Frontiers in Heart Failure

Heart failure (HF) is a complex clinical syndrome that is a consequence of any functional or structural impairment of left ventricular filling or pumping of blood. It is considered as a crucial healthcare issue and has been called “the epidemic of the 21st century”, namely because of its rising prevalence and the considerably high mortality, morbidity, and care expenditures it poses to the health care systems; HF prevalence is increasing with advancing age. 2-3% of the general population worldwide has HF, whereas among elderly individuals (≥80 years of age) about 12% of both genders have HF. Mortality is exceptionally high, since almost half of the patients will die 5 years after the establishment of diagnosis. The cost of HF care is high, mostly driven by the frequent hospitalizations for HF, and will remain an important concern for the healthcare systems. The estimated HF prevalence and cost of care will significantly increase in the near future, in part because of the longer survival of HF patients due to the continuous optimization of life-prolonging medical and interventional therapies, as well as the aging of the population in the developed countries, which eventually leads to a greater number of individuals at risk for incident HF. Therefore, strategies aiming to HF prevention and improvement of care efficiency are urgently needed. The purpose of this chapter is to provide an in-depth look at the current definitions, epidemiology, cost and health care policies regarding HF in the developed world.

Despite painstaking investigations on the pathogenetic mechanisms of heart failure, there still remains a long distance to completely understand the complexity of the events dominating its progression. In this direction, many efforts have been made by recruiting both basic physiology and imaging techniques in order to overcome gaps that are present in diagnostic and therapeutical interventions in heart failure. Intact heart muscle physiology and circulation are the cornerstone for a comprehensive insight into the mechanistic understanding of the relationship between contractility, coronary blood flow, and myocardial perfusion. The latter seems to be a major cause of cardiac muscle damage leading to progression into systolic heart failure. Therefore, it is a matter of urgency to re-evaluate and extend the spectrum of imaging techniques for achieving a better assessment of myocardial perfusion based on fundamental concepts of cardiac cellular and subcellular physiology.

Heart failure is a worldwide health challenge representing the most common admission diagnosis in patients aged ≥65 years. It is associated with worse prognosis even compared to that of most malignancies, despite therapeutic improvements. Research efforts are underway to combat this complex disease by increasing our understanding of the underlying molecular mechanisms associated with the structural and functional abnormalities. Here we review the molecular changes associated with the fundamental derangements observed in heart failure such as the depressed myocardial contractility and relaxation, increased cardiac fibrosis, increased cardiomyocyte stiffness and profound cytoskeletal changes.

Heart Failure (HF) is a complex clinical syndrome characterized by compromised cardiac output that leads to inadequate blood supply failing to meet the requirements of the metabolizing tissues of the body. HF is a silent epidemic that affects ~2% of the general population in the western world and its prevalence is steadily increasing. Although survival has improved, high morbidity and mortality render HF the most devastating cardiovascular disorder with considerable financial burden on public health care. The phenotypic variability of HF syndrome reflects the complexity of the underlying genetic background of the disease, as well as the interindividual susceptibility to external triggers. Although acquired clinical conditions account for the majority of HF development, a proportion of HF cases are due to inherited pathological states comprising myocardial disorders, mitochondrial diseases, metabolic disorders and congenital heart defect syndromes. Among those, inherited forms of cardiomyopathies constitute “naturally-occurring” disease models that provide the opportunity for an in depth investigation of the genotype–phenotype relationships. Advances in technology permitting high-throughput whole genome genotyping and sequencing, have provided invaluable insights into the genetic architecture, disease evolution and therapeutic response. However, despite the enormous wealth of genetic information derived from those studies and their contribution towards the identification of disease-specific genetic variants in complex diseases such as HF, a considerable amount of genetic information related to heritability is missing. In this chapter, we will review knowledge regarding the underlying complex genetic architecture of both acquired and inherited forms of HF, the role of epigenetics as a significant modifier mechanism in disease susceptibility and phenotypic heterogeneity, as well as advances in the field of pharmacogenetics of HF.

Heart failure is an important cause of morbidity and mortality worldwide and despite recent advances in therapeutic management, hospitalization rates remain high. The complex interactions of various physiologic, psychological, social, and health care delivery issues make heart failure a challenging chronic disease to manage. A better understanding of the underlying pathophysiological mechanisms, as well as novel diagnostic and therapeutic approaches, may result in cost-effective strategies achieving more drastic control of the epidemic. Prompt diagnosis and optimal treatment of heart failure can affect long-term outcome. A tool with diagnostic, prognostic, and treatment-guiding properties in this respect would be valuable. Recent evidence in the field of molecular biology and heart failure pathophysiology has led to the identification of novel biomarkers that may have significant advantages. Furthermore, heart failure is associated with several cardiac and non-cardiac comorbidities that play an integral role in its development, progression, and response to treatment. The comorbidity burden is highly associated with hospitalization rate in patients with heart failure and preserved left ventricular ejection fraction, as well as in those with heart failure and reduced ejection fraction. In the current review we address these issues and try to analyze this patient population focusing on the need for re-hospitalization and the poor prognosis.

Heart failure is a syndrome affecting not only the heart, but in fact all the organs and systems of the body. Therefore, common serum laboratory variables, such as creatinine, play an important role in diagnosis and follow-up of specific organ dysfunction in heart failure. Actually, treatment is tailored according to these variables. More recently, natriuretic peptides were suggested as a valuable tool for the diagnosis of acute and chronic heart failure, substituting echocardiography at the emergency department. Furthermore, these peptides are used for the prognosis of heart failure patients. Many newer biochemical markers related to a variety of pathophysiological processes, such as inflammation, oxidative stress, remodeling of the extracellular matrix and neurohormones, have been investigated in the past few years. Some of them have shown promising characteristics, not only as diagnostic tools, but also as potential treatment targets. Finally, manipulation of genes via micro-RNAs has emerged as a vast new era in the understanding and treatment of heart failure. In this chapter, the majority of laboratory variables and biochemical markers used in heart failure will be discussed. Moreover, information will be given for the clinical benefits of an integrated approach in the management of heart failure patients. Latest advances regarding novel biomarkers will be also presented.

Echocardiography is a valuable diagnostic tool for the management of heart failure (HF), by demonstrating structural and functional abnormalities in individuals characterized by increased risk of developing HF, patients with clinical features indicating HF, or cases of symptomatic HF. Echocardiography evaluates cardiac structural and functional parameters, having an important role in investigating the aetiology of heart conditions and providing prognostic information. During past years, two-dimensional echocardiography has been a valuable technique because of its ability to provide reliable diagnostic and prognostic information in HF patients. On the other hand, Doppler ultrasound, as a non-invasive tool, contributes to the identification of systolic and diastolic dysfunction. In clinical trials, the predictive value of ejection fraction has been consistently demonstrated; lower ejection fraction has been related to higher risk of cardiac death. Although a normal left ventricular function is observed in 40–50% of HF patients based on the results of recent clinical trials, the development of a global parameter, reflecting the remodelling process and functional abnormalities, is required. In this regard, recently developed three-dimensional volumetric measures of left ventricular anatomy and function seem very promising; however, more trials should be performed for further validation. Echocardiographic evaluation is considered as an essential part of HF management, despite the fact that no single examination meets all imaging requirements for HF investigation. Other modalities can provide additional evidence regarding specific questions, such as tissue characterization.

Diuretics are first line drugs to improve symptoms of heart failure patients; however they do not increase their long term survival. Administration of medications blocking the neurohormonal activation, such as angiotensin converting enzyme(ACE) inhibitors (alternatively, angiotensin II receptor blockers in patients with intolerance to ACE inhibitors), mineralocorticoid receptor antagonists and beta blockers, lead to long term improvement of both symptoms and prognosis of chronic heart failure patients with reduced ejection fraction (EF<40%). Digoxin and ivabradine are also therapeutic options for heart failure patients in specific clinical scenarios. LCZ 696 is the new promising medication that improves more effectively cardiovascular outcomes in chronic heart failure cases in comparison to ACE inhibitors. In contrast, there are no available life prolonging medications for patients with preserved ejection fraction (EF>50%), and treatment remains empirical targeting only to symptomatic improvement. Treatment of comorbidities, including renal dysfunction, anemia and depression, may improve the well-being and quality of life in chronic heart failure patients, although evidence-based data are still limited.

Despite therapeutic advances in the medical treatment of HF patients, the prognosis remains poor. Coronary revascularization in patients with ischaemic cardiomyopathy is associated with amelioration of symptoms and survival benefit. Percutaneous coronary intervention with stenting is associated with excellent outcome, high procedural success rate, low event rates, and can be safely performed in patients with ischaemic cardiomyopathy. Patients with complex coronary artery disease require surgical revascularization (Coronary Artery Bypass Grafting - CABG). Cardiac resynchronization therapy (CRT) aims to re-establishing synchronous contraction between the left ventricular free wall and the interventricular septum, resulting in an increase in stroke volume. In clinical terms, this is translated in functional class improvement. This generally involves biventricular pacing (pacing of the left and right ventricle through separate leads). Surgical strategy for the management of patients with end-stage ischaemic heart disease includes “conventional” techniques (surgical revascularization, the most common surgical procedure, surgical ventricular restoration in patient with a dyskinetic part in the left ventricle and mitral valve surgery for mitral regurgitation). Mechanical circulatory support aims to restore blood flow and pressure, and thus end-organ function, in patients with profound cardiogenic shock or in endstage patients (stage D) with advanced NYHA III-IV symptoms as a bridge to transplantation or as lifelong support (destination therapy). Heart transplantation is associated with excellent long-term results in terms of symptomatic relief and prognostic benefit under strict criteria involving the recipient and the donor. In the face of evolving technology, lifetime mechanical support provides a realistic alternative to heart transplantation.

Heart disease still remains one of the leading causes of mortality in the developed world. Therefore, finding the right cure for cardiovascular disease remains a current umnet medical need. However, the recent advances in understanding the molecular basis of myocardial dysfunction, the characterization of novel properties of cardiac progenitors, the identification of the plasticity of several subpopulations of cardiac cells and the development of more efficient gene transfer technologies, has made heart failure another excellent candidate for cell and gene-based therapies.