INTRODUCTION:

Cardiovascular ailment stays to be a serious but unsolved health problem of human beings¹. About 62 million Americans anyhow have one kind of cardiovascular sickness and, of these, about 32 million are female. While it is known for quite a while those distinctions exist between the genders with respect to coronary illness, it has just been over the most recent 10 years that these inconsistencies in occurrence, horribleness, mortality, hazard elements, analysis, and treatment have been investigated^2-3. About a part of the world's cardiovascular weight is predicted to happen in the Asia Pacific district. Circulatory strain is a significant determinant of this weight, with an impressive possible advantage of pulse dropping down to degree of any event 115 mmHg systolic pulse⁴. The mass of CVD is expanding strongly in creating nations, mostly in view of atherosclerosis-related diseases. Information from China ensnares urbanization, westernization of diet, and expanding paces of smoking, stoutness, and diabetes in sickness pathogenesis. Information from India recommends a potential specific vulnerability of South Asians to the atherogenic impacts of metabolic danger factors. The scarcity of epidemiologic information from these and numerous other more unfortunate nations restricts our insight, in any event, of CVD examples and commonness^5-6.

Figure 1: Distribution of CVD deaths due to Inflammatory Heart Disease, Rheumatic Heart Disease, Hypertensive Heart Disease, Ischaemic Heart Disease, Cerebrovascular Disease, and other diseases.

Biomarkers in Diagnosis of Different Cardiac Diseases:

Cardiac markers in blood:

Cardiac biomarkers are found in the blood, in general these markers are hormones, proteins and enzymes. The main biomarkers are cardiac troponin, creatinine kinase, and myoglobin.

Cardiac troponin:

Levels of troponin in the blood are usually very low, but mar or injury to the heart result in it’s release and hence rise in the levels of troponin in the blood. Troponin appears in the bloodstream immediately after the heart attack. There are three different types of troponin available namely Troponin T, Troponin I, and Troponin C. These collectively get engage in the regulation of contraction of heart and skeletal muscles. Having a troponin range in between 0.04ng/ml and 0.39ng/ml is indicative of abnormality in the heart⁷.

Table 1: Range of troponin in blood stream and indication⁸.

S. No.	Range of troponin levels	Indications
1	Below 0.04 ng/mL	Normal
2	Above 0.4 ng/mL	Probable heart attack

Creatinine kinase:

Creatine kinase condensed as CK, and having elective names like phosphocreatine kinase and creatine phosphokinase otherwise called Creatine Phosphokinase (CPK) or phosphocreatine kinase. Clinically, creatine kinase is measured in blood tests as a marker of harm of CK-rich tissue, for example, in cardiovascular failure (myocardial localized necrosis), serious muscle breakdown (rhabdomyolysis), and immune system myositides. This isoenzyme found especially in vertebrate skeletal and myocardial muscle that catalyze the transfer of a high-energy phosphate group from phosphocreatine to ADP with the formation of ATP and creatine⁹.

Myoglobin:

A monomeric form of protein/Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the cardiac and skeletal muscle tissue of vertebrates in general and in almost all mammals. Myoglobin is now and again estimated notwithstanding troponin to help analyze a cardiovascular failure. It is likewise not unmistakable for discovering a heart attack. It shows up in both serum and spit bio-liquids and can be utilized to identify AMI¹⁰.

Lactate dehydrogenase (LDH or LD):

On blood tests, a raised degree of lactate dehydrogenase ordinarily shows tissue harm, which has numerous expected causes, mirroring its far reaching tissue appropriation. LDH is communicated broadly in body tissues, for example, platelets and heart muscle. Since, it is delivered during tissue harm, it is a marker of basic wounds and sickness like cardiovascular breakdown. Isoform LDH-1 is discovered to be communicated in heart muscle where isoform LDH-2 is discovered fundamentally in blood serum. A significant degree of LDH-1 than LDH-2 recommends myocardial dead tissue. LDH levels are likewise high in tissue breakdown or hemolysis¹¹.

Glycogen phosphorylaseisoenzyme BB (GPBB):

Glycogen phosphorylaseisoenzyme BB is abbreviated as GPBB, it is one of the isoforms of protein glycogen phosphorylase. GPBB is known to introduce in heart and mind tissues. GPBB is helpful in early determination of intense coronary disorder. A quick ascent in blood levels of GPBB can be seen in unstable angina and myocardial localized necrosis. After the 1-3 hrs of ischemia GPBB is gotten raised¹².

Neopterin:

It is a marker of macrophage inception, atherosclerotic plaque development, tacky top aggravation, and intracoronary clumps advancement. Neopterin has been amassed in discovering a relationship between the blazing cycle and left ventricular (LV) work, as depicted by left ventricular release division (LVEF)¹³.

Serum amyloid A:

In a sub-study of TIMI 11A, raised SAA levels anticipated expanded danger of 14-day mortality in patients with ACS. In the Women's Ischemia Syndrome Evaluation (WISE) investigation of ladies alluded for coronary angiography as a result of suspected ischemia, raised SAA values were corresponded with angiographic seriousness of CAD and 3-year hazard for cardiovascular occasions¹⁴.

Natriuretic peptides:

Hemoglobin A1c (A1c):

It is another "stunt" biomarker. The hemoglobin A1c one of the oldest and most generally used biomarkers in CVD avoidance, management, and visualization. Since it mirrors the past 3 months of glycemic control, the A1c infrequently lies¹⁵

Adrenomedullin:

Adrenomedullin is a peptide of 52 amino acids and a segment of an antecedent, pre-proadrenomedullin, which is orchestrated and present in the heart, adrenal medulla, lungs, and kidneys. It is a powerful vasodilator, with inotropic and natriuretic properties, the creation of which has been demonstrated to be invigorated by both cardiovascular weight and volume overload. The level of circling adrenomedullin is raised in patients with cardiovascular breakdown and is higher in patients with more extreme cardiovascular breakdown¹⁶.

Chromogranin and Galectin-3:

A polypeptide hormone created by the myocardium, which has powerful negative inotropic properties and raised plasma levels in patients with cardiovascular breakdown. A protein created by initiated macrophages, for which plasma levels have been accounted for to anticipate unfriendly results in patients with cardiovascular breakdown ¹⁷.

D-dimer:

The most encouraging biomarker for use in presumed intense dismemberment right now is D-dimer. It is a thrombotic marker. Significantly, it is now generally accessible for clinical use including purpose of-care quick tests. D-dimer is a fibrin piece seen in coagulopathic issues, and estimations are regularly utilized in the finding of PE. Checked height was found in patients with aortic ailments¹⁸.

Cytokines:

Fetuin-A:

Fetuin-A (Figure 10) has been perceived as a mitigating cytokine and modulator in the atherosclerotic process. Fetuin-A levels have been discovered diminished in SA patients giving chest torment, contrasted with controls, however higher than in patients with AMI^19-20.

Stromal Cell-Derived Factor-1 (SDF-1; CXCL-12):

The stromal cell-inferred factor-1 (SDF-1) is a little cytokine that has a place with the bigger group of intecrines, chemokines. It is discharged because of any vascular injury or ischemia and manages enlistment of CXCR4+ cells on the vascular divider and there is proof its essential function in tissue recovery and revascularization²¹.

Anti-Inflammatory Cytokines:

Growth and Differention Factor (GDF-15):

It is a cytokine engaged with cell-separation and embryogenesis and has placed with the superfamily of proteins called "changing development factor-beta familyGDF-15 shows high articulation in placental tissue and an exceptionally low articulation in ordinary tissue. GDF-15 increments during tissue injury and fiery states and is related with cardiometabolic hazard²¹.

Interleukin-4 (IL-4):

IL-4 is a pleiotropic cytokine delivered by Th2 lymphocytes, eosinophils, basophils, and pole cells. Since IL-4 represses the amalgamation of favorable to fiery cytokines it is commonly viewed as calming.IL-4 has likewise been demonstrated to be expanded in patients with CAD. More elevated level of IL-4 is portrayed to left ventricular brokenness²².

Interleukin-10(IL-10):

This cytokine is essentially communicated in monocytes and type 2 T aide cells, pole cells, CD4+CD25+Foxp3+ administrative T cells, and a specific subset of enacted T cells and B cells. Diminished IL-10 levels have been accounted for in patients with intense MI, UA and different ACS. Patients with raised degrees of IL-10 had expanded danger of myocardial localized necrosis and demise most likely close to 24 hrs. and a half a year. There has been discovered a raised degree of this in Coronary conduit sickness, angina and inherent heart surrenders²³.

Pro-inflammatory cytokines:

Interferon-gamma (IFN-γ):

IFN-γ is a Th1 cytokine that is delivered by T and NK cells following synergistic enactment by IL-12 and IL-18. Studies have demonstrated that IFN-γ assumes a significant function in atherosclerosis. In hypertension and in suggestive cardiovascular breakdown the degrees of this cytokine have been found to be raise²⁴.

Interleukin-1

More significant levels of IL-1 have been accounted for in patients with CAD, UA, intense MI and have been related with antagonistic occasions actuating coronary stenting²⁴.

Tumor necrosis Factor-alpha (TNF-alpha):

TNF-α is a cytokine with a diversity of favorable to provocative exercises. It is fundamentally created by macrophages, endothelial cells and smooth muscle cells of atherosclerotic supply routes. TNF-α may impact the atherosclerotic cycle both by giving metabolic irritations and by rising the statement of cell grip particles. Without a doubt, higher plasma convergences of TNF-α have been discovered in patients with untimely CAD, intense MI, PAD, and CHF.

Novel Cardiovascular Biomarkers under Evaluation:

There are various CVD biomarkers under assessment. A few arrangements exist right now to characterize CVD biomarkers. Most regularly, biomarkers can be gathered dependent on infection particularity, for example, biomarkers of cardiovascular breakdown (BNP, N-terminal prohormone of mind natriuretic peptide (NT-proBNP), atrial natriuretic peptide [ANP], ST-2 and so forth), of atherosclerotic coronary sickness (troponin T or I, creatinine phosphokinase-MB and so on.), or they can be assembled by their utilization such as in intense changes (copeptin, high affectability Troponin, galectin-3, ST2) versus in the incessant phase of CVD to gauge forecast (coronary calcium by CT). On the other hand, CVD biomarkers can be assembled by the pathologic cycle they speak to, for example, aggravation (e.g., C-receptive protein, interleukin 6, Fibrinogen, monocyte chemotactic protein-1, tumor necrosis factor alpha and so forth) oxidative pressure (e.g., isoprostanes), and metabolic (e.g., lipoprotein (a), low-thickness lipoproteins, high thickness lipoprotein, ApoB 100, Lipoprotein-related phospholipase A2, Homocysteine, nutrient D, fibroblast development factor 23, adiponectin, glycated hemoglobin, haptoglobin and so on ²⁵.

Figure 2: Key Novel Heart Failure Biomarkers. The above diagram illustrates various biomarkers which are responsible for Inflammation, Neurohormonal therapy, Extra Cellular Matrix Remodeling, Oxidative Stress, Myocyte Stretch and Myocardial Injury²⁶.

Higher convergence of BNP in the blood of a patient who presents to a trauma center is related with more noteworthy likelihood of a finding of cardiovascular breakdown. Additionally, higher BNP fixation on admission to the clinic is likewise connected with more noteworthy in-emergency clinic mortality. NT proBNP, which is a steadier type of BNP, is likewise prescient of a finding of cardiovascular breakdown. It is critical to see, in any case, that BNP levels are contrarily connected with stoutness and may likewise be affected by presence of kidney illness. Neutrophil gelatinase-related lipocalin (NGAL), another glycoprotein covalently bound to grid metaloproteinase-9, is delivered by renal cylindrical cells in light of renal aggravation and injuryGalectin-3 is an energizing biomarker with a significant part being developed and guideline of heart fibrosis and redesigning. In patients determined to have intense decompensated cardiovascular breakdown, blood Galectin-3 level has demonstrated to be prescient of mortality on transient follow-up²⁷.

Diagnosis Tests:

· Nuclear Imaging: Produces images by detecting radiation from different parts of the body after the administration of a radioactive tracer material.

· Ultrasound Tests: Such as echocardiograms use ultrasound, or high frequency sound waves, to create graphic images of the heart's structures, pumping action, and direction of blood flow.

· Radiographic Tests: Use x-ray machines or very high tech machines (CT, MRI) to create pictures of the internal structures of the chest.

Electron-Beam Computed Tomography or EBCT:

EBCT helps to detect the calcium deposits or calcifications in the walls of the coronary arteries. These are early markers of atherosclerosis and coronary heart disease. This is not a routine test in coronary heart disease.

Artificial Intelligence Benefit of Early Detection:

CVDs still remains the major cause of morbidity and mortality and consequently, early diagnosis is of most importance. Health care expenditures are overwhelming where costs are skyrocketing, predominantly because of the augmenting costs of care of advanced disease. Congestive heart failure distress more than 5million people and preoccupies more than $30 billion in health-care expenditures annually in the United States alone. The aim for recognizing a marker or markers for early CVDs that could help as a surrogate for disease progression and ultimate morbid events is to ameliorate the precision for early detection and treatment. Screening tests to link early vascular and cardiac functional and structural abnormalities identify the high occurrence of abnormalities in asymptomatic individuals without clear-cut risk factors for CVDs. According to the American Heart Association (AHA), CVDs (CVD) kills one woman every minute in the United States. Additionally, one woman from every three women will experience some form of CVD during their lifetime. Heart attacks, heart valve problems, strokes, and arrhythmia are all forms of CVDs and although the rate of CVD in America is staggeringly high, the AHA reports that most cases are preventable by early detection and leading a more heart-healthy lifestyle.

Early Detection in Primary Care:

Early detection of CVDs can be the difference between life and death. By being cognizant of the early signs of CVD, you’ll have a better chance of catching threats early on. We must note that there are two major hurdles in making Primary Care the front-line of heart care. First, is a technology gap – currently, there is no simple to use medical device suitable for the screening of asymptomatic patients, that is able to detect and diagnose a sufficiently broad range of heart diseases, including ALVD, that is suitable for widespread use in Primary Care. Compounding this technology gap is the second hurdle, knowledge and experience gap. This second hurdle is because of the complexity of the human heart, which requires a high level of knowledge and experience to effectively be able to understand. Heart disease is never just one disease, and each disease has a multi-symptom nature. The lack of an appropriate device coupled with the heart’s complexity explains why heart disease was always regarded as the domain of cardiology, and why Primary Care did not play a bigger role. But the times are changing. For Primary Care to be the new Front-line of heart care, an appropriate medical device needs to be able to detect and diagnose the onset of a “broad-range” of heart disease, coupled with strong AI support acting as the physician’s assistant. Only then can it be considered effective for the widespread screening of asymptomatic patients. From the cardiologist’s perspective, by implementing new technology and start detecting the earlier onset of CVDs in Primary Care, there are tangible benefits as well²⁷.

The technology will be able to detect the earlier onset of heart disease in just around the corner and will be accessible soon for the world. Its name is Cardio-HART by Cardio Phoenix Inc, an AI-Powered heart diagnostic device for the earlier detection of up to 95% of all common heart diseases. In the end, such a device will help to better coordinate Primary Care with Cardiology Care and foster greater inter-level collaboration, salutary not only the patient, their families, but also the healthcare insurers that must provide for, and pay for, those patients in their time of greatest need.

Scope and Recommendation:

Efficient and conventional biomarkers of CVDs are used to diagnose and have an important prognostic significance. Advances in biomarker research and developments associated to CVD have led to more sensitive screening methods, a greater emphasis on its early detection and diagnosis, and improved treatments resulting in more probable clinical outcomes. The detection of acute coronary syndrome is conventionally based on union of chest pain, ECG attributes and elevated serum biomarker levels. Thus, the diagnosis of acute coronary syndrome is dependent on the biomarkers. Hence, biomarkers play a crucial role in estimating the CVDs in affected individuals. Creatine kinase (CK) is a widely used test, with the recent CKMB assay contributing greater specificity and sensitivity. Cardiac troponins ease early and rapid diagnosis; enable effective risk stratification in patients with infarction of those who will benefit from aggressive medical or surgical intervention. MicroRNAs have been associated to posttranscriptional regulation of gene expression in major cardiac physiological and pathological processes. Upon tension or various pathological conditions, this class of non-coding RNAs has been found to modulate different cardiac pathological conditions, such as contractility, arrhythmia, myocardial infarction, hypertrophy, and inherited cardiomyopathies. Cardiac biomarkers have made a great impact on management and our understanding of molecular mechanisms of different disease conditions. However, the biomarkers that are currently in use do not reflect the multiple disease pathways that are required in a broad spectrum of cardiac disease conditions ranging from acute coronary syndrome to heart failure (heart failure with preserved ejection fraction) to pulmonary hypertension or arrhythmias. It can take [depending on marker] between 2 hrs and 24 hrs for the level to increase in the blood. Additionally, determining the levels of cardiac markers in the laboratory - like many other lab measurements - takes considerable time. Therefore, cardiac biomarkers are not useful in diagnosing a myocardial infarction in the acute phase. The clinical manifestations and results from an ECG are more precise in the acute situation. However, in 2010, research at the Baylor College of Medicine revealed that, using diagnostic nanochips and a swab of the cheek, cardiac biomarker readings from saliva can, with the ECG readings, determine within minutes whether someone is likely to have had a heart attack²⁸.

Modern technologies like Artificial Intelligence (AI), Biosensor and high-speed data communication made it possible to collect the high-resolution data in real time. The high-resolution data can be analyzed with advance Machine Learning (ML) algorithms, it will not only help to discover the disease patterns but also an real-time and objective monitoring of bio-signals can help to discover the unknown patterns linked with CVDs (CVD). The longitudinal study of the measurable bio signals using sensor can detect the novel patterns with the aid of ML, such patterns has a potential to act as a digital marker got CVDs (Fig 3). The classical systems of the CVD like abnormal rhythm, rapid heart rate, high blood pressure can be easily measure in real-time using the digital sensors. These patterns can help to track the CVD in early stage. The machine learning techniques viz. anomaly detection, K-Nearest Neighbor (KNN) method and Convolutional Neural Network (CNN) can detect the patterns corresponding to the CVD with required clinical sensitivity and specificity

Figure 3: The machine leaning phases.

Data Acquisitions and Labeling:

In this phase the data of the measurable bio-signal having the significant impact of the various CVD biomarkers are recoded using the high precision sensors. The data acquired will be labeled by the clinicians for the underlying health conditions. The data acquisitions and labeling need to be multicentric to capture the CVD biomarkers specific variations in biosignal for different strata of the population^29-34.

Training the ML Model:

The labeled data is experienced in to train the supervise ML model.

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Received on 24.08.2021 Modified on 18.02.2022

Asian J. Pharm. Res. 2022; 12(3):229-234.

DOI: 10.52711/2231-5691.2022.00038