Causes That Lead to Heart Failure

Heart Failure (HF) is a serious condition that occurs when the heart is unable to pump enough blood and oxygen to support other organs in the body. Generally in an adult population, the estimated prevalence rate is around 2% (1-3%) but sharply upsurges to about 5-9% in people aged 65 years and above.[1, 2] In the United States, the number of adults living with heart failure is on the rise, increasing from about 5.7 million (2009-2012) to about 6.5 million (2011-2014).[1] Grounded on this data, it was projected that the number of people living with heart failure will increase by 46% from 2012 to 2030, accounting for more than 8 million American adults.

Currently, the existing data on HF is estimated to be 26 million adults worldwide, and it is expected to increase continually due to three main factors; ageing population, increasing prevalence of co-morbidities or risk factors, and improved survival of post myocardial infarction.[3, 4] HF can be broadly classified based on ejection fraction.

Patients with ejection fraction ≤ 40% are termed as HF with reduced ejection fraction (HFrEF), and those with ejection fraction ≥ 50% are termed HF with preserved ejection fraction (HFpEF).

Patients whose ejection fraction is in between the two are considered as borderline ejection fraction[5] or midrange ejection fraction (HFmrEF).[6] The signs and symptoms of HF are often deceptive with a wide differential diagnosis, making clinical presentation thought-provoking, due to the fact that the ‘old way’ of ascertaining suspected patients with HF – medical history, physical examination, chest radiography, electrocardiography, and standard laboratory investigations, have been noted to be partially reliable.[7] Due to the extensive burden of the disease coupled with the complexity of the syndrome of HF, mechanisms to supplement the information established from clinical history and physical examination are currently necessary.

Get quality help now

Sweet V

Verified

Proficient in: Heart Disease

4.9 (984)

“ Ok, let me say I’m extremely satisfy with the result while it was a last minute thing. I really enjoy the effort put in. ”

+84 relevant experts are online

Hire writer

Biomarkers have been known since its inception in 1989 and was initially recognized as a “measurable and quantifiable biological parameter used to assess health and physiology in patients in terms of disease risk and diagnosis”[8] This definition was later altered to suit a National Institute of Health working group and hence defined biomarker as “an objectively measured parameter that is an indicator of normal biological processes, pathogenic process or as a response to pharmacological therapy.”[9] Biomarker-guided management, diagnosis and treatment have increasingly gained popularity most importantly in the acute settings – where majority of patients with HF are mostly found initially.[10] This is purposely due to the accruing number of evidences that have evolved suggesting that molecular biomarkers can help unravel the pathophysiology of HF, which will aid in predicting the disease’ adverse consequence, provide innovative drug target, and judge therapeutic efficacy.

In this review therefore, we discuss the available guidelines regarding HF biomarkers, emphasized the general procedures for evaluating novel biomarkers, as well as the clinical utility of both established and emerging biomarkers in HF diagnosis, risk stratification, management and probable prevention approaches. Lastly, we will discuss the future approach and the advent of Omics in the discovery of HF biomarkers.

1.1. Available Guidelines on Heart Failure Biomarkers

Major practical guidelines have recognized the utility of recommended biomarkers in diagnosis and management of HF, as summarized in Table I. The American College of Cardiology Foundation/American Heart Association (ACC/AHA), Heart Failure Society of America (HFSA) and the European Society of Cardiology (ESC) have all established the usefulness of the natriuretic peptides (NPs) to provide assistance in the diagnosis of HF in suspected patients.[5, 6, 11, 12] The HFSA and ESC have however alerted on the use of the NPs in certain instances. For instance, using the NPs in screening patients without the existence of symptoms of HF is not recommended by the HFSA guidelines. The ESC on the other hand has noted a high negative predictive value of NPs at certain precise threshold, and hence recommended their use to rule out HF but not to ascertain diagnosis. The ACC/AHA guideline has given the NPs a Class I recommendation for prognosis or disease severity of HF once there is established HF diagnosis, and a Class IIa and IIb recommendations to guide therapy in chronic HF and acutely decompensated HF respectively. Consequently, the ACC/AHA 2017 update has given a Class IIa recommendation for NPs to aid in the prevention of development of LV dysfunction or new-onset HF.

In clinical settings, the utilities of novel biomarkers are less established. Whereas the ACC/AHA guidelines recommended the use of biomarkers of myocardial injury (cardiac troponins I and T) and myocardial fibrosis (sST2 and galectin 3) in HF, the ESC has not realized any strong evidence to recommend the use of sST2 and galectin 3, but gave a class Ic recommendation for use of cardiac troponins in patients with suspected acute HF. The HFSA refused to acknowledge no other biomarker apart from the NPs. Upon the analysis of these differences in recommendations of novel biomarkers by the various guidelines, we sought to delineate the criteria used to evaluate such biomarkers in order to be of clinical importance.

Though there are different kinds of biomarkers in living organisms (such as physiological parameters, clinical images, and tissue-specimen biopsies), ideal biomarkers are in constant circulation other than those routinely determined as part of clinical care such as electrolytes or hemoglobin.[13] Many objective criteria have been proposed to evaluate the possible relevance of these biomarkers in clinical settings. For a novel biomarker to be selected and used clinically in diagnosis and management of cardiovascular diseases, six phases of evaluation have been proposed by AHA, which include the proof of concept, incremental value, clinical utility, prospective validation, clinical outcome and cost effectiveness.[14] In addition to these, Morrow and de Lemos [15] devised the benchmarks that a biomarker should fulfil to be clinically useful.

They stated more categorically that a useful biomarker should be cost effective and allow repetitive and precise measurements with a rapid processing time. It should provide information that is above the one provided by clinical assessment with a superior performance compared with other available tests, and above all, it should assist decision making and enhance clinical care.[15] In a succeeding review, van Kimmenade and Januzzi [16] also proposed four main criteria specifically for HF biomarkers: (1) thorough evaluation have been carried on to assess those markers in a wide range of patients characteristics of the diagnosis with rigorous statistical methods; (2) they can be easily, quickly and accurately measured with defined biological variability and low analytical imprecision of the assay; (3) they demonstrate an important component of HF pathophysiology; and (4) they provide clinically useful information for caregivers and patients to assist in diagnosis, risk stratification and management by providing additional information to the standard clinical laboratory data.[16] Lastly and more specific to the field of heart failure, the National Academy of Clinical Biochemistry has expounded comparable objectives for novel biomarkers to be used in clinical settings. In that definition, biomarkers must be able to recognize fundamental causes of HF, authorize presence of HF syndrome, assess its severity, and foresee the risk of the disease progression.[17] Thus far, only the NPs fulfil all the above criteria, however, other multiple novel biomarkers are gaining relevance and hence needed to be well studied.

Various cardiac remodeling, altered renal function and neurohormonal activation pathways depicted by the pathophysiology of the progression of HF due to cardiac insult, cardiac injury and ventricular dysfunction, have shown their actions influenced for biological investigations. In actual fact, from the inception of HF risk factors to progression of the syndrome, there are numerous proteins whose measurements depict significant information about HF.[18] These protein markers can mostly reveal pathophysiological characteristics of HF, including biochemical wall stress, inflammation, myocyte injury, neurohormonal upregulation, myocardial remodeling and extracellular matrix turnover.[5] Table II gives the classification of the established and some emerging HF biomarkers.

Biomarkers for myocyte stretch, especially the natriuretic peptides (BNP and NT-proBNP) are the most referenced biomarkers and against which other markers are constantly compared. Since HF is characterized by progressive fatigue and dyspnea leading to reduced tolerance to exercise, increasing wall stress and neurohormonal activation stimulates BNP and NT-proBNP discharge which are adversely associated with left ventricular (LV) systolic function.

The Natriuretic Peptides (NPs) are peptide hormones synthesized by the brain, heart and other organs. In the heart, these hormones are provoked by atrial and ventricular distention and neurohormonal stimulations in response to HF. Brain Natriuretic Peptide (BNP) is a natriuretic hormone that are usually recognized originally in the brain but are discharged predominantly from the ventricles of the heart in reaction to volume expansion and overload. Cleavage of the prohormone (proBNP) produces biologically active amino acid BNP in addition to the inert amino acid N-terminal pro-BNP (NT-proBNP). The Atrial Natriuretic Peptide (ANP) on the other hand, is released by the myocardial cells in the atria or sometimes the ventricles in response to intravascular volume expansion and/or increasing wall stress.[19]

BNP and its precursor NT-proBNP are particularly useful in ascertaining whether acute dyspnea is caused by HF. Again, the concentrations of these biomarkers in patients who have been diagnosed with chronic HF suggest valuable indication about prognosis which has led to their exploration as focus for HF therapy.[16] In normal patients, concentrations of circulating BNP and NT-proBNP are found to increase with age and appears to be higher in women than in men.[20] When these two factors are ruled out, healthy adults have BNP levels of 25pg/mL or less and NT-proBNP levels of less than 70pg/mL.[21] However, in the presence of acute dyspnea, these levels or concentrations increase drastically to about BNP ≤ 100pg/mL or NT-proBNP ≤ 300pg/mL which are clear indications to rule out HF as the cause of dyspnea.[22, 23] Above these risk brinks is an indication of higher risk of adverse outcome, whereas below this verge is a considerably lower risk.[24] In view of these the authors of the ESC guidelines for HF have set a lower BNP cut-off value (35 pg/mL) and NT-proBNP (125 pg/mL) to refute HF allegations in patients with slow onset of HF signs and symptoms which reflect lower NP levels as compared to those at the emergency department.[6]

Currently, researchers have tailored their work in the field of focusing on the role of monitoring NP concentrations for both hospitalized patients and the larger populace in order to modify their therapy for HF for each individual patient’s need. This is chiefly because NP values strongly correlate with the hemodynamic parameters such as pulmonary capillary wedge pressure and LV edge-diastolic pressure, thereby signify the actual hemodynamic status of the patient.[25] Another reason is due to the availability of authorized computerized and point-of-care tests rendering the assessment of the NPs very suitable, cost effective and rapid for the physician and patient as a whole. During admission and prior to discharge of patients from the hospital, a universal agreement has been debated on the measurement of BNP concentrations in cases of severe HF intensification that demand hospitalization.[26] This consensus is in conformity with the fact that many findings have demonstrated the decrease in BNP concentrations during admissions to foretell better results, whereas patients with comparatively constant or augmented BNP values are more likely to experience readmission or increased mortality rates.[24, 27, 28]

Results from different studies have concluded that approximately 20 % to 30 % mortality reduction are recorded for biomarker-guided HF care above traditional clinical care [29], and potential studies have confirmed that progressive patient evaluation of NPs are indications of increased concentration of HF medications and decrease in concentrations of NPs.[30, 31] In an echocardiography evidence, Weiner and colleagues [32] concluded that there is an improved LV volume and cardiac function when oteins such as cardiac fatty acid binding protein, creatine kinase, myoglobin and troponins, only the latter has emerged as the yardstick of care marker for establishing the presence of myocardial infarction.[94]

1.7.1. Cardiac Troponins (I and T): The use of high sensitive troponin (hsTn) assay which allow for determination of trivial amount of myocardial injury or necrosis may be particularly useful to identify cardiotoxicity, which in-turn predicts risk for HF and other cardiovascular occurrences.[95] In fact, the advent of hscTn in HF has been of great tool in the hands of researchers and clinicians for early and strong prediction and prognostication. For instance, in the study of Latini and co-researchers, when standard assay was employed in the determination of cardiac troponins, only 10 % of the patients with chronic HF had detectable TnT and it was associated with increased risk of death and readmissions. However, when high sensitivity cardiac troponin assay was used on that same cohort, almost 92 % of the patients had detectable TnT.[96]

Slightest increase of circulating cTn concentrations have mostly been realized in patients with HF exclusive of ischemia or coronary artery disease, signifying continuing myocyte injury or necrosis in affected individuals.[97, 98] Many reports have indicated that increase of cTn is accompanied with weakened hemodynamics, gradual LV dysfunction and upsurge rate of mortality in patients with HF.[97-99] Convincingly in the ADHERE-HF registry, approximately 6.2 % of patients with acute decompensated HF who had elevated levels of cTn were later found to be linked with adverse in-hospital mortality.[100] These earlier observations have been thoroughly confirmed especially after the discovery of highly sensitive assays of cTn (hscTn) in recent times.[96, 101] Following this approach, significantly greater number of patients with acute decompensated HF were found to have high concentrations of hsTnT, and these levels were further noted to be independent predictors of all-cause mortality in a multivariable model which included NT-proBNP and sST2.[102]

Owing to the aforementioned findings that increased concentrations of serum troponins have direct association with disease severity, worse clinical outcome and subsequent mortality, two main researches that targeted the reduction of troponin levels over time found better prognosis than persistent elevation of troponins in both acute and chronic HF patients.[103, 104] Subsequently, the writing committee for ESC has also recommended assessment of troponin levels in all patients presenting with suspected acute HF.[6] These notwithstanding, since the most vital addition a biomarker can provide in clinical setting is to affect management and ultimately improve clinical outcome, recent and future research on hscTn must be focused on tailoring medical therapy according to the rise in the levels of hscTn.