasticity rather than functional or behavioral outcome.
The authors declare no conflict of interest.
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