Author + information
- Received September 27, 2012
- Accepted October 5, 2012
- Published online February 1, 2013.
- Eugene Braunwald, MD∗ ()
- ↵∗Reprint requests and correspondence:
Dr. Eugene Braunwald, TIMI Study Group, 350 Longwood Avenue, Boston, Massachusetts 02115.
Despite major improvements in the treatment of virtually all cardiac disorders, heart failure (HF) is an exception, in that its prevalence is rising, and only small prolongations in survival are occurring. An increasing fraction, especially older women with diabetes, obesity, and atrial fibrillation exhibit HF with preserved systolic function. Several pathogenetic mechanisms appear to be operative in HF. These include increased hemodynamic overload, ischemia-related dysfunction, ventricular remodeling, excessive neurohumoral stimulation, abnormal myocyte calcium cycling, excessive or inadequate proliferation of the extracellular matrix, accelerated apoptosis, and genetic mutations. Biomarkers released as a consequence of myocardial stretch, imbalance between formation and breakdown of extracellular matrix, inflammation, and renal failure are useful in the identification of the pathogenetic mechanism and, when used in combination, may become helpful in estimating prognosis and selecting appropriate therapy. Promising new therapies that are now undergoing intensive investigation include an angiotensin receptor neprilysin inhibitor, a naturally-occurring vasodilator peptide, a myofilament sensitizer and several drugs that enhance Ca++ uptake by the sarcoplasmic reticulum. Cell therapy, using autologous bone marrow and cardiac progenitor cells, appears to be promising, as does gene therapy. Chronic left ventricular assistance with continuous flow pumps is being applied more frequently and successfully as destination therapy, as a bridge to transplantation, and even as a bridge to recovery and explantation. While many of these therapies will improve the care of patients with HF, significant reductions in prevalence will require vigorous, multifaceted, preventive approaches.
During the past half-century, the advances in the prevention, diagnosis, and management of cardiovascular disease (CVD) have been nothing short of spectacular. Age-adjusted CVD-related deaths have declined by about two-thirds in industrialized nations (1). Mortality rates associated with the acute coronary syndromes (ACS), valvular and congenital heart disease, uncontrolled hypertension, and many arrhythmias all have fallen dramatically.
Heart failure (HF) is a notable exception to these encouraging trends. Indeed, after normal delivery, it is the most common cause of hospitalization. Annual hospital discharges in patients with a primary diagnosis of HF have risen steadily since 1975, and now exceed 1 million discharges per year, although they may at last be leveling off (2,3) (Fig. 1), or actually decreasing, in the United States (4,5). In Europe, hospitalizations for HF are clearly declining (6,7). HF is primarily a disease of the elderly that affects about 10% of men and 8% of women over the age of 60 years, and its prevalence rises with age (Fig. 2) and has risen overall. In the United States, patients with a primary diagnosis of HF now make >3 million physician visits per year. The direct and indirect costs of HF in the United States are staggering; in 2010 they were estimated to be US $39.2 billion (8). The estimated lifetime cost of HF per individual patient is $110,000/year (-2008 US dollars), with more than three-fourths of this cost consumed by in-hospital care (9).
Survival after a diagnosis of HF has improved during the past 30 years; the age-adjusted death rate has declined (4–6), and the mean age at death from HF has risen (7,10). However, despite these modest improvements, the 5-year mortality is still approximately 50%—worse than that of many cancers (11). Among Medicare patients, 30-day mortality is 10% to 12% (12), and the 30-day readmission rate after hospital discharge is 20% to 25% (13).
How can this so-called “HF paradox”—that is, the striking improvements in the prognosis of individual cardiac conditions, such as ACS, severe hypertension, valvular and congenital heart diseases, but a growing prevalence of HF—be explained? Three possibilities warrant consideration. The first is that, while the risk for mortality in each of these disorders has been reduced, the patients are not “cured” (with the exception of those with certain congenital malformations). For example, while early mortality in patients with acute myocardial infarction may have declined by 75% during the past half-century (14), survivors still have coronary artery disease (CAD) and remain at risk for subsequent episodes of ischemic myocardial damage with further loss of myocardium and possibly HF. A second possible explanation may be related to the increased frequency of myocyte death with aging and with the adverse cardiac consequences of comorbid conditions, the prevalences of which rise with age. These comorbid conditions include hypertension; type 2 diabetes mellitus; chronic renal disease; chronic obstructive pulmonary disease; and dysrhythmias, especially atrial fibrillation (15). The third possible explanation is that the slow but progressive improvement in HF prognosis mentioned previously simply increases the prevalence of this condition. Whatever the explanation(s), one might conclude that with the continued aging of the population, HF will remain a major health problem, not only in industrialized nations but also in the developing world.
Given this magnitude, attention is being directed, appropriately, to identifying individuals at higher risk for HF. Risk factors include increased body mass index, abdominal fat accumulation, elevated fasting blood glucose, elevated systolic blood pressure, elevated apolipoprotein B/apolipoprotein A ratio, and cigarette smoking. In a large-scale (1 million person-years) study that included both outpatients and inpatients from all age groups in an insured population in Georgia, CAD, hypertension, diabetes, and valvular heart disease most frequently preceded the diagnosis of HF (16).
The clinical–hemodynamic profile of patients with HF appears to be changing (10). In a registry of >110,000 patients hospitalized with HF, the proportion with heart failure and a preserved ejection fraction (HFPEF), usually defined as an EF >50%, was approximately 40%, and in-hospital mortality was only slightly lower than that in patients with HF and reduced EF (HFREF) (17). Also, a smaller percentage of patients with HFPEF than of patients with HFREF die from CVD-related causes (18). As a group, HFPEF patients are older and more commonly female, with greater hypertension, obesity, anemia, and atrial fibrillation compared to those with HFREF (19). Diastolic dysfunction may remain asymptomatic for years, but age, renal dysfunction, hypertension, and progression of this dysfunction all appear to be associated with the development of overt HF in this population (20,21).
Acute decompensation heart failure (ADHF), that is, the new onset of severe HF or the sudden intensification of chronic HF, is a life-threatening condition that usually requires hospitalization and is, in fact, the most common cause of hospital admission among patients with HF. ADHF may result from 1 or more precipitating events, including the development of a variety of dysrhythmias; ACS; a rapid increase in the need for an increased cardiac output of the failing heart by conditions such as infection, anemia, and pulmonary thromboembolism superimposed on chronic HF (22); discontinuation of treatment of chronic HF; and progression of the underlying disease. Based on data from >100,000 hospitalizations in ADHERE (Acute Decompensated Heart Failure National Registry), a simple prognostic tool was established with findings that can be obtained easily at presentation. In a multivariate analysis, elevations in age, blood urea nitrogen, creatinine, and heart rate; lower systolic pressure and serum sodium; the presence of dyspnea at rest; and the lack of long-term treatment with a β-blocker were identified as independent predictors of mortality (23).
The mechanisms involved in HF have been investigated from a variety of perspectives during the past half-century. These perspectives have sometimes been referred to as “models” (24).
In 1967, the author and his colleagues defined HF as “a clinical syndrome characterized by well known symptoms and physical signs. . . . [It is] the pathological state in which an abnormality of myocardial function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues during ordinary activity” (25). Support for this hemodynamic model of HF came from the observation that, in HF resulting from absolute or relative increases in hemodynamic load, there is actually a reduction in the intrinsic contractility of cardiac muscle. This was reflected in a reduction in force development of isolated cardiac muscle obtained from the failing hearts of experimental animal preparations with pressure overload (26) and then from isolated myocytes obtained from patients with HFREF (27).
Important hemodynamic changes in HF result from ventricular remodeling, which is common in patients with chronic dysfunction of the ventricular pump, and which varies by HF type (28). In patients with HFPEF, the volume of the left-ventricular (LV) cavity is typically normal, but the wall is thickened, and the ratios of LV mass/end-diastolic volume and the myocardial stiffness modulus are both increased (29). In contrast, in patients with HFREF, the LV cavity is typically dilated, and there is either a normal or reduced ratio of LV mass/end-diastolic volume. At the cellular level, both cardiomyocyte diameter and myofibrillar density are higher in HFPEF than in HFREF (30).
The size, shape, and thickness of the extracellular matrix (ECM) are important determinants of the architecture of the intact ventricles and thereby their pumping function. The ECM can be thought of as a scaffolding, or internal skeleton, of the ventricles (31). Remodeling of the ECM occurs with replacement fibrosis following myocardial infarction, a process that has been referred to as a “morphologic footprint of earlier myocardial necrosis” (32). Myocardial necrosis enhances the release of growth factors in the connective tissue, which results in the formation of new fibroblasts. When this process is inadequate, such as after infarction, there is thinning of the ventricular wall, possible ventricular aneurysm formation, and further impairment of LV pump function. The increased synthesis of ECM enhances myocardial stiffness in pressure overload hypertrophy and reduces the rate of ventricular relaxation (and filling) as well as contraction (emptying) (33). Fibrosis can be stimulated by long-term activation of the renin-angiotensin-aldosterone system, especially by aldosterone (34).
Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes involved in the degradation of the ECM. Their activity can be inhibited by a group of proteins termed tissue inhibitors of MMP. The myocardial fibrosis consequent to myocardial infarction and pressure-load hypertrophy may be associated with changes in ECM degradation resulting from an imbalance between MMPs and tissue inhibitors of MMPs, favoring the latter, and causing excessive fibrosis. Conversely, overexpression of MMPs may play an important role in ventricular remodeling in patients with dilated cardiomyopathy as well as in patients with ventricular volume overload states such as valvular regurgitation (31). Both imbalances can affect hemodynamics adversely.
Renal sodium and water retention are integral components of the HF syndrome because they play a crucial role in the genesis of dyspnea and edema, 2 cardinal clinical manifestations of the syndrome. This consideration led to the cardiorenal model of HF, which emphasizes the close interplay between these 2 organ systems. Both diuretics and dietary sodium restriction are crucial to the management of congestion in patients with HF. However, when such therapy is intensified in patients with severe HF, it may lead to renal failure (the cardiorenal syndrome), a condition that is associated with a high mortality rate.
In the 1960s, it became clear that, in healthy subjects, activation of the adrenergic nervous system is an important regulator of cardiac performance during exertion; it increases myocardial contractility and redistributes cardiac output (25,35) (Fig. 3). In acute HF, enhanced contractility resulting from adrenergic activation stimulates the depressed contractility of the failing heart and, by causing vasoconstriction, raises the blood pressure and aids in the perfusion of vital organs. However, prolonged activation of the adrenergic nervous system and of the renin-angiotensin-aldosterone system causes maladaptive remodeling of the ventricles and further myocardial injury, thereby initiating a vicious cycle in what has become known as the neurohumoral model of HF. The importance of this model became even clearer when it was discovered that blockade of these 2 systems prolongs survival in patients with HF (Fig. 4).
Abnormal Ca2+ cycling model
Cardiac contraction results from the interaction of the thick (myosin) and thin (actin) myofilaments; this interaction is triggered by the cytoplasmic [Ca2+]. The importance of Ca2+ to cardiac contraction has been appreciated since the classic experiments described by Ringer in 1883 (36). In the abnormal calcium cycling model of HF, dysregulation of Ca2+ fluxes are considered central to the depression of the myocardial contractility that occurs in certain types of HF (Fig. 5). During depolarization of the cell membrane, Ca2+ enters the myocyte through L-type Ca2+ channels located in the indentations of the membrane known as transverse tubules, which are in close proximity to the sarcoplasmic reticulum (SR). This influx stimulates the release of much greater quantities of Ca2+ from the SR into the cytoplasm through the Ca2+ release channels, also known as the ryanodine receptors (RyR2).
After reaching a critical concentration, the cytoplasmic Ca2+ activates the contractile system of the myocyte, thereby triggering contraction. The sarcoendoplasmic reticular adenosine triphosphate–driven [Ca2+] pump (SERCA2a) returns cytoplasmic Ca2+ to the SR against a concentration gradient. This reduction in cytoplasmic [Ca2+] shuts off contraction and initiates myocyte relaxation (Fig. 6).
Dysregulation of Ca2+ movements has been demonstrated in certain types of HF. A diastolic leak of Ca2+ through altered RyR2 lowers the Ca2+ content of the SR, reducing the Ca2+ that can be released during activation, thereby weakening contraction (37). While there is agreement that abnormal function of these receptors occurs in certain types of HF, there is controversy regarding the molecular cause of “leaky” RyR2 receptors. Some have attributed it to hyperphosphorylation of this receptor at serine 2808 by phosphokinase A (38); others, to the phosphorylation of a nearby amino acid, serine 2814, by another enzyme, Ca2+/calmodular-dependent protein kinase II (39).
A second major abnormality of Ca2+ fluxes that may play a crucial role in the development of HF is a loss of function of the SERCA2a pump, which reduces the Ca2+ content of the cardiac SR and hence the quantity of this ion that can be released during myocyte activation, causing systolic dysfunction and ventricular tachyarrhythmias (40). This defect in SERCA2a function also reduces the quantity and speed of removal of Ca2+ from the cytoplasm, thereby inhibiting ventricular relaxation and causing diastolic dysfunction. Phospholamban is a protein that is in close proximity to and regulates SERCA2a (Fig. 6). In the dephosphorylated state, phospholamban inhibits SERCA2a. Stimulation of β-adrenergic receptors normally causes the phosphorylation of phospholamban and thereby disinhibits (stimulates) SERCA2a, enhancing both cardiac contraction and relaxation (Fig. 6). This “contractile reserve” provided by adrenergic stimulation may be reduced in HF, with the desensitization of myocardial β-receptors that occurs in this condition (41).
Cell death model
All types of HF are characterized by an increased rate of cell death (42), which has been attributed to a variety of stresses, including abnormal elevations in circulating neurohormones; excessive adrenergic activity; inflammation; oxidative stress; toxins, such as alcohol or cancer chemotherapeutic agents; and infiltrative processes. Apoptosis is a highly regulated type of cell death that normally increases with aging and is further accelerated in the presence of pressure overload. It has been suggested that, over time, the resulting deletion of myocytes leads to HF (43). Myocardial necrosis, the dominant type of cell death in myocardial infarction, also occurs in doxorubicin-induced and other toxic cardiomyopathies (42), as well as in Ca2+-induced mitochondrial damage, which occurs during reperfusion following severe ischemia (44). In autophagy, cells digest their own intracellular proteins and lipids, a process that may be normal (protective) when these substances are altered and become toxic, but when accelerated may become maladaptive and result in increased cell death (45).
Until about 5 years ago, the search for genes associated with specific diseases (including CVD) focused largely on so-called “candidate genes,” which encode the abnormal proteins in diseased hearts. This approach allowed the identification of a number of important monogenic disorders involved in the cardiomyopathies that lead to HF (46,47) and led to the genetic model of HF. Inherited cardiomyopathies are caused by mutations in the genes that encode sarcomeric proteins (hypertrophic cardiomyopathy) (46,48) and/or mutations in the genes that encode diverse proteins causing impaired contraction and cell death (familial dilated cardiomyopathy), including genes for nuclear envelope proteins (49) and desmosomal proteins crucial for intercellular attachments in arrhythmic right-ventricular cardiomyopathy (48).
The current emphasis on genetics is focused on scanning the entire genome in an unbiased manner to search for genetic variants associated with specific diseases using genome-wide association studies (50). Because HF is a syndrome, not a disease, genome-wide association studies in HF are designed to search for loci associated with the conditions that lead to HF, such as CAD, hypertension, hyperlipidemia, and diabetes mellitus (51). A recent analysis identified 13 loci spread throughout the genome that are associated with an increased risk for CAD. Three new genetic loci for dilated cardiomyopathy were recently described (52,53). While this approach and these discoveries are exciting, they represent only the initial step in elucidating the mechanisms by which genetic abnormalities can affect cardiac function and the development of HF. The next challenge will be to link these loci with specific genes and, in turn, with biological function and dysfunction.
An important new chapter in biology opened 20 years ago, when a new regulatory mechanism involving small (∼22-nucleotide) RNAs, or micro RNAs (miRs), were described (54). Almost 1,000 of these molecules have been isolated and more are being discovered regularly; they are found in all life forms and are critically important to posttranscriptional gene regulation. Many investigators are currently attempting to gain an understanding of the role of these molecules in health and disease (55). It appears that miRs exert control over processes integral to normal and disordered cardiac function, including excitation–contraction coupling, myocyte hypertrophy, ventricular dilatation, apoptosis, and myocardial fibrosis (56). For example, it has been reported that the absence of miR-22 in genetically altered mice was associated with reduced activity of SERCA2 in the myocytes and with an impaired response to pressure overload (57). In addition to their presence in tissues, miRs may enter the bloodstream, from which they can be isolated and have the potential to become a new class of biomarkers (58) in a number of conditions, including HF. Pharmacologically induced changes in the activity of miRs could become a new class of therapeutics (59).
Although the definition of a biomarker includes virtually any measurement that can be made on a biological system, this discussion is restricted to substances measured in the blood other than genetic markers, electrolytes, and commonly used markers of hepatic or renal function. These biomarkers aid in the diagnosis of HF, provide an estimate of prognosis, and help in the identification of apparently healthy people who are at excessive risk for HF (60). Biomarkers that are currently available reflect at least 7 pathobiological processes operative in HF (Fig. 7), help to identify the specific ones involved in individual patients, and aid in guiding management plans. The increased availability of point-of-care and rapid-turnaround methodologies, and the declining costs of analysis of several of the most frequently used biomarkers, are facilitating their widespread use.
In the assessment of the clinical value of any individual biomarker, it is important to determine whether it provides independent incremental information when added to previously available information, which can be estimated by determining whether it increases the c statistic (61), as well as by calculating the net reclassification improvement index and the integrated discrimination improvement index (62). Despite the importance of these rigorous statistical tests, measurements of biomarkers, even those that are not independent predictors of risk on multivariate analysis, may nonetheless be of clinical importance because they provide information on the pathogenesis of HF and can help to direct treatment. For example, in patients with abnormally elevated levels of a natriuretic peptide (NP) and troponin, an abnormally elevated concentration of a marker for ECM remodeling might not add discriminatory diagnostic power but might suggest that a drug that reduces collagen deposition may be beneficial (see subsequent discussion).
Markers of myocyte stretch
Atrial NP (ANP) was the first NP elaborated by stretched cardiac tissue to be identified and studied in patients with HF (63). However, because of its instability and other analytic problems, it was soon replaced by B-type NP (BNP) and its prohormone fragment, N-terminal pro B–type natriuretic peptide (NT-proBNP), peptides derived largely from the ventricles. These 2 peptides are now the most widely used biomarkers in the care of patients with known or suspected HF (64,65). In addition, mid-regional (MR) proANP, a precursor of ANP, does not pose the same analytical problems as does ANP and has been reported to have been as accurate as BNP and NT-proBNP in diagnosing HF (66) and in estimating the prognosis of patients with HF (67). In patients with chronic CAD and normal EF, MR-proANP has also been reported to predict CVD-related death or hospitalization for HF and to identify patients who might benefit from the administration of an angiotensin-converting enzyme (ACE) inhibitor (68).
NPs are of enormous clinical value in diagnosing HF in patients with dyspnea of unknown etiology (64–66,69,70); in patients with heart disease without clinical manifestations of, but who are at risk for, HF; and in apparently healthy patients who are at higher risk for HF (71). However, like any laboratory measurement, NP levels must be interpreted in the context of a patient’s characteristics, such as age and body mass, and laboratory tests, including cardiac imaging.
There is some controversy regarding the clinical value of NP-guided therapy for HF (72). However, 2 meta-analyses have reported significant advantages of NP-guided therapy in terms of survival (73,74). In the larger of these (1,726 patients), NP-guided therapy was compared with usual care in 8 moderate-scale trials, and a significantly lower mortality was reported with NP-guided therapy (hazard ratio = 0.76). However, in these trials, NP-guided therapy was of little value in 2 subgroups—patients age >75 years and those with HFPEF. Like all meta-analyses, these were limited by differences in the characteristics of the populations studied, the peptide concentrations targeted, and the treatment algorithms employed. Fortunately, a robust, adequately sized multicenter trial of a single-target NP level and the use of guideline-approved therapies in both treatment arms of pre-specified subgroups is now underway (GUIDE-IT [Guiding Evidence Based Therapy Using Biomarker Intensified Treatment]; NCT01685840).
ST2 is a protein that exists in soluble and membrane-bound forms, the latter being the receptor for interleukin 33. When the myocardium is stretched, the ST2 gene is upregulated, and the concentration of circulating soluble ST2 rises rapidly. The level of circulating ST2 has been reported to be a predictor of HF and death in patients with ST-segment elevation myocardial infarction (75), ADHF, and/or chronic HF (76). This biomarker provides prognostic information that is independent of and in addition to that offered by NT-proBNP (77), although the release of both seems to occur in response to the same stimulus—cardiac stretch.
The 2 cardiac-specific troponins (cTn)—I and T (cTnI and cTnT, respectively)—exist in 2 pools in myocytes. The larger is an integral constituent of the myofibrillar protein apparatus and is released slowly over several days after cell death; the second, smaller source of cTn resides in a cytoplasmic pool this is released relatively rapidly, within 1 to 2 hours of myocyte injury. It is not yet clear whether irreversible injury is required or whether reversibly injured cells whose membranes have transiently become more permeable can also release this pool (78).
cTnI and cTnT have become the most accurate and widely used markers of myocardial necrosis in patients with ACS. However, in 1997, it was reported that cTnI is also present in the serum of patients with severe HF without ischemia (79), and it was then observed that levels of cTnI and cTnT were predictive of adverse clinical outcomes in these patients (80). This observation has been amply confirmed, particularly as progressively more sensitive assays for cTn have become available (81,82). The release of troponin from the heart in HF has been considered to be due to myocyte injury, apparently irrespective of the mechanism involved, that is, ischemia, necrosis, apoptosis, or autophagy.
Using standard assays, abnormal elevations of circulating cTn have been reported in about one-quarter of patients with HF and denoted a poor prognosis, generally defined as death or early readmission for HF (60). Using high-sensitivity assays (hsTn), abnormal elevations in circulating troponins have been detected in virtually all patients with ADHF (83–86), in a majority of a population with chronic HF (87), in some patients with stable CAD and normal EF (88), as well as in a minority of general populations of apparently healthy elderly (89) and middle-aged persons (90). Serial measurements of hsTn in populations with ADHF (86) and chronic HF (87) have been reported to provide additional prognostic information; cTn levels that rose during hospitalization portended a poorer outcome than did stable or declining levels.
The importance of the ECMs in ventricular remodeling is discussed in the Mechanisms and Management sections. Serum peptides derived from collagen metabolism reflect both the synthesis and degradation of collagen and thus constitute a “window” on the ECM (91,92). The ratio of pro collagen type I aminoterminal propeptide (PINP), a marker of collagen synthesis, to collagen type I cross-linked carboxyterminal telopeptide, a marker of collagen breakdown, is a useful serum marker of collagen accumulation (93). A multimarker panel consisting of increased levels of MMP-2, tissue inhibitor of MMP-4, and collagen III N-terminal propeptide (PIIINP), accompanied by decreased levels of MMP-8, has been reported to be characteristic of HFPEF (92). Elevated ECM turnover has also been reported in patients with ADHF (91).
Aldosterone is a stimulant of collagen synthesis and enhances cardiac fibrosis in HF and in ventricular hypertrophy secondary to pressure overload. The administration of the aldosterone receptor antagonist spironolactone in patients with chronic HF in RALES (Randomized Aldactone Evaluation Study) reduced elevated levels of markers of collagen synthesis (PINP and PIIINP) and was associated with clinical benefit (94). In patients with acute myocardial infarction complicated by HF, levels of PINP and PIIINP rose (94). The administration of eplerenone, a specific aldosterone antagonist, was reported to have reduced elevated levels of PINP and PIIINP, findings associated with reductions in mortality and hospitalization for HF (95). These findings are examples of how biomarkers can be used to identify pathologic processes in patients with HF and thereby to help direct specific therapy (see Management section).
In 1956, the author participated in the description of the elevation of C-reactive protein (CRP), an inflammatory biomarker, in HF (96), an observation that has been confirmed and expanded on as assay methods have improved (97,98). The concentration of a number of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6 (99) (Fig. 8), have also been reported to have been elevated in HF. In elderly subjects without HF, abnormal elevations in 3 inflammatory markers (CRP, tumor necrosis factor α, and interleukin-6) were reported to have been associated with a significant, 4-fold increase in the development of HF (98). The presence and levels of these biomarkers was correlated with the severity of HF; they appeared to have been independent predictors of outcome and to have provided important clues to the pathogenesis of HF. They could, in the future, become useful in testing novel antiinflammatory therapies in such patients.
Adrenomedullin is a vasodilator peptide derived in part from the heart but also synthesized in vascular smooth muscle and endothelial cells (100). Because of its short half-life and instability, an assay for the MR sequence of its precursor (MR-proADM) has been developed and reported to be an independent predictor of mortality in ADHF (67,101) and of adverse outcomes in chronic HF (102) and stable CAD (68). While this marker has excellent sensitivity in detecting HF, its specificity has been questioned because of reported elevations in sepsis, glomerulonephritis, and chronic renal failure—perhaps not surprising given its synthesis in multiple tissues (102).
The concentration of circulating arginine vasopressin is elevated in patients with severe HF, but as is the case with ANP and adrenomedullin, its direct measurement is fraught with difficulties. Instead, copeptin, the C-terminal segment of pre-provasopressin, has been reported to be an excellent surrogate highly predictive of adverse outcomes in patients with ADHF (103) and chronic, stable CAD (68).
Biomarkers of renal failure
Neutral Gelatinase-Associated Lipocalin
Neutral gelatinase-associated lipocalin, a polypeptide marker of renal injury (104,105), is elevated in patients with ADHF and renal failure, that is, with the cardiorenal syndrome. Its elevation at the time of hospital discharge is a strong indicator of renal tubular damage and of adverse prognosis.
Kidney Injury Molecule-1
Kidney injury molecule-1 is a glycoprotein expressed in the proximal tubule in renal injury and both its presence in patients with HF as well as its correlation with NT-proBNP suggest that renal involvement occurs in many patients with severe HF (106,107).
The field of proteomics is likely to provide distinct “fingerprints” of circulating proteins in a variety of disorders, including HF (108). Just as genome-wide association studies (see Mechanisms section) represent an “unbiased” (i.e., not hypothesis-driven) search for genetic variants, liquid chromatography combined with mass spectroscopy has been used to carry out a search for plasma proteins in the proteome of patients with ADHF (109,110). This approach revealed that quiescin Q6 (QSOX1), a protein involved in the formation of disulfide bridges, was (along with BNP) associated with ADHF. After the discovery and isolation of QSOX1, its association with ADHF was validated in a second group of patients. Then, QSOX1 was reported to have been induced in the hearts of rats with HF following thoracic aortic constriction, lending credence to the specificity of this marker (109). The challenge now is to determine its biological significance and whether it provides information that could be useful to clinicians.
There has recently been an interest in multimarker strategies to examine panels of biomarkers that assess different pathophysiologic pathways (Fig. 9) (60). An early study in patients with HFREF reported that a combination of proBNP, hsCRP, and myeloperoxidase (a marker of oxidative stress) provided greater predictive accuracy than did any of these markers individually (111). Subsequently, multimarker approaches to predict the risk for mortality in patients with ADHF (112–114), the development of HF (115), and CVD-related death in community-based cohorts (116) have been described.
In a recent study of ambulatory patients with chronic HF, Ky et al. (77) tested the hypothesis that a group of 7 biomarkers, each reflecting a different pathophysiologic pathway in a manner analogous to those shown in Figure 7, could be combined into a multimarker score that would predict the risk for an adverse outcome, defined as death, cardiac transplantation, or placement of a ventricular-assist device. Each of these 7 biomarkers and their pathways were reported to have been independently associated with such an outcome. These biomarkers were BNP (neurohormonal activation), soluble fms-like tyrosine kinase receptor (vascular remodeling), hsCRP (inflammation), ST2 (myocyte stretch), cTnI (myocyte injury), uric acid (oxidative stress), and creatinine (renal function). The combined multimarker integer score provided an excellent assessment of risk (Fig. 9), with the hazard ratios of the intermediate- and higher-risk tertiles (adjusted for clinical risk) significantly elevated, to 3.5 and 6.8, respectively, compared to that of the lowest-risk tertile.
During the last quarter of the 20th century, the treatment of chronic HFREF improved substantially with the development of 3 classes of drugs (ACE inhibitors/angiotensin II receptor blockers [ARBs], aldosterone antagonists, and β-adrenergic blockers), as well as internal cardioverter defibrillation and cardiac resynchronization therapy. These important developments came about largely as a consequence of years of preclinical and clinical research culminating in large-scale, multicenter clinical trials. The results of these trials are reflected in changes in the practice guidelines (18,117,118), which, in turn, have become standards of care expected by patients, physicians, and payers.
The therapeutic picture has been less favorable for HFPEF, in which, other than an emphasis on rigorous control of hypertension, rapid ventricular rate, and fluid retention, there is relatively little new that can be offered to the millions of patients with this disorder. However, 3 possible advances are under investigation. First, the phosphodiesterase-5 inhibitor sildenafil is being studied in a Phase II trial, RELAX (Phosphodiesterase-5 inhibition to improve clinical status and exercise capacity in diastolic heart failure) (119). Second, the Phase III TOPCAT (Aldosterone Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart Failure) trial (NCT00094302) has completed enrollment and is now in its follow-up phase (120). Third, the Phase II PARAMOUNT (Prospective Comparison of ARNI with ARB on Management of Heart Failure with Preserved Ejection Fraction) trial is underway to investigate the effects of an angiotensin receptor neprilysin inhibitor, LCZ696, which combines in 1 molecule the ARB valsartan and the endopeptidase inhibitor that blocks the metabolism of the NPs. The latter action increases the generation of myocardial cyclic guanosine 3′,5′-monophosphate, which enhances myocardial relaxation and reduces ventricular hypertrophy. This dual blocker has been reported to have reduced NT-proBNP and left-atrial size to a significantly greater extent than valsartan alone in patients with HFPEF (121). This drug is currently undergoing a Phase III trial in patients with HFREF (PARADIGM-HF [Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure]).
In ADHF, the prevalence of death or readmission for HF within 6 months approaches 40% (122), and the currently available pharmacologic therapies have remained relatively unchanged during the past 3 decades. A string of Phase III trials in patients with ADHF have yielded largely negative results. Recent examples include PROTECT (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline) (123), ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated HF) (124), and EVEREST (Effects of Oral Tolvaptan [a selective vasopressin 2 antagonist] in Patients Hospitalized for Worsening HF) (125), although the latter reported some improvement in dyspnea (126).
The management of ADHF requires rapid assessment and prompt treatment of any precipitating condition(s) (see Epidemiology section). Vasodilators (nitroglycerine, nitroprusside, or nesiritide) remain useful for hypertensive and normotensive patients, but hypotension must be carefully avoided in patients with ADHF. However, a number of other vasodilators are being investigated. One compound, serelaxin, or recombinant human relaxin-2, is a naturally occurring peptide that is upregulated in normal pregnancy and that has undergone a positive phase II trial in patients with a normal or elevated blood pressure (127). In the RELAX-AHF trial, serelaxin or placebo was added to a regimen of standard therapy in 1,161 patients hospitalized with ADHF, evidence of congestion, and systolic pressure >125 mm Hg. Serelaxin was associated with improved dyspnea, less early worsening of HF, and greater early reductions in signs and symptoms of congestion. CVD-related mortality and all-cause mortality at 6 months (both exploratory endpoints) were each reduced. There were no significant reductions in CVD-related death or readmission for HF or renal failure (128). This agent is expected to undergo further study.
Positive inotropic agents
Impaired myocardial contractility represents a core problem in many patients with HF, both acute and chronic, and the search for tolerable and effective positive inotropic agents has gone on for decades. Drugs that increase the intracellular concentration of cyclic adenosine monophosphate, such as sympathomimetic amines and phosphodiesterase-3 inhibitors, are powerful positive inotropic agents whose activity results from an increase in cytoplasmic [Ca2+]. This increase is accompanied by increases in myocardial oxygen demands, which lead to the development, exacerbation, or intensification of ischemia and/or life-threatening dysrhythmias. Although these agents typically improve hemodynamics and reduce symptoms of HF when infused intravenously for short periods (129,130), they often shorten survival (131).
Myofilament Ca2+ Sensitizers
Attention is now focused on the development of inotropic agents that do not raise intracellular [Ca2+] but instead increase myofilament sensitivity to Ca2+(129). Levosimendan is a Ca2+ sensitizer with both inotropic and vasodilatory activity, the latter related to phosphodiesterase-3 inhibition (132,133). The guidelines for the treatment of HF published by the European Society of Cardiology recommend levosimendan in patients with symptomatic HFREF without hypotension (18). The vasodilatory activity of levosimendan makes it unsuitable in patients with hypotension. The effects of this drug on survival are not clear, and it is not available in the United States.
The small-molecule selective myosin activator mecamtiv mecarbil (134) raises stroke volume by prolonging the ejection period and increasing fractional shortening. Importantly, it does not elevate the velocity of shortening or of force development and therefore may not be “oxygen wasting,” as are drugs that raise intracellular cyclic adenosine monophosphate. It has undergone Phase I and II testing and appears to be well-tolerated (in the absence of tachycardia) (135,136). Mecamt