Heart failure has two distinctive subtypes

Heart failure has two distinctive subtypes
Chronic HF Acute HF Persistent; stable, worsening or decompensated1 Rapid onset or change in the signs and symptoms of HF, resulting in the need for urgent therapy (ESC)1 Development of acute or progressive symptoms of HF resulting in the need for hospitalization of the patient (ACC/AHA)2 HF=heart failure; ESC=European Society of Cardiology; ACC=American College of Cardiology; AHA=American Heart Association 1. Dickstein et al. Eur Heart J 2008;29:2388–442; 2. Hunt et al. J Am Coll Cardiol 2009;53:e1–90

Acute heart failure presentation in the ER Pulmonary congestion
alveolar edema1 Dyspnea Rales 3rd heart sound Chest X-ray pulmonary congestion Systemic congestion1 Fatigue Jugular venous distention Weight gain/peripheral edema Renal dysfunction2 Increased creatinine Clinical presentation Acute heart failure presentation in the ER: Pulmonary congestion is an almost universal finding In patients presenting to the emergency room (ER) with acute heart failure (AHF), the most common clinical symptoms and signs are dyspnea (89%), pulmonary rales (67%), and peripheral edema (66%; based on findings of the ADHERE study1). These signs and symptoms are all features of congestion (pulmonary or peripheral), which is an almost universal finding in AHF. Tiredness/ fatigue is also common. Pulmonary congestion, which causes dyspnea, is due to increased pulmonary capillary wedge pressure (PCWP), itself a result of increased left ventricular filling pressure. Hemodynamic changes often precede clinical manifestations, but are not detected until patients become symptomatic.2 Hemodynamic congestion refers to a state of volume overload or fluid redistribution resulting in increased left ventricular (LV) filling pressure, the clinical manifestations of which include a constellation of signs and symptoms including cardiopulmonary symptoms (respiratory distress, third heart sound, rales, interstitial/alveolar edema, signs of congestion on chest x-ray). Systemic congestion is evidenced by jugular venous distention, and peripheral edema (ankles, legs, ascites). Patients presenting with acute congestive HF may be discharged when clinical symptoms resolve, even though hemodynamic abnormalities remain. This may increase the risk of rehospitalization, and leave patients at risk of further cardiac damage (hemodynamic congestion increases LV wall stress and contributes to neurohormonal activation; it may also contribute to LV remodeling and progression of HF). Therefore, it is important that congestion is recognized by physicians treating AHF. However, there are limitations to the therapeutic options available for managing congestion. Treatment of congestion in patients with AHF is based largely on use of diuretics to relieve volume overload; however, diuretics are often associated with adverse effects and may not fully relieve symptoms. Thus, there is an unmet need for new treatments to improve hemodynamic and clinical congestive symptoms in AHF. Abbreviations AHF=acute heart failure; ER=emergency room; LV=left ventricular; PCWP=pulmonary capillary wedge pressure References Adams et al. Am Heart J 2005;149:209–16 Gheorghiade et al. Am J Med 2006;119:S3–10 Key communication points AHF is characterized by both clinical symptoms and hemodynamic abnormalities, which usually relate to clinical (pulmonary/peripheral) and hemodynamic congestion Hemodynamic congestion may be present before onset of clinical symptoms and/or after clinical symptoms resolve New treatment modalities may be needed to adequately address congestion in AHF Hemodynamic presentation LV filling pressure increased PCWP (25–30 mmHg) Elevated NT-pro-BNP Cardiac wall stress Elevated troponin 1. Gheorghiade et al. Am J Med 2006;119:S3–10; 2. Adams et al. Am Heart J 2005;149:209–16

Mortality following admission for acute heart failure exceeds that of most cancers
Female survival rates (%): HF, MI and other malignancies Male survival rates (%): HF, MI and other malignancies Cumulative probability of survival Cumulative probability of survival 1.0 0.8 0.6 0.4 0.2 1.0 0.8 0.6 0.4 0.2 Breast MI MI Bladder Bowel Prostate Ovarian Bowel HF HF Mortality following admission for AHF exceeds that of most cancers A Scottish study examined data obtained from the National Health Service regarding patients with a first admission to a Scottish hospital in 1991 for AHF, MI or the four most common types of cancer specific to men and women (lung, large bowel, prostate and bladder for men and breast, lung, large bowel and ovarian for women). Five-Year survival rates were then compared. With the exception of lung cancer, AHF was associated with the poorest 5-year survival rate (approximately 25% for both sexes) and the median survival time was 16 months. Abbreviations AHF=acute heart failure; MI=myocardial infarction Reference Stewart et al. Eur J Heart Fail 2001;3:315–22 Key communication points AHF mortality exceeds that of most cancers The 5-year survival rate for AHF is approximately 25% Lung Lung Month of follow-up Month of follow-up All patients with a first admission to any Scottish hospital in 1991 for HF, MI or the four most common types of cancer specific to men and women were identified, and 5-year survival rates compared Stewart et al. Eur J Heart Fail 2001;3:315–22

Hospitalization for acute heart failure is a significant and growing healthcare burden
Acute HF is the most frequent cause of hospitalization in subjects aged >65 years1,2 Hospitalization for acute HF is an important predictor of post-discharge mortality and readmission in patients with chronic HF3 the combined incidence of death or rehospitalization within 60 days of hospitalization for acute HF is 30–50%4 after hospitalization for HF, 10% of patients die within a month, there is a 50% rate of rehospitalization at 6 months, and a 25–35% incidence of death at 12 months2,5,6 Over 1 million hospitalizations with a primary diagnosis of HF occur each year in the USA3 HF diagnosis at hospital discharge has tripled over the last three decades3 this trend will likely continue due to an aging population, improved survival after MI, and better prevention of sudden cardiac death4 AHF represents a major economic burden to healthcare systems In the US, the average cost of each hospital admission for a patient with AHF was USD18,667 in 20037 Hospitalization for acute heart failure is a significant and growing healthcare burden In individuals aged over 65 years, acute heart failure (HF) is the most frequent cause of hospitalization.1,2 Furthermore, in patients with chronic HF, hospitalization for acute HF is one of the most important predictors of post-discharge mortality and readmission.3 Indeed, the combined incidence of death or rehospitalization within 60 days of hospitalization for acute HF is 30–50%.4 At 6 months after hospitalization for HF, the rate of rehospitalization is ~50%. Patients with acute HF also have a high risk of mortality, with 10% of patients dying within a month and a mortality rate of 25–35% at 12 months.2,5,6 HF is the primary diagnosis cited for over 1 million hospitalizations each year within the USA.3 However, the incidence of HF is increasing, with hospital discharge data indicating that the diagnosis of HF at discharge has tripled over the last three decades.3 This trend in increasing HF incidence is likely to continue due to an aging population, improved survival after myocardial infarction (MI), and improved prevention of sudden cardiac death.3 AHF represents a major economic burden to healthcare systems. Indeed, in the US, the average cost of each hospital admission for a patient with AHF was USD18,667 in 20037 Abbreviations HF=heart failure; MI=myocardial infarction; USA=United States of America References Tavazzi et al. Eur Heart J 2006;27:1207–15 Hunt et al. J Am Coll Cardiol 2009;53:e1–90 Gheorghiade & Pang. J Am Coll Cardiol 2009;53:557–73 Dickstein et al. Eur Heart J 2008;29:2388–442 Harjola et al. Eur J Heart Fail 2010;12:239–48 Siirilä-Waris et al. Eur Heart J 2006;27:3011–7 Ng et al. Congest Heart Fail 2008;14:202–10. Key communication points Hospitalization for acute HF is an important predictor of post-discharge mortality and readmission The incidence of HF hospitalization is high and increasing HF=heart failure; MI=myocardial infarction 1. Tavazzi et al. Eur Heart J 2006;27:1207–15; 2. Hunt et al. J Am Coll Cardiol 2009;53:e1–90; 3. Gheorghiade & Pang. J Am Coll Cardiol 2009;53:557–73; 4. Dickstein et al. Eur Heart J 2008;29:2388–442; 5. Harjola et al. Eur J Heart Fail 2010;12:239–48; 6. Siirilä-Waris et al. Eur Heart J 2006;27:3011–7; 7. Ng et al. Congest Heart Fail 2008;14:202–10.

Months after re-assess
Current therapies do not provide optimal relief from acute heart failure signs and symptoms Only 58% of patients hospitalized for acute HF show good symptom relief with standard therapy at 6 hours1,2 Signs and symptoms of congestion after hospitalization predict poor survival‡3 100 Missing 6% Worse 5% 80 No change or mild improvement 31% 60 Survival (%) p<0.0001 40 No congestion (80) 1–2 congestion (40) 3–5 congestion (26) 20 Re-assessed at 4–6 weeks Significant improvement 58% Treatment of acute heart failure remains suboptimal Data from URGENT Dyspnoea, an international, multicenter, observational cohort study of 534 patients hospitalized for AHF has revealed that only 58% of patients had good symptom relief at 6 hours.1,2 In addition the ESC Heart Failure Pilot Survey collated date from 1892 patient with acute heart failure in Europe and it was noted that 24% of patients still had signs of congestion at discharge.3 This suboptimal treatment may have consequences for the patients. Indeed, a study of 146 patients with AHF discharged after admission to the hospital has reported that patients with symptoms of congestion at discharge were at an increased risk of mortality compared with patients with no symptoms of congestion at discharge.4 Abbreviations HF=heart failure References Mebazaa et al. Eur Heart J 2010;31:832–41 Hogg & McMurray. Eur Heart J 2010;31:771–772 Maggioni et al. Eur J Heart Fail 2010;12:1076–84 Lucas et al. Am Heart J 2000;140:840–7 Key communication points Treatment of patients with acute heart failure is suboptimal with some not receiving symptom relief and many having symptoms of congestion at discharge Poor relief of congestion at discharge is associated with poor prognosis N=524 Months after re-assess 24% of patients hospitalized for HF in Europe have signs of congestion at discharge4 ‡Patients with New York Heart Association class IV HF (n=146) were re-assessed for signs of congestion 4–6 weeks after discharge. Criteria for congestion were orthopnea, raised jugular venous pressure, the need to increase the dose of diuretic during the past week, and attending staff assessment of weight; 1. Mebazaa et al. Eur Heart J 2010;31:832–41; 2. Hogg & McMurray. Eur Heart J 2010;31:771–2; 3. Lucas et al. Am Heart J 2000;140:840–7; 4. Maggioni et al. Eur J Heart Fail 2010;12:1076–84

Patients have a poor prognosis following heart failure hospitalization
Analysis of HF data from the Atherosclerosis Risk in Communities (ARIC) population-based study from four communities in the USA (1987–2002) 45 40 35 30 25 20 15 10 5 Mortality (%) Patients have a poor prognosis following heart failure hospitalization The Atherosclerosis Risk in Communities (ARIC) study is a population-based study from four communities within the USA (1987–2002). Incident heart failure (HF) was defined by the International Classification of Diseases codes for HF from hospitalization or death certificates. There were 1,282 incident HF cases over 198,417 person-years. Survival and case fatality were calculated for hospitalized HF and did not include incident HF deaths without previous hospitalization for HF. Deaths for the survival analysis were defined as all-cause mortality occurring until the end of Of those patients hospitalized with HF, the median follow-up was 2.5 years after hospitalization. Thirty-day, 1-year, and 5-year case fatalities following hospitalization for HF were 10.4, 22.0 and 42.3%, respectively. Abbreviations ARIC=Atherosclerosis Risk in Communities; HF=heart failure; USA=United States of America Reference Loehr et al. Am J Cardiol 2008;101:1016–22 Key communication points After hospitalization for HF, the mortality rate is high After hospitalization for HF in the ARIC study, one-tenth of patients died within 30 days, over one- fifth of patients died within 1 year and almost half died within 5 years 30 days 1 year 5 years Time following hospitalization for HF Loehr et al. Am J Cardiol 2008;101:1016–22

Acute heart failure is associated with high in-hospital mortality
Estimations of in-hospital mortality rates vary between studies from 3.8 to 11.0%1–5 Difference in in-hospital mortality may be due to variations in length of hospital stay6 There are geographical differences in average length of hospital stay1–5 ~4–6 days in the US surveys ~8–11 days in the European surveys Study N In-hospital mortality rate (%) Length of hospital stay (days) ADHERE1* 107,362 4.0 4.3 (median) OPTIMIZE-HF2* 48,612 3.8 6.4 (mean) Goldberg et al * 2,604 5.1 4.0 (median) Rudiger et al † 312 11.0 8–11.5 (mean) Euro-HF survey5‡ 11,327 6.9 *USA; †Europe (Switzerland and Finland); ‡Europe (24 European countries) Acute heart failure is associated with high in-hospital mortality Acute heart failure (HF) results in high mortality rates. Outcomes data from surveys and registries of patients with acute HF indicate the in-hospital mortality rate varies considerably (~4–11%).1–5 A reason for the difference in mortality rates may lie in the time spent in hospital. Studies with a short hospital stay had a lower in-hospital mortality rate than studies with a longer hospital stay.1–5 Moreover, the highest mortality rate of patients with acute HF is during the first few days following an index event; therefore, increasing the time spent in hospital may increase the deaths recorded in hospital.5 The duration of hospital stays for acute HF appear to vary by region, with a mean stay of approximately 4–6 days in reported US surveys compared with approximately 8–11 days in the European surveys.1–5 In addition to the long hospital stays associated with acute HF, many of these hospitalizations include a spell in the intensive care unit (ICU). An Italian observational study found that of the patients admitted to hospital for acute HF, 69% spent time in the intensive cardiac care unit.6 Abbreviations ADHERE=acute decompensated heart failure registry; Euro-HF=European heart failure study; HF=heart failure; ICU=intensive care unit; OPTIMIZE-HF=organized program to initiate life-saving treatment in hospitalized patients with heart failure; USA=United States of America References Adams et al. Am Heart J 2005;149:209–16 Gheorghiade et al. JAMA 2006;296:2217–26 Goldberg et al. Am J Med 2005;118:728–34 Rudiger et al. Eur J Heart Fail 2005;7:662–70 Cleland et al. Eur Heart J 2003;24:442–63 Tavazzi et al. Eur Heart J 2006;27:1207–15 Key communication points Acute HF is associated with high rates of in-hospital mortality Variations in mortality rate may be due to differences in the duration of hospital stay 1. Adams et al. Am Heart J 2005;149:209–16; 2. Gheorghiade et al. JAMA. 2006;296:2217–26; 3. Goldberg et al. Am J Med 2005;118:728–34; 4. Rudiger et al. Eur J Heart Fail 2005;7:662–70; 5. Cleland et al. Eur Heart J 2003;24:442–636; 6. Tavazzi et al. Eur Heart J 2006;27:1207–15

Several factors are associated with poor 1-year mortality in patients with acute heart failure
The most important triggers of acute HF hospitalization in a study of 312 patients hospitalized with acute HF were elevated BP and acute ischemia, while CHD was the most frequent underlying heart disease 30-day mortality was greater in patients with elevated troponin levels than those without Presentation: shock vs no shock (13/299) LVEF: <50% vs ≥50% (159/79) LVEF: <35% vs ≥35% (83/155) CrCI <50 mL/min vs CrCl ≥50 mL/min (109/157) Age: >65 years vs ≤65 years (228/84) CHD vs no CHD (193/119) Age: >75 years vs ≤75 years (147/165) Site: center 1 vs center 2 (93/216) Troponin ≥0.1 μg/L vs <0.1 μg/L (88/199) Diabetes vs no diabetes (100/212) History of HF vs no history of HF (224/88) Gender: men vs women (176/136) History of elevated BP vs no hypertension (168/144) Several factors are associated with poor one-year mortality in patients with acute heart failure A prospective study of 312 consecutive patients hospitalized with acute heart failure (HF) at two European centres (Switzerland and Finland) aimed to identify risk factors for an unfavourable outcome. Survival estimates for all-cause mortality were estimated using Kaplan- Meier analysis and the log rank test was used to compare the mortality of subgroups. In total, 28% of patients had new onset acute HF and 72% had worsening (decompensation) of chronic HF. Coronary heart disease (CHD) was the most common underlying disease and was present in more than half the patients. Thirty-day mortality was significantly higher in patients with cardiogenic shock (p=0.001) or elevated troponin T levels (p=0.002) than in those without. Odds ratios for one-year mortality were significantly higher in patients with cardiogenic shock, left ventricular (LV) dysfunction, renal insufficiency (creatinine clearance [CrCl] <50 mL/min), CHD, and advanced age (>65 years). Abbreviations BP=blood pressure; CHD=coronary heart disease; CrCl=creatinine clearance; HF=heart failure; LV=left ventricular; LVEF=left ventricular ejection fraction Reference Rudiger et al. Eur J Heart Fail 2005;7:662–70 Key communication point Risk of one-year mortality is higher in acute HF patients with cardiogenic shock, LV dysfunction, renal insufficiency, coronary heart disease, or advanced age compared with those without these risk factors Odds ratio Rudiger et al. Eur J Heart Fail 2005;7:662–70

The pathophysiology of heart failure results in an increasingly downward spiral
Acute decompensated HF is associated with frequent hospitalizations1 after initial stabilization, there are high rates of mortality and rehospitalizations2 with each hospitalization, there is likely myocardial and renal damage that contributes to progressive LV or renal dysfunction, leading to an inevitable downward spiral3 current therapies only treat symptoms and do not target the underlying mechanisms leading to cardiac and renal injury Chronic HF Myocardial/renal damage Increased risk of decompensations Acute decompensation Hospitalization Cardiac and/or renal function The pathophysiology of heart failure results in an increasingly downward spiral A review of heart failure (HF) studies highlights that acute decompensated HF is associated with a high mortality and high frequency of rehospitalizations.1 In the Euro Heart Failure Survey (Euro-HF), which included 11,327 patients hospitalized with HF across Europe, 24% were rehospitalized at least once in the 3 months after the initial hospitalization.1,2 In addition, high mortality rates are observed in the first year after the initial hospitalization, ranging from 27–43% of patients across different HF studies.1 The hemodynamic and neurohormonal changes that occur during an episode of acute decompensated HF, together with effects of drug treatment, may result in myocardial injury or renal damage.3 This means that although the patient may show short-term improvement, there is a further decrease in cardiac and/or renal function. This increases the risk of decompensation and progression of HF, setting up a downward spiral of decompensation, further residual cardiac/renal damage, and increased risk of further decompensations.3 Thus, with each rehospitalization for acute HF, myocardial or renal injury contributes to progressive left ventricular (LV) or renal dysfunction, leading to an increasing frequency of acute events with high rates of hospitalization and increased risk of mortality. Current therapies only treat symptoms and do not target the underlying mechanisms leading to cardiac and renal injury. Abbreviations Euro-HF=Euro Heart Failure Survey; HF=heart failure; LV=left ventricular References Alla et al. Heart Fail Rev 2007;12:91–5 Cleland et al. Eur Heart J 2003;24:442–636 Gheorghiade et al. Am J Cardiol 2005;96:11G–17G Key communication points Acute decompensated HF is associated with high readmission and mortality rates With each decompensation, there is more residual cardiac/renal damage, increasing the risk of further decompensations Hospitalization Hospitalization More rapid decline in chronic HF Cardiac and renal damage/ incomplete recovery Time LV=left ventricular 1. Alla et al. Heart Fail Rev 2007;12:91–5; 2. Cleland et al. Eur Heart J 2003;24:442–636; 3. Gheorghiade et al. Am J Cardiol 2005;96:11G–17G

The pathophysiology of acute heart failure remains poorly understood
Acute HF involves a complex set of interactions between systems Heart Peripheral vasculature The pathophysiology of acute heart failure remains poorly understood The pathophysiology of acute heart failure (HF) involves a complex set of interactions between the heart, kidney and peripheral vasculature. There is reasonable understanding of the hemodynamics involved in HF, such as increased ventricular filling pressures causing back-up of pressure and fluid, and consequently congestion and edema; and reduced cardiac output causing hypoperfusion and dysfunction of target organs, plus increased ischemia and further worsening of HF. However, these descriptions of the hemodynamic responses in HF do not fully explain the complex interactions between the heart, kidney and peripheral vasculature, or capture the role of circulating mediators that commonly occur in acute HF. Further research is required to identify the exact mechanisms involved in the ‘cross-talk’ between systems, and the relative contribution of these mechanisms in the pathogenesis of acute HF. This task is further complicated by the fact that the precise mechanisms implicated in connecting the heart, kidney and peripheral vasculature, and their relative importance, may vary between patients. Abbreviations HF=heart failure Reference Felker et al. Circ Heart Fail 2010;3(2):314–25 Key communication points Much of the pathophysiology of acute HF is poorly understood Many different mechanisms have been implicated in the pathogenesis of HF, but their relative importance and exact roles remain uncertain Kidney The exact mechanisms and the relative contribution of each is uncertain and is likely to vary between patients Felker et al. Circ Heart Fail 2010;3:314–25

Pathophysiological components
Facing the challenges of AHF complex syndrome with three main pathophysiological components Pathophysiological components Underlying mechanisms Impaired cardiac function coupled with rapid increases in afterload or preload due to: vasoconstriction or uncontrolled BP1 acute rise in systemic vascular resistance fluid overload due to renal impairment, dietary indiscretion, medications, etc1,2 fluid redistribution to pulmonary circulation1 Myocardial and renal overload Initiation phase 1 Accelerated cardiomyocyte and renal cell death during AHF episodes due to: ischemia due to sudden O2 supply-demand mismatch1,3 apoptosis induced by stretch, norepinephrine, Ang II, inflammatory cytokines or oxidative stress4–7 Myocardial and renal cell death 2 Amplification phase Facing the challenges of acute heart failure Acute heart failure (HF) is a complex syndrome with three main pathophysiological components: Myocardial and renal overload. A large proportion of patients hospitalized for acute HF present with high blood pressure, which may be due to increased vascular resistance/stiffness. An increase in vascular resistance/stiffness can lead to reduced capacitance in large veins and increased arterial resistance, resulting in heightened preload and afterload, respectively. In combination with reduced cardiac contractility, increased preload and afterload can lead to redistribution of fluid to the lungs.1 Fluid overload may also be the result of renal dysfunction, the use of certain medications (e.g. non-steroidal anti-inflammatory drugs), or dietary noncompliance.1,2 Myocardial and renal cell death. Myocardial ischemia during an acute HF episode occurs in approximately 20% of patients. Activation of the pathophysiological processes in acute HF may cause additional myocardial necrosis, leading to further reductions in cardiac contractility.3 Markers of apoptosis are increased in patients with acute HF,4 and cardiomyocyte apoptosis can by induced by stretch, norepinephrine, angiotensin II, inflammatory cytokines and oxidative stress.5–7 Acute HF may also cause renal cell death; activation of the renin-angiotensin-aldosterone system and neurohormonal and inflammatory pathways during acute HF can lead to renal dysfunction with hypoxic and vasoconstrictive injury, possibly resulting in tubular necrosis.1 Myocardial remodeling and renal dysfunction. Extracellular matrix (ECM) turnover contributes to pathological myocardial remodeling. Markers of collagen synthesis (procollagen type III N-terminal peptide) and ECM degradation (matrix metalloproteinase-2 and tissue inhibitors of matrix metalloproteinases-1) are elevated in acute HF patients compared to those with chronic stable HF, indicating acceleration of pathological myocardial remodeling during acute HF.8 Acute HF can also accelerate the development of renal dysfunction by reducing renal perfusion, which consequently decreases glomerular filtration rate, and through activation of neurohormonal and inflammatory pathways. Ultimately, renal dysfunction may lead to tubular necrosis and nephron loss.1 Abbreviations Ang II=angiotensin II; CF=cardiac fibroblasts; ECM=extracellular matrix; GFR=glomerular filtration rate; HF=heart failure; MMP-2=matrix metalloproteinase-2; NSAIDs=non-steroidal anti-inflammatory drugs; TIMP-1=tissue inhibitors of matrix metalloproteinases-1 References Cotter et al. Eur J Heart Fail 2008;10:165–69 Hunt et al. J Am Coll Cardiol 2009;53:e1–e90 Cotter et al. Am Heart J 2008;155:9–18 Bott-Flügel et al. Eur J Heart Fail 2008;10:129–32 Feng & Wang. J Geriatr Cardiol 2008;5:1–6 Tsutsui et al. Am J Physiol Heart Circ Physiol 2011;301:H2181–90 Oikonomou et al. Hellenic J Cardiol 2011;52:30–40 Biolo et al. Circ Heart Fail 2010;3:44–50 Key communication points Acute HF is a complex syndrome There are three main pathophysiological components of acute HF: (1) myocardial and renal overload; (2) myocardial and renal cell death; and (3) myocardial remodeling and renal dysfunction Myocardial remodeling and renal dysfunction Activation of matrix metalloproteinases (MMP-2, TIMP-1)8 Stimulation of cardiac fibroblasts (CF) with increased collagen deposition8 Nephron loss and decreased GFR1 3 AHF=acute heart failure; Ang II=angiotensin II; BP=blood pressure; GFR=glomerular filtration rate; MMP-2=matrix metalloproteinase-2; NSAIDS=non-steroidal anti-inflammatory drugs; TIMP-1=tissue inhibitors of matrix metalloproteinases-1 1. Cotter et al. Eur J Heart Fail 2008;10:165–9; 2. Hunt et al. J Am Coll Cardiol 2009;53:e1–e90; 3. Cotter et al. Am Heart J. 2008;155:9–18; 4. Bott-Flügel et al. Eur J Heart Fail 2008;10:129–32; 5. Feng & Wang. J Geriatr Cardiol 2008;5:1–6; 6. Tsutsui et al. Am J Physiol Heart Circ Physiol 2011;301:H2181–90; 7. Oikonomou et al. Hellenic J Cardiol 2011;52:30–40; 8. Biolo et al. Circ Heart Fail 2010;3:44–50

Signalling exists between the heart and kidneys in acute heart failure
Decreased cardiac performance Decreased cardiac output and/or systemic vasoconstriction* Increased sodium and water retention Blood vessel High renal venous pressure Impaired renal function Neurohormonal activation Signalling exists between the heart and kidneys in acute heart failure As well as intrinsic/pre-existing structural kidney disease caused by diabetes, hypertension and atherosclerosis, renal dysfunction can be caused by acute heart failure (HF). For example, the effects of acute HF lead to decreased cardiac output and/or systemic vasoconstriction, high renal venous pressures and neurohormonal activation. All of these factors lead to worsening renal function. In turn, the impaired renal function leads to increased sodium and water retention and decreased cardiac performance, establishing a vicious cycle. Abbreviations HF=heart failure Reference Gheorghiade & Pang. J Am Coll Cardiol 2009;53:557–73 Key communication points As well as intrinsic/pre-existing kidney disease, renal dysfunction can be caused by the effects of HF Kidney Intrinsic renal disease Diabetes Hypertension Atherosclerosis *Most patients do not have low cardiac output Gheorghiade, Pang. J Am Coll Cardiol 2009;53:557–73

Myocardial injury is an important marker in heart failure
The importance of myocardial injury in acute HF has not been well studied Myocardial injury may be related to: hemodynamic abnormalities neurohormonal abnormalities/activation an ischemic event, such as a MI high LV diastolic pressure inotropic stimulation Troponin, a marker of myocardial damage, is often released in patients with acute HF In acute HF, troponin release is a prognostic indicator associated with: 3-fold increase in in-hospital mortality 2-fold increase in post-discharge mortality 3-fold increase in the rehospitalization rate Myocardial injury is an important marker in heart failure The importance of myocardial injury in acute heart failure (HF) has not been well studied and remains an area of investigation. However, some useful information is known. Myocardial injury may be related to hemodynamic and/or neurohormonal abnormalities or the result of an ischemic event, such as myocardial infarction (MI). Injury may also be the consequence of a high left ventricular (LV) diastolic pressure, further activation of neurohormones, and/or inotropic stimulation. Troponin is a marker of myocardial damage, and is often released in patients with acute HF, which likely reflects myocardial injury. Troponin release is associated with a three-fold increase in in-hospital mortality, a two-fold increase in post-discharge mortality and a three-fold increase in rehospitalization. Abbreviations HF=heart failure; LV=left ventricular; MI=myocardial infarction Reference Gheorghiade & Pang. J Am Coll Cardiol 2009;53:557–73 Key communication points Myocardial injury is an important marker in HF Troponin, a marker of myocardial damage, is often released in acute HF and is associated with a poor prognosis Gheorghiade & Pang. J Am Coll Cardiol 2009;53:557–73

Acute heart failure syndrome episodes are associated with transient increases in NT-proBNP and troponin I, a marker of cell injury/death1 NT-pro-BNP NT-pro-BNP levels in patients with AHFS 2,500 2,500 *† 2,000 2,000 ‡ 1,500 1,500 fmol/mL fmol/mL 1,000 1,000 ‡ 500 500 Control Stable HF AHFS Admission Discharge Recompensation Troponin I Troponin I levels in patients with AHFS 0.12 0.12 0.10 *† 0.10 0.08 0.08 * ng/mL 0.06 ng/mL 0.06 ‡ 0.04 0.04 0.02 0.02 Acute heart failure syndrome episodes are associated with transient increases in N-terminal pro-B-type natriuretic peptide and troponin I, a marker of cell injury/death An assessment of markers for myocyte injury/death in patients with acute heart failure syndrome (AHFS; n=39), patients with chronic stable systolic heart failure (HF; n=21) and control subjects without HF (n=20) revealed that N-terminal pro B-type natriuretic peptide (NT-pro-BNP) levels were markedly elevated in patients with AHFS compared with control subjects and patients with stable HF. This increase was transient and the levels of NT-pro-BNP in patients with AHFS steadily decreased following admission to hospital. Troponin I levels were also elevated in both patients with stable HF and AHFS compared with control subjects (p<0.05 for both comparisons), although troponin I levels in patients with AHFS were significantly greater than those in patients with stable HF (p<0.05 for AHFS and stable HF comparison). The increase in troponin I levels in patients with AHFS was transient and levels of troponin I were significantly decreased following chronic recompensation.1 In a study of circulating cardiac troponin I in patients with HF, the troponin I concentration (mean±SEM) was 72.1±15.8 pg/mL in patients with severe congestive HF (n=35), and 20.4±3.2 and 36.5±5.5 pg/mL in healthy (n=55) and hospitalized (n=25) control subjects, respectively (p<0.01 versus HF patients). None of the patients with HF had evidence of acute myocardial infarction or injury.2 Thus, troponin I, a marker for cardiac myocyte injury and/or death, is elevated during episodes of AHFS and in patients with severe congestive HF. In a study on rat papillary muscles, overstretching caused a 2.4- and a 21-fold increase in the generation of reactive oxygen species and in apoptotic myocyte cell death, respectively. Addition of a nitric oxide-releasing drug (C ) prevented the formation of superoxide anion and programmed cell death. Overstretching is therefore coupled with oxidant stress and myocyte cell death.3 Abbreviations AHFS=acute heart failure syndrome; HF=heart failure; NT-pro-BNP= N-terminal pro-B-type natriuretic peptide References Biolo et al. Circ Heart Fail 2010;3:44–50 Missov et al. Circulation 1997;96:2953–58 Cheng et al. J Clin Invest 1995;96:2247–59 Key communication points Markers of cell injury/death are elevated during AHFS episodes and in patients with severe congestive HF Non-ischemic processes that occur during AHFS, such as mechanical strain and oxidative stress, can cause myocyte cell death Control Stable HF AHFS Admission Discharge Recompensation *p<0.05 vs control; †p<0.05 vs stable; ‡p<0.05 vs admission Troponin, a marker of myocyte injury and/or death, is known to be elevated in patients with HF without evidence of acute myocardial infarction2 Episodes of AHFS are associated with non-ischemic processes known to cause myocyte death, including mechanical strain and oxidative stress3 These data suggest that episodes of acute HF decompensation may be associated with cardiac myocyte injury and/or death AHFS=acute heart failure syndrome; NT-pro-BNP=N-terminal pro-B-type natriuretic peptide 1. Biolo et al. Circ Heart Fail 2010;3:44–50; 2 Missov et al. Circulation 1997;96:2953–58; 3. Cheng et al. J Clin Invest 1995;96:2247–59

Cumulative risk (all-cause mortality)
RELAX AHF: increases from baseline in hs-cTnT levels are associated with increased mortality in patients with AHF Increased hs-cTnT levels from baseline were associated with increased 180-day mortality At Day 2, an increase in hs-cTnT ≥20% over baseline, indicative of substantial additional myocardial necrosis, nearly doubled the risk of mortality through Day 180 Troponin T 0.20 <20% increase ≥20% increase 0.15 HR 1.80 (95%CI 1.16, 2.78) p=0.0076 Cumulative risk (all-cause mortality) 0.10 RELAX-AHF: increase from baseline in hs-cTnT levels was associated with increased mortality in patients with AHF In the RELAX-AHF study, 1161 patients hospitalized for acute heart failure with systolic blood pressure >125 mmHg and mild-to-moderate renal impairment, and who had received i.v. furosemide (or equivalent), were randomized within 16 hours of presentation to serelaxin 30 µg/kg/d (n=581) or placebo (n=580). An increase in hs-cTnT levels ≥20% from baseline was associated with a significant increase risk of 180-day mortality (hazard ratio 1.80, 95% confidence interval 1.16, 2.78). Increases in hs-cTnT levels from baseline at Days 2, 5 and 14 were also associated with increased 180-day mortality. At Day 2, an increase in hs-cTnT ≥20% over baseline, indicative of substantial additional myocardial necrosis, almost doubled the risk of mortality through Day 180. Abbreviations hs-cTnT=high sensitivity cardiac troponin T; RELAX-AHF=RELAXin in Acute Heart Failure Reference Metra et al. J Am Coll Cardiol 2013;61:196–206 Key communication point In the RELAX-AHF study, an increase in hs-cTnT levels was associated with increased 180-day mortality. 0.05 0.00 Study day Number at risk: <20% increase ≥20% increase AHF=acute heart failure; CI=confidence interval; HR=hazard ratio; hs-cTnT=high sensitivity cardiac troponin T; KM=Kaplan-Meier; RELAX-AHF=RELAXin in Acute Heart Failure Metra et al. J Am Coll Cardiol 2013;61:196–206

Cell death and injury in heart failure: multiple mechanisms and evolving concepts
Mechanical stress Oxidative stress Growth or death signals Cell fate decision Apoptosis (Programmed cell death e.g. development) Mitochondrial or intracellular signal cascade Activation of caspases DNA fragmentation No inflammation Necrosis (Accidental cell death e.g. ischemia) Energy exhaustion Excessive free radicals Membrane disintegration Cell swelling and spillage Pro-inflammatory Necroptosis (Programmed necrosis) Alternative mode for cell to die under chronic stress Activated in presence of innate immune or mitochondrial stress Promoted by oxidative stress RIPK1 / RIPK3 complex key to execution Cell death and injury in heart failure: multiple mechanisms and evolving concepts It has been well established that cells can die via different processes, such as apoptosis (programmed cell death) or by necrosis (accidental cell death). These processes may occur to myocardial cells in response to various stimuli, such as oxidative or mechanical stress, in acute heart failure. Another process called necroptosis, a kind of programmed cell necrosis, has been postulated and this process could also play a role in mediating myocardial cell death in acute heart failure. Abbreviations DNA=deoxyribonucleic acid; RIPK= receptor-interacting serine/threonine-protein kinase Reference Liu. Can J Cardiol 1999;15:8–10B Li, Liu. Circ Res 2009;104:896–904 Li et al. Hypertension 2010;56:1109–17 Li et al. Cell 2012;150:339–50 Vandenbeele et al. Nat Review Molec Cell Biol 2010;11:700–14 Key communication point Myocardial damage may occur in acute heart failure via different processes DNA=deoxyribonucleic acid; RIPK=receptor-interacting serine/threonine-protein kinase Liu. Can J Cardiol 1999;15:8–10B; Li et al. Circ Res 2009;104:896–904; Li et al. Hypertension 2010;56:1109–17; Li et al. Cell 2012;150:339–50; Vandenabeele et al. Nat Review Molec Cell Biol 2010;11:700–14

Inflammatory cytokine expression is associated with worsening renal function, cardiac stress and increased mortality in acute heart failure TNF-α and IL-6 are inflammatory cytokines In a study in 465 patients hospitalized for AHF with blood samples taken ~48 hours post-admission: Elevated levels of TNF-α significantly correlated with worsening renal function (assessed using cystatin C; p<0.001) Elevated levels of IL-6 significantly correlated with increased cardiac stress (assessed using NT-proBNP; p<0.001) Furthermore, elevated IL-6 was an independent predictor of 1-year mortality Kaplan-Meier survival curves for patients with AHF with IL-6 above or below the median 1.0 0.8 Inflammatory cytokine expression is associated with worsening renal function, cardiac stress and increased mortality in acute heart failure Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are inflammatory cytokines. In this study, 465 patients hospitalized for AHF (diagnosed using European Society of Cardiology [ESC] guidelines) underwent blood sampling ~48 hours post-admission to analyze levels of markers including cystatin C, N-terminal pro-B-type natriuretic peptide (NT-proBNP), TNF-α and IL-6. Levels of TNF-α and IL-6 were assessed relative to renal function (evaluated using cystatin C) and cardiac stress (evaluated using NT-proBNP). Patients were followed-up for 12 months to assess all-cause mortality incidence relative to inflammatory marker levels. The main findings of this study were that elevated levels of TNF-α significantly correlated with worsening renal function (assessed using cystatin C; p<0.001) and elevated levels of IL-6 significantly correlated with increased cardiac stress (assessed using NT-proBNP; p<0.001). Furthermore, elevated IL-6 was an independent predictor of 1-year mortality (p<0.001). TNF-α was not an independent predictor of mortality in the overall patient population, but did have significant prognostic value in the subgroup of patients with both low cystatin C and low NT-proBNP (p=0.03). Abbreviations AHF=acute heart failure; ESC=European Society of Cardiology; IL-6=interleukin-6; NT-pro-BNP= N-terminal pro-B-type natriuretic peptide; TNF-α=Tumor necrosis factor-α References Lassus et al. Biomarkers 2011;16:302–310. Key communication points Elevated levels of inflammatory markers are associated with worsening renal function and cardiac stress in patients with AHF Furthermore, elevated levels of inflammatory markers, such as IL-6, are also associated with increased risk of mortality in patients with AHF 0.6 Survival 0.4 IL-6 below median p<0.001 0.2 IL-6 above median Time (days) Median IL-6=15.2 ng/L (15.2 pg/mL) TNF-α=Tumor necrosis factor-α; IL-6=interleukin-6 Lassus et al. Biomarkers 2011;16:302–310

MMP-2 levels in patients with AHFS TIMP-1 levels in patients with AHFS
Episodes of acute heart failure syndrome are associated with marked and transient increases in markers for extracellular matrix turnover1 10.0 PIIINP 8.5 PIIINP levels in patients with AHFS *† 7.5 7.5 ‡ μg/L 5.0 μg/L 6.5 2.5 5.5 4.5 Control Stable HF AHFS Admission Discharge Recompensation 3,000 MMP-2 *† 2,600 MMP-2 levels in patients with AHFS 2,000 2,200 ‡ ng/mL ng/mL ‡ 1,000 1,800 1,400 Control Stable HF AHFS Admission Discharge Recompensation TIMP-1 TIMP-1 levels in patients with AHFS 1,000 *† 800 750 700 ng/mL 500 ng/mL 600 ‡ 250 500 Episodes of acute heart failure syndrome are associated with marked and transient increases in markers for extracellular matrix turnover An assessment of markers for extracellular matrix (ECM) turnover in patients with acute heart failure syndrome (AHFS; n=39), patients with chronic stable systolic heart failure (HF; n=21) and control subjects without HF (n=20) revealed that procollagen type III N-terminal peptide (PIIINP), a marker of collagen synthesis, was significantly increased in patients with AHFS compared with control subjects and patients with stable HF (p<0.05 for both comparisons). The increase in PIIINP was transient, and levels of PIIINP in AHFS patients were significantly decreased following chronic recompensation. Similarly, matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of matrix metalloproteinases-1 (TIMP-1) were also significantly increased in patients with AHFS compared with control subjects and patients with stable HF (p<0.05 for all comparisons). These increases in MMP-2 and TIMP-1 in patients with AHFS were transient and decreased following chronic recompensation. Thus, episodes of AHFS are associated with increases in markers for ECM turnover.1 In a study that examined markers of ECM turnover in control subjects without hypertension (n=39), control patients with hypertension (n=14), patients with left ventricular hypertrophy (LVH) but without chronic heart failure (CHF) (n=23), and patients with LVH and CHF (n=26), levels of MMP-13 were significant decreased in patients with LVH (with or without CHF) compared with control subjects. Furthermore, TIMP-1 was elevated in patients with LVH and CHF but not in those with LVH without CHF. Higher levels of TIMP-1 were associated with increased left ventricular (LV) mass and decreased LV volume/mass ratio, and TIMP-1 levels >1200 ng/mL were predictive of having LVH with CHF. The results of this study indicate that the development of CHF may involve changes in the levels of MMPs and TIMPs, such as a decrease in MMP-13 and an increase in TIMP-1.2 Abbreviations AHFS=acute heart failure syndrome; CHF=chronic heart failure; ECM=extracellular matrix; HF=heart failure; LV=left ventricular; LVH= LV hypertrophy; MMP=matrix metalloproteinase; PIIINP=procollagen type III N-terminal peptide ; TIMP=tissue inhibitors of matrix metalloproteinases References Biolo et al. Circ Heart Fail 2010;3:44–50 Ahmed et al. Circulation 2006;113:2089–96 Key communication point Acceleration of pathological myocardial remodeling may occur during episodes of acute HF decompensation 400 Control Stable HF AHFS Admission Discharge Recompensation *p<0.05 vs control; †p<0.05 vs stable; ‡p<0.05 vs admission In cross-sectional studies of patients with HF with diastolic dysfunction, alterations in circulating MMP and TIMP levels are related to the extent of LV remodeling and predict clinical outcomes2 These data suggest that episodes of acute HF decompensation may be associated with an acceleration of pathological myocardial remodeling PIIINP=procollagen type III N-terminal peptide 1. Biolo et al. Circ Heart Fail 2010;3:44–50; 2. Ahmed et al. Circulation 2006;113:2089–96

Collagen type I degradation
Episodes of acute heart failure are associated with increased oxidative stress and collagen synthesis Collagen type I synthesis (PIP concentration) Collagen type I degradation (CITP concentration) ** ** Acute HF Post-acute HF‡ Acute HF Post-acute HF‡ Oxidative stress (urinary 8-iso-PGF2α concentration) Serum antioxidant capacity (Total antioxidant status) ** * Episodes of acute heart failure are associated with free radical generation and collagen synthesis, promoting myocardial remodeling A key step in the progression of myocardial remodeling is rebuilding of the myocardial extracellular matrix, which is predominantly composed of collagen fibers. Free radical generation (oxidative stress) has been linked with myocardial remodeling. This study of 43 patients hospitalized with acute heart failure (HF) assessed: collagen type I synthesis (measured using serum concentration of the carboxy-terminal propeptide of procollagen type I [PIP]); collagen type I degradation (measured using levels of the 12-kDa carboxy-terminal telopeptide of collagen type I [CITP]); oxidative stress (measured using urinary excretion of 8-iso-prostaglandin F2α); total antioxidant status. Assessments were made at admission (acute HF) and after approximately 2 weeks of conventional treatment (post-acute HF). Relative to the post-acute phase, oxidative stress was significantly elevated in the acute phase (p<0.0001), with a reduction in serum antioxidant capacity observed at the same time (p<0.01). In addition, collagen type I synthesis levels were significantly increased, whereas degradation was reduced (both p<0.0001). Overall, these results indicate increased oxidative stress and collagen synthesis during acute episodes of HF. Abbreviations HF=heart failure; CITP=carboxy-terminal telopeptide of collagen type I; 8-iso-GF2α=8-iso-prostaglandin F2α; PIP=procollagen type I carboxy-terminal peptide References Kunishige et al. Circ J 2007;71:1893–7 Key communication point Increased oxidative stress and collagen synthesis are apparent during episodes of acute HF Acute HF Post-acute HF‡ Acute HF Post-acute HF‡ *p<0.01; **p< vs acute phase; ‡Post-acute HF measurements taken ~2 weeks after admission Myocardial remodeling involves rebuilding of the myocardial extracellular matrix, which is predominantly composed of collagen fibers Free radical generation has also been linked with myocardial remodeling These data from a study in 43 patients with acute HF demonstrate increased markers of collagen type I synthesis and oxidative stress, and reduced collagen type I degradation and total antioxidant status during the acute HF phase compared with ~2 weeks after admission CITP=carboxy-terminal telopeptide of collagen type I; 8-iso-PGF2α=8-iso-prostaglandin F2α; PIP=procollagen type I carboxy-terminal peptide Kunishige et al. Circ J 2007;71:1893–7

Renal impairment is common in patients with heart failure
Renal dysfunction in HF is often attributable to co-morbidities1 diabetes, hypertension, and arteriosclerosis prevalence of renal dysfunction increases with HF severity, increasing age and history of hypertension or diabetes2 Worsening renal function occurs in 20–30% of patients during hospitalization for HF1 Renal abnormalities promote sodium and water retention1 Approximately 20% of patients have worsening renal function soon after discharge1 may result from further neurohormonal and hemodynamic abnormalities (low cardiac output and/or high venous pressure), aggravated by high-dose loop diuretics Renal impairment is common in patients with heart failure In acute HF, structural renal dysfunction due to diabetes, hypertension and atherosclerosis are common.1 Furthermore, the prevalence of renal dysfunction increases with HF severity, age, a history of hypertension or diabetes.2 The consequences of renal abnormalities in acute HF are promotion of sodium and water retention.1 When patients are hospitalized for HF, renal function worsens in 20–30% of cases.1 In addition, soon after hospital discharge, approximately 20% of patients experience worsening renal function.1 This worsening during or after discharge may result from further neurohormonal and hemodynamic abnormalities (low cardiac output and/or high venous pressure), which may be aggravated by high-dose loop diuretics.1 Abbreviations HF=heart failure Reference Gheorghiade & Pang. J Am Coll Cardiol 2009;53:557–73 Key communication points Renal impairment is common in HF, often as a result of co-morbidities Renal function worsens in approximately one-fifth of patients with acute HF during hospitalization or soon after discharge 1. Gheorghiade & Pang. J Am Coll Cardiol 2009;53:557–73 2. Dickstein et al. Eur Heart J 2008;29:2388–442

Worsening renal function (WRF) is associated with poor prognosis in patients hospitalized for AHF
Kaplan-Meier HF hospitalization and CV mortality free survival curves 1.0 WRF defined as absolute or % increase in serum creatinine (s-Cr) that developed during hospitalization (s-Cr increase <0.3 mg/dL or <25% from baseline) 0.8 55% 0.6 Proportion of event free survival WRF defined as absolute and % increase in serum creatinine (s-Cr) that developed during hospitalization (s-Cr increase ≥0.3 mg/dL and ≥25% from baseline 0.4 p<0.001 28% 0.2 Worsening renal function (WRF) is associated with poor prognosis in patients hospitalized for AHF This study was designed to investigate the effect of worsening renal function (WRF) on prognosis in patients hospitalized with acute heart failure (AHF). A total of 318 consecutive patients who were admitted to hospital for AHF at the Institute of Cardiology, Brescia, Italy were followed for 480±363 days. The incidence of WRF was assessed using the definition of a ≥25% and a ≥0.3 mg/dL increase in serum creatinine (s-Cr) from admission at any time during the hospitalization. The prognostic significance of WRF was then determined by assessing the effect of WRF on cardiovascular (CV) mortality and HF hospitalizations (co-primary endpoint) using Kaplan-Meier analysis. On admission, s-Cr was 1.51±0.84 mg/dL (range, 0.40 to 9.70 mg/dL; median, interquartile range, [IQR] 1.30, 1.00– 1.70 mg/dL). During the follow-up period, 53 patients (17%) died and 132 (41%) were rehospitalized for HF. WRF occurred in 107 patients (34%) patients. Kaplan-Meier analysis showed that patients who developed WRF (increase in s-Cr from admission of ≥25% and ≥0.3 mg/dL) during the index hospitalization had a significantly higher incidence of subsequent CV death and HF hospitalizations than patients with an increase in s-Cr from admission of <25% or <0.3 mg/dL (p<0.001). This study shows that WRF is common in patients hospitalized with AHF. Furthermore, when defined as both an absolute and percentage increase from baseline, WRF is a powerful indicator of subsequent CV mortality and HF hospitalization. Abbreviations AHF=acute heart failure; CV=cardiovascular; HF=heart failure; s-Cr=serum creatinine; WRF=worsening renal function Reference Metra et al. Eur J Heart Fail 2008;10:188–95 Key communication point In patients hospitalized with AHF, worsening renal function is associated with subsequent CV mortality and HF hospitalization, especially if worsening renal function is defined as both an absolute and percentage increase in serum creatinine from baseline. Patients at risk Absolute and percent s-Cr change: <0.3 or 25% ≥0.3 and 25% Days Metra et al. Eur J Heart Fail 2008;10:188–95

Change in serum creatinine from baseline to Day 2
RELAX AHF: worsening renal function increases the risk of 180-day mortality in patients with AHF Previous studies indicate that the relationship between renal dysfunction and adverse outcomes is linear, and a ≥0.3 mg/dL increase in serum creatinine has been suggested to define worsening renal function1,2 In RELAX-AHF, worsening renal function, defined as a serum creatinine increase ≥27 µmol/L (0.3 mg/dL) from baseline to Day 2, was significantly associated with increased mortality through Day 1803 Death through Day 180 Change in serum creatinine from baseline to Day 2 Hazard ratio (95% CI) p value <27 μmol/L increase* 27 μmol/L increase* n/N KM % (95% CI) 75/919 8.2 (6.6, 10.2) 23/167 13.8 (9.4, 20.0) 1.76 (1.11, 2.82) 0.017 RELAX-AHF: worsening renal function increased the risk of 180-day mortality in patients with AHF In the RELAX-AHF study, 1,161 patients hospitalized for acute heart failure with systolic blood pressure >125 mmHg and mild-to-moderate renal impairment, and who had received i.v. furosemide (or equivalent), were randomized within 16 hours of presentation to serelaxin 30 µg/kg/d (n=581) or placebo (n=580).1 Previous studies indicate that the relationship between renal dysfunction and adverse outcomes is linear, and a ≥0.3 mg/dL increase in serum creatinine has been suggested to define worsening renal function2,3 In RELAX-AHF, worsening renal function, defined as a serum creatinine increase ≥27 µmol/L (0.3 mg/dL) from baseline to Day 2 was significantly associated with increased mortality through Day 180 (p=0.017).1 Abbreviations RELAX-AHF=RELAXin in Acute Heart Failure Reference 1. Metra et al. J Am Coll Cardiol 2013;61:196–206 2. Cotter et al. Am Heart J. 2008;155:9– Gottlieb et al. J Card Fail 2002;8:136–41 Key communication point In the RELAX-AHF study, worsening renal function, defined by increases in creatinine or cystatin C, was associated with increased 180-day mortality. *0.3 mg/dL AHF=acute heart failure; CI=confidence interval; KM=Kaplan-Meier; RELAX-AHF=RELAXin in Acute Heart Failure 1. Cotter et al. Am Heart J. 2008;155:9– Gottlieb et al. J Card Fail 2002;8:136–41 3. Metra et al. J Am Coll Cardiol 2013;61:196–206

Cumulative risk (all-cause mortality)
RELAX AHF: worsening renal function increases the risk of 180-day mortality in patients with AHF Cumulative risk (all-cause mortality) 0.20 Cystatin C Study day 0.00 0.15 0.10 0.05 Number at risk: <22 nmol/L increase ≥22 nmol/L increase HR 2.10 (95%CI 1.38, 3.20) p<0.001 <22 nmol/L increase (0.3 mg/L) ≥22 nmol/L increase (0.3 mg/L) RELAX-AHF: worsening renal function increased the risk of 180-day mortality in patients with AHF In the RELAX-AHF study, 1,161 patients hospitalized for acute heart failure with systolic blood pressure >125 mmHg and mild-to-moderate renal impairment, and who had received i.v. furosemide (or equivalent), were randomized within 16 hours of presentation to serelaxin 30 µg/kg/d (n=581) or placebo (n=580). Worsening renal function, defined as an increase in plasma cystatin C ≥22 nmol/L from baseline to Day 2 was significantly associated with increased mortality through Day 180 (p<0.001). Abbreviations RELAX-AHF=RELAXin in Acute Heart Failure Reference Metra et al. J Am Coll Cardiol 2013;61:196–206 Key communication point In the RELAX-AHF study, worsening renal function, defined by increases in creatinine or cystatin C, was associated with increased 180-day mortality. AHF=acute heart failure; CI=confidence interval; HR=hazard ratio; RELAX-AHF=RELAXin in Acute Heart Failure Metra et al. J Am Coll Cardiol 2013;61:196–206

Class of recommendation Level of evidence† (A–C)
The evidence base for many commonly used acute heart failure treatments is limited with no proven long-term benefits Group Medication Class of recommendation Level of evidence† (A–C) Diuretics IV loop diuretics I B Vasodilators IV nitrates IIa Sodium nitroprusside IIb IV opiates Morphine C Inotropes* IIa or IIb “The treatment of acute heart failure remains largely opinion-based with little good evidence to guide therapy” “Intravenous nitrates—efficacy and safety still uncertain” The evidence base for many commonly used acute heart failure treatments is limited with no long- term benefits proven Recent guidelines on heart failure (HF) management have recognized that there is very limited evidence of efficacy for the pharmacological agents currently used for acute HF treatment.1 Currently, treatment for acute HF consists of diuretics in almost all patients, plus either vasodilators or inotropic agents depending on a patient’s clinical characteristics. However, the use of these agents is based on limited evidence, generally from small, single-centre studies assessing the effect on acute hemodynamic parameters.1,2 There is very limited evidence on the effect of these agents on outcomes or even symptoms of acute HF. Only very recently developed drugs have clinical evidence of efficacy in acute HF.2 Many therapies for acute HF are based on expert opinion (‘level of evidence: C’). Furthermore, new therapies and technologies have failed to improve survival or decrease repeat hospital stays.3 Abbreviations HF=heart failure; RCT=randomized controlled trials References McMurray et al. Eur Heart J 2012;33:1787–847 Metra et al. Heart Fail Rev 2009;14:299–307 Peacock et al. J Am Coll Cardiol 2010;56:343–51 Key communication point There is limited efficacy evidence for agents currently used to treat acute HF †A=data derived from multiple RCTs or meta-analyses; B=data derived from a single RCT or large non-randomized studies; C=consensus of opinion of the experts and/or small studies, retrospective studies, registries *Inotropic agents are not recommended unless the patient has hypotension (systolic blood pressure [SBP] <85 mmHg), hypoperfusion or shock due to safety concerns IV=intravenous; RCT=randomized controlled trial Adapted from McMurray et al. Eur Heart J 2012;33:1787–847

Large randomized controlled trials in acute heart failure have failed to demonstrate outcome benefits Trial name Patient population Intervention Primary endpoint Significant effect? OPTIME-CHF1 951 patients admitted with exacerbation of systolic HF i.v. milrinone vs pbo for 48 hours Length of hospitalization for CV causes  VERITAS2 1,448 patients hospitalized with AHF i.v. tezosentan vs pbo for 24–72 hours Change in dyspnea, incidence of death and worsening HF at 7 days SURVIVE3 1,327 patients hospitalized with AHF i.v. levosimendan vs dobutamine All-cause mortality at 180 days EVEREST4 4,133 patients hospitalized with AHF Tolvaptan 30 mg once-daily vs pbo for 60 days All-cause mortality and CV death or hospitalization for HF ASCEND-HF5 7,141 patients hospitalized for AHF i.v. nesiritide vs pbo for 24 hours–7 days Change in dyspnea and 30-day all-cause mortality or HF hospitalization PROTECT6 2,033 patients hospitalized for AHF i.v. rolofylline vs pbo for up to 3 days Composite of survival, HF status and renal function Large randomized controlled trials in acute heart failure have failed to demonstrate outcome benefits While there is a lack of data on the effect of therapies in patients with acute heart failure (HF), there have been some studies in this patient population, including OPTIME-CHF, VERITAS, SURVIVE, EVEREST, ASCEND-HF and PROTECT.1–6 These studies assessed the effect of a range of treatments for HF, however only levosimendan caused a significant improvement to the primary endpoint, although no significant improvement was observed in a later study when compared with dobutamine.1–6 In OPTIME-CHF, there was no significant improvement in length of hospitalization after 48 hours’ treatment with milrinone versus placebo in patients with an exacerbation of systolic HF.1 In VERITAS, intravenous (i.v.) tezosentan for 24–72 hours did not improve dyspnea, or incidence of death or worsening HF in patients hospitalized with acute HF.2 Similarly, in SURVIVE, levosimendan did not significantly reduce all-cause mortality at 180 days compared with dobutamine in patients hospitalized with acute HF.3 In EVEREST, tolvaptan for 60 days showed no effect on all-cause mortality and cardiovascular (CV) death or HF hospitalization compared with placebo.4 Even nesiritide, which was approved for acute HF by the Food and Drug Administration (FDA) in 2001 has not shown conclusive efficacy. The largest study so far for nesiritide in 7141 patients showed that nesiritide was not associated with a significant reduction in 30-day all-cause mortality or HF hospitalization compared with placebo. Furthermore, these was no improvement in dyspnea at 6 or 24 hours after treatment.5 Rolofylline also failed to improve the composite endpoint of survival, HF status and renal function versus placebo.6 It is clear that even agents currently used to treat acute HF have shown little evidence of efficacy in clinical trials. Abbreviations ASCEND-HF=Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure trial; CV=cardiovascular; EVEREST=Efficacy of Vasopressin antagonism in hEart failuRE: outcome Study with Tolvaptan; HF=heart failure; i.v.=intravenous; OPTIME-CHF=Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure; REVIVE=Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy; SURVIVE=Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support; VERITAS=Value of Endothelin Receptor Inhibition with Tezosentan in Acute heart failure Studies References 1. Cuffe et al. JAMA 2002;287:1541–7; 2. McMurray et al. JAMA 2007;298:2009–19; 3. Mebazaa et al. JAMA 2007;297:1883–91; 4. Konstam et al. JAMA 2007;297:1319–31; 5. O’Connor et al. N Engl J Med 2011;365:32–43; 6. Massie et al. N Engl J Med 2010;363:1419–28 Key communication point No therapies for acute HF have shown a consistent significant improvement in the primary endpoint pbo=placebo 1. Cuffe et al. JAMA 2002;287:1541–7; 2. McMurray et al. JAMA 2007;298:2009–19; 3. Mebazaa et al. JAMA 2007;297:1883–91; 4. Konstam et al. JAMA 2007;297:1319–31; 5. O’Connor et al. N Engl J Med 2011;365:32–43; 6. Massie et al. N Engl J Med 2010;363:1419–28

There is a need for therapeutic advances in acute heart failure
The therapeutic approach to acute HF has not changed much in the last few decades1 few randomized controlled trials are available in this patient population the therapeutic portfolio available for patients with acute HF is limited only one drug in the USA and one drug in Europe have been approved in the last 15 years1–3 Acute HF has recently received attention from researchers, clinicians, regulatory agencies and the pharmaceutical industry, due to its unique diagnostic and management challenges2 There is a need to identify treatment strategies and regimens that reduce mortality and the incidence of HF rehospitalization in patients post-acute HF1 There is a need for therapeutic advances in acute heart failure There has been little change in the therapeutic approach to acute heart failure (HF) in the last few decades and the portfolio of available therapies is very limited.1 Of those therapies that are available, there is a lack of clinical trial data and robust long-term outcome data in the acute HF population.1 In the last 15 years, there have only been two new drugs approved for acute HF – nesiritide in the USA and levosimendan in Europe.1–3 In recent years, acute HF has received new attention from researchers, clinicians, regulatory agencies and the pharmaceutical industry due to its unique diagnostic and management challenges.2 As a result, there is need to identify those treatment strategies and regimens that have a beneficial effect on HF rehospitalizations in patients after acute HF.1 Abbreviations HF=heart failure; USA=United States of America References Felker et al. Circ Heart Fail 2010;3:314–25 Gheorghiade et al. Circulation 2005;112:3958–68 Hunt et al. J Am Coll Cardiol 2009;53:e1–90 Key communication points There has been little change in the therapeutic approach to acute HF in the last few decades There is a need for new therapeutic approaches in acute HF 1. Felker et al. Circ Heart Fail 2010;3:314–25; 2. Gheorghiade et al. Circulation 2005;112:3958–68; 3. Hunt et al. J Am Coll Cardiol 2009;53:e1–90

Treatment of acute heart failure: immediate, intermediate and long-term goals
Current guidelines split treatment goals into:1–3 Goals of in-patient therapy for acute HF:4 Immediate (emergency department) Relieve symptoms and stabilize the hemodynamic condition Intermediate (in-hospital stabilization) Initiate pharmacological therapy and minimize length of hospitalization Long-term (post-discharge) Prevent rehospitalization Clinical goals Hemodynamic goals Resolution of dyspnea and orthopnea SBP ≥80 mmHg Resolution of ascites and peripheral edema Right atrial pressure ≤8 mmHg JVP ≤8 cm H2O PCWP ≤16 mmHg Control of hypertension Systemic vascular resistance ≤1,200 dynes/s/cm-5 Minimize adverse effects of treatment, reduce duration and cost of stay Initiate treatments that improve long-term outcome Treatment of acute heart failure: immediate, intermediate and long-term goals (1) Guidelines split the goals of treatment for acute heart failure (HF) into three sections: immediate, intermediate and long-term.1–3 The immediate goals are to relieve symptoms and stabilize hemodynamics, while preserving organ function (e.g renal function). Dyspnea and other symptoms and signs of cardiopulmonary congestion are the primary manifestations of acute HF and require immediate attention on presentation to the emergency department or hospital ward. Patients need to be stabilized initially by early administration of diuretics, vasoactive substances, and/or noninvasive ventilation (e.g. continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BiPAP]). The immediate goals of treatment for acute HF involve resolving dyspnea, orthopnea, ascites and peripheral edema, reducing jugular venous pressure and controlling hypertension.4 Attainment of these goals is achieved when the following hemodynamic targets are reached: systolic blood pressure (SBP) ≥80 mmHg, right atrial pressure ≤8 mmHg, pulmonary capillary wedge pressure (PCWP) ≤16 mmHg, and systemic vascular resistance ≤1,200 dynes/s/cm-5. Additional clinical goals are to minimize adverse effects of treatment, reduce duration and cost of stay and initiate treatments that improve long-term outcomes.4 The intermediate treatment phase begins once the patient is stabilized and dyspnea is improved. Because a significant number of patients continue to have signs and symptoms of HF, the goals of this phase are continued hemodynamic and symptomatic improvement while preventing myocardial and renal injury. The intermediate goals are to initiate pharmacological therapy and minimize the length of hospital stay, and the long-term goals are to prevent rehospitalization.1–3 Abbreviations BiPAP=bilevel positive airway pressure; CPAP=continuous positive airway pressure; HF=heart failure; JVP=jugular venous pressure; PCWP=pulmonary capillary wedge pressure; SBP=systolic blood pressure References Gheorghiade et al. Circulation 2005;112:3958–68 Dickstein et al. Eur Heart J 2008;29:2388–442 Hunt et al. J Am Coll Cardiol 2009;53:e1–90 Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008 Key communication points Guidelines split the goals of treatment for acute HF into three sections: immediate, intermediate and long-term The immediate goals are to relieve symptoms and stabilize the hemodynamic condition JVP=jugular venous pressure; PCWP=pulmonary capillary wedge pressure 1. Gheorghiade et al. Circulation 2005;112:3958–68; 2. Dickstein et al. Eur Heart J 2008;29:2388– Hunt et al. J Am Coll Cardiol 2009;53:e1–90; 4. Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008

There are four essential endpoints for assessing acute heart failure therapies
1. Improvements in signs and symptoms Symptom relief (as assessed by Visual Analog Scale, Likert scale, other) Measures of congestion relief (reduction in edema, rales, JVP, weight) 2. Improvement of in-hospital measures In-hospital mortality Length of stay Worsening of HF in hospital (failure to improve or worsening signs and symptoms of HF despite therapy) 3. Prevention of end-organ damage Renal dysfunction or injury (blood urea nitrogen, creatinine, cystatin C, other markers) Myocardial injury (troponin) There are four essential endpoints for assessing acute heart failure therapies As no single endpoint can capture all the elements of the clinical course of acute heart failure (HF), it is suggested that four different domains are assessed and reported in phase III studies of therapies for acute HF. The four domains are: improvements in signs and symptoms; improvement in in-hospital measures; prevention of end-organ damage; and reductions in post-discharge events. Within each domain there are different suggested endpoints that can be measured in clinical trials depending on their appropriateness to the therapy or patient population. Signs and symptoms: as the primary symptom of acute HF is breathlessness, this is an important measure in phase III studies. However, for improvement in breathlessness to be considered clinically important it needs to rapid, substantial and sustained beyond a few hours and therefore needs to be measured at multiple timepoints and under standardized conditions. Measure of congestion relief provide supportive evidence of clinical effect, but are probably not suitable as primary efficacy endpoints. In-hospital measures: these assessments provide an indication of efficacy in the timeframe between immediate symptom relief and post-discharge outcomes. Worsening HF is increasingly accepted as an important clinical measure and been a component of the primary endpoint in several phase III studies. Length of hospital stay can be influenced by factors not related to clinical status, and in-hospital mortality is only relevant in very ill patients. Prevention of end-organ damage: markers of end-organ damage are powerful predictors of outcomes in acute HF and a valuable assessment in clinical trials. Post-discharge events: as these are a major unmet need in acute HF and an important target for therapy, their assessment is important in clinical trials. Formal adjudication of endpoints is important to ascertain the role of HF as opposed to other comorbid conditions; e.g. in the assessment of HF hospitalization. Days hospitalized or dead could be influenced by cultural variability not related to clinical status. Long-term mortality is unlikely to be affected by short-term treatments and is not an appropriate assessment in this setting. Abbreviations CV=cardiovascular; HF=heart failure; JVP=jugular venous pressure; HF=heart failure; LV=left ventricular Reference Felker et al. Circ Heart Fail 2010;3:314–25 Key communication point There are four different effects that should be measured when assessing acute HF therapies: improvements in signs and symptoms; improvement in in-hospital measures; prevention of end-organ damage; and reductions in post-discharge events 4. Reductions in post-discharge events 30-day rehospitalization Death and rehospitalization at 60 days Days hospitalized or death within 60 days Mortality (all-cause or CV) at 180 days Felker et al. Circ Heart Fail 2010;3:314–25; Agency for Healthcare Research and Quality ( accessed November 2012)

Relaxin-2 and Serelaxin

Serelaxin is a recombinant form of the human hormone relaxin-2 that acts directly on CV tissues
Structure of native and manufactured human relaxin-2 Relaxin-2 is a naturally occurring peptide hormone which mediates systemic hemodynamic and renal adaptive changes during pregnancy Structure of human relaxin-2: 53 amino acids (2 chains connected by 2 disulphide bonds) Human relaxin-2 is one of seven peptides in the relaxin family of hormones Relaxin-2 mediates its effects via specific G-protein-coupled receptors: RXFP1 (LGR7) and RXFP2 (LGR8) Cardiovascular tissues are equipped with relaxin receptors that are activated by circulating or regionally generated relaxin -2 to mediate diverse signaling pathways Relaxin acts directly on CV tissues Serelaxin is a recombinant form of human relaxin-2 Human relaxin-2 is a 53 amino acid peptide belonging to a family of peptide hormones, the relaxin peptide family.1,2 Serelaxin is the recombinant form of human relaxin-2. Relaxin acts by binding to specific leucine-rich repeat-containing G-protein-coupled receptor family, which are also known as relaxin family peptide (RXFP) receptors.1 In humans, relaxin binding sites have been identified in blood vessels and heart tissue.1 Relaxin contributes to the important systemic and renovascular adaptive changes of pregnancy that allow the pregnant mother to adjust to the demands of pregnancy.1 Hemodynamic and renovascular adaptive changes are seen coincident with a rise in circulating endogenous relaxin levels during the first trimester of pregnancy: global arterial compliance increases, systemic vascular resistance falls, and cardiac output, renal blood flow and glomerular filtration rate increase in this period, and remain altered throughout pregnancy.1 Studies in rats and humans indicate that administration of exogenous relaxin-2 produces effects on systemic hemodynamics and renal circulation that mimic maternal vasodilation in pregnancy.4 Therefore, it was postulated that pharmacologic use of relaxin may produce these beneficial effects on the cardiovascular system in heart failure. Abbreviations AHF=acute heart failure; i.v.=intravenous; LGR=leucine-rich repeat-containing G-protein-coupled receptor; RXFP=relaxin family peptide receptor References Teichman et al. Heart Fail Rev 2009;14:321–9 Kong et al. Moll Cell Endocrinol 2010;320:1–15 Dschietzig et al. Pharmacol Therap 2006;112:38–56 Conrad. Hypertension 2010;56:2–9 Key communication points Serelaxin is a recombinant form of human relaxin-2. Relaxin contributes to the important systemic cardiovascular and renovascular adaptive changes of pregnancy that allow the pregnant mother to adjust to the demands of pregnancy. Exogenous administration of relaxin mimics the vasodilatory effects seen in pregnancy, indicating a potential for pharmacologic use or relaxin to produce beneficial effects in heart failure. Relaxin MCA1 mAb (+) Relaxin MCA1 mAb (-) Positive immunostaining for relaxin and precursor forms in both the endothelium and vascular smooth muscle of a small renal artery from a virgin female rat Teichman et al. Heart Fail Rev 2009;14:321–9; Jeyabalan et al. Adv Exp Med Biol 2007;612:65–87 Kong et al. Moll Cell Endocrinol 2010;320:1–15; Du et al. Nat Rev Cardiol 2010;7:48–58 Novak J. et al. FASEB J. 2006; 20: 2352–2362 30

Serelaxin triggers multiple pathways following binding to its receptor
eNOS Serelaxin triggers multiple pathways following binding to its receptor Serelaxin and human relaxin-2 act by binding to G-protein-coupled receptors, also known as relaxin family peptide (RXFP) receptors.1 RXFP1 has been found to be localized in small renal and mesenteric arteries and in the aorta in rats and mice, and RXFP2 is thought to have a similar distribution. In humans, relaxin binding sites have been identified in blood vessels and heart tissue.1 An important intracellular second messenger in relaxin signaling is cAMP. Binding of serelaxin to its receptor leads to activation phosphoinositide-3-kinase (PI3K) and adenylyl cyclase to induce increases in cAMP in target cells. The rise in intracellular cAMP levels also activates protein kinase A (PKA) and cAMP response element (CRE) to cause changes in gene expression for various proteins, including iNOS.2 These multiple pathways activated by serelaxin trigger systemic and renal hemodynamic effects indirectly by mediating changes in modulators of vascular tone and structure such as NO, endothelin type B receptor [ETBR] matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF).1,2 Abbreviations RXFP=relaxin family peptide receptor; NO=nitric oxide; Endothein References Teichman et al. Heart Fail Rev 2009;14:321–9 Du et al. Nat Rev Cardiol 2009;7:48–58 Key communication points Serelaxin mediates its effects through binding to specific high-affinity G-protein-coupled receptors. Serelaxin triggers multiple pathways to influence vascular structure and function. iNOS VEGF MMPs ETBR NOS=nitric oxide synthase; ETBR=endothelin type B receptor; MMP=matrix metalloproteinase; VEGF=vascular endothelial growth factor Adapted from Du et al. Nat Rev Cardiol 2009;7:48–58

Relaxin mediates maternal hemodynamic improvements during pregnancy
PARAMETER PREGNANCY Systemic vascular resistance (dyn.s.cm2) Cardiac output (L/min) Global arterial compliance (mL/mm Hg) Renal vascular resistance (dyn.s.cm2) Renal blood flow (mL/min/1.73m2) Creatinine clearance (mL/min/1.73m2) Onset of hemodynamic changes coincident with relaxin elevation during 1st trimester of pregnancy; similar but smaller changes observed during the luteal phase of menstrual cycle The beneficial effects of relaxin see in pregnancy may be beneficial in acute heart failure Relaxin mediates maternal hemodynamic improvements during pregnancy Relaxin-2 or relaxin, produced by the corpus luteum and/or placenta, is essential for normal pregnancy and parturition in many species.1 In some species relaxin is responsible for relaxation of the female reproductive tract (lengthening the interpubic ligament and softening the tissues of the birth canal) in preparation for labor.2 Important systemic and renovascular adaptive changes of pregnancy that allow the pregnant mother to adjust to the demands of pregnancy.3 Hemodynamic and renovascular adaptive changes are seen coincident with a rise in circulating endogenous relaxin levels during the first trimester of pregnancy: global arterial compliance increases, systemic vascular resistance falls, and cardiac output, renal blood flow and glomerular filtration rate increase in this period, and remain altered throughout pregnancy.4,5 It has been suggested that the effects of relaxin on the cardiovascular system may be beneficial in heart failure.6 References Kong et al. Moll Cell Endocrinol 2010;320:1–15 Dschietzig et al. Pharmacol Therap 2006;112:38–56 Schrier, RW, et al. Am J Kid Dis 1987; 284–9; Teichman et al. Heart Fail Rev 2009;14:321–9 Baylis, C. Am J Kid Dis 1999; 34:1142–4; Jeyabalan et al. Adv Exp Med Biol 2007;612:65–87 Key communication points Relaxin contributes to the important systemic cardiovascular and renovascular adaptive changes of pregnancy that allow the pregnant mother to adjust to the demands of pregnancy. Exogenous administration of relaxin mimics the vasodilatory effects seen in pregnancy, indicating a potential for pharmacologic use or relaxin to produce beneficial effects in heart failure. Baylis. Am J Kid Dis 1999; 34:1142–4; Schrier et al. Am J Kid Dis 1987; 284–9; Dschietzig et al. Pharmacol Therap 2006;112:38–56 ; Jeyabalan et al. Adv Exp Med Biol 2007;612:65–87

Relaxin is expressed in myocardial tissues and levels are elevated in patients with heart failure
Plasma levels of relaxin determined by ELISA Expression of human relaxin-2 mRNA in myocardial tissues determined by RT-PCR * *# 25 20 15 10 5 Pulmonary artery Left ventricle Coronary Sinus Antecubital vein Mean plasma levels of relaxin (pg/mL) Severe CHF Moderate CHF Controls Relaxin is expressed in myocardial tissues and levels are elevated in patients with heart failure The expression of relaxin was examined in patients with congestive heart failure (CHF) and New York Heart Association (NYHA) class IV (severe CHF) (n=14) or NYHA class II (moderate CHF) (n=13), and in control subjects (n=13) who were undergoing cardiac catheterization for suspected coronary artery disease and had no evidence of structural cardiovascular disease. Human relaxin-2 mRNA was detected by RT-PCR in left ventricles, right atria, mammary arteries, and saphenous veins from control subject. The GAPDH-normalized expression of human relaxin-2 mRNA was elevated in left ventricles from patients with CHF compared with control subjects (2.6±0.4 vs 1.0±0.2 arbitrary units, p<0.05). Similarly, the expression of relaxin-2 mRNA was elevated in right atria from patients with CHF compared with control subjects (3.8±1.0 vs 1.0±0.1 arbitrary units, p<0.05). Plasma levels of relaxin in the left ventricle, pulmonary artery, coronary sinus and antecubital vein, measured by ELISA, were 4- to 6-fold higher in patients with moderate CHF than in control subjects. In patients with severe CHF, plasma levels of relaxin were 2.2- to 2.6-fold higher than those in patients with moderate CHF, and 12- to 16-fold higher than those in control subjects. Abbreviations CHF=congestive heart failure; ELISA=enzyme-linked immunosorbent assay; GAPDH=glyceraldehyde-3-phosphate dehydrogenase; mRNA= messenger ribnucleic acid; NYHA=New York Heart Association; RT-PCR=reverse transcriptase polymerase chain reaction; vs=versus References Dschietzig et al. FASEB J 2001;15:2187–95 Key communication points Relaxin is expressed in the human heart. Plasma levels of relaxin are elevated in patients with CHF. *p<0.05 vs controls p<0.05; *severe CHF vs controls; §moderate CHF vs controls; #severe vs moderate CHF Relaxin is constitutively expressed in human myocardial tissues Expression of relaxin is elevated in patients with CHF compared with individuals with no evidence of structural cardiovascular disease CHF=congestive heart failure; ELISA=enzyme-linked immunosorbent assay; GAPDH=glyceraldehyde-3-phosphate dehydrogenase; mRNA= messenger ribonucleic acid; RT-PCR=reverse transcriptase polymerase chain reaction; vs=versus Dschietzig et al. FASEB J 2001;15:2187–95

Serelaxin has potential multi-mechanistic effects which may address the pathophysiology of AHF
↓ Myocardial overload; ↑ Renal function 1 ↑Tissue healing ↓ Inflammation ↑ Cell survival ↑ Cell preservation 2 ↓ Inflammatory cell infiltration ↓ Oxidative stress ↑ Angiogenesis ↑ Stem cell survival ↓ Apoptosis ↓ Ca2+ overload ↓ Infarct size Serelaxin Vasorelaxation* ↑ Endothelial NO* ↓ SVR, ↑ RBF, ↑ GFR ↓ ET-1 Volume redistribution Remodeling ↓ Fibrosis ↑ ECM remodeling 3 ↑ Matrix metalloproteinases ↓ Vessel stiffness ↓ Collagen synthesis ↑ Collagen breakdown Serelaxin has potential multi-mechanistic effects which may address the pathophysiology of acute heart failure Data from various experimental animal models have demonstrated the potential cardioprotective effects of relaxin which may beneficial effect of three main pathophysiological components of acute heart failure (HF): Decreasing myocardial overload (preload and afterload). Serelaxin may reduce myocardial overload through its vasorelaxant effects. Relaxin promotes vasorelaxation by increasing nitric oxide production from the endothelium and decreasing endothelin-1- and angiotensin II-mediated vasoconstriction. Relaxin also reduces platelet aggregation. Increasing cell preservation. Relaxin has a number of anti-inflammatory effects, including reducing inflammatory cell infiltration and oxidative stress, that may be cardioprotective. In addition, relaxin promotes cell survival by reducing oxidative stress-mediated apoptosis, calcium overload and infarct size. By stimulating angiogenesis, and improving stem cell survival and cell-cell coupling, relaxin may also facilitate myocardial tissue healing. Serelaxin may therefore promote cell preservation via a number of different mechanisms. Decreasing cardiac remodeling. Relaxin decreases cardiac fibroblast (CF)-stimulated protein synthesis and increases atrial natriuretic peptide secretion, indicating that serelaxin may reduce pathological cardiac remodeling. In addition, relaxin has a number of antifibrotic properties; relaxin decreases CF activation and proliferation, inhibits collagen synthesis and promotes collagen breakdown. Serelaxin may therefore also ameliorate cardiac fibrosis. Abbreviations CF=cardiac fibroblast; CV=cardiovascular; HF=heart failure References Du et al. Nat Rev Cardiol 2010;7:48–58 Key communication point Serelaxin has the potential to exert a variety of beneficial CV effects that may ameliorate the pathophysiology of acute HF *Selective dilation of pre-constricted vessels; AHF=acute heart failure; ECM=extracellular matrix; ET-1=endothelin-1; GFR=glomerular filtration rate; NO=nitric oxide; RBF=renal blood flow; SVR-systemic vascular resistance Adapted from Du et al. Nat Rev Cardiol 2010;7:48–58

RELAX-AHF: study design
A Phase III, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of serelaxin, in addition to standard therapy, in subjects hospitalized for AHF Randomized: 1,161 patients hospitalized with AHF, normal to elevated BP and mild-to-moderate renal impairment Double-blind randomized treatment period Placebo (n=580) Screening Screening occurred after ≥40 mg i.v. furosemide Serelaxin 30 µg/kg/d (n=581) In addition to standard HF therapy‡ RELAX-AHF: study design RELAX-AHF was a Phase III, randomized, double-blind, placebo-controlled study conducted across 96 sites in 11 countries.1–3 A total of 1,161 patients with acute heart failure (AHF), normal to elevated blood pressure and mild-to-moderate renal impairment were enrolled in RELAX-AHF. Patients were randomized (1:1) in a double-blind manner, within 16 hours from presentation, to receive placebo or serelaxin 30 µg/kg/day on top of standard of care.1–3 The 30 µg/kg/day dose of serelaxin was selected based on its favorable efficacy and safety profile in Pre-RELAX-AHF.2,4 The study drug was administered as an i.v. infusion for 48 hours. Study drug administration was stopped if, at any time during dosing, SBP fell to <100 mmHg.3,4 Abbreviations AHF=acute heart failure; i.v.=intravenous; RELAX-AHF=RELAXin in Acute Heart Failure; SBP=systolic blood pressure References Clinicaltrials.gov 2009 (NCT ) RLX.CHF.003 (Pre-RELAX-AHF/ RELAX–AHF) Study Protocol Teerlink et al. Lancet 2013;381:29–39 Ponikowski et al. Am Heart J 2012;163:149–55.e1 Key communication point RELAX-AHF was a Phase III, randomized, double-blind, placebo-controlled study conducted in 1,161 patients to assess the efficacy and safety of serelaxin in patients with AHF. <16 h Presentation h 5 d 14 d 60 d 180 d 48 h study drug infusion (i.v.) period Post-discharge evaluation period Teerlink et al. Lancet 2013;381:29–39; Ponikowski et al. Am Heart J 2012;163:149–55.e1

RELAX-AHF: key inclusion criteria
SBP >125 mmHg Hospitalized for AHF, defined as including all of the following at screening: dyspnea at rest or with minimal exertion pulmonary congestion by chest X-ray BNP ≥350 pg/mL or NT-proBNP ≥1400 pg/mL Able to be randomized within 16 hours from hospital presentation (including ED) Received i.v. furosemide ≥40 mg (or equivalent) between admission to emergency services (either ambulance or hospital, including ED) and screening Mild-to-moderate renal impairment, defined as a sMDRD eGFR between 30–75 mL/min/1.73 m2 RELAX-AHF: inclusion criteria The RELAX-AHF program had two phases – Pre-RELAX-AHF and RELAX-AHF. Pre-RELAX-AHF was the Phase II dose-finding portion of the study and RELAX-AHF was designed to provide a fuller evaluation of the efficacy and safety of serelaxin in a patient population with the same characteristics as those enrolled for preliminary investigation of serelaxin in Pre-RELAX-AHF. As such, RELAX-AHF and Pre-RELAX-AHF shared common inclusion criteria, i.e. patients aged ≥18 years with acute heart failure (AHF) and with normal or elevated blood pressure and mild-to-moderate renal insufficiency on screening. Patients presenting in hospital with AHF were eligible for the study if they displayed all of the following signs: dyspnea at rest or with minimal exertion, pulmonary congestion on chest X-ray, and increased natriuretic peptide concentrations (B-type natriuretic peptide [BNP] ≥350 pg/mL or NT-proBNP ≥1400 pg/mL). Patients were screened only if they had received i.v. furosemide at a dosage ≥40 mg (in the ambulance or on admission to hospital). Patients were screened to identify those meeting criteria of SBP >125 mmHg and mild-to-moderately impaired renal function (simplified Modification of Diet in Renal Disease estimated glomerular filtration rate 30–75 mL/min/1.73 m2). Screening and randomization were required to take place within 16 hours of initial presentation. Abbreviations AHF=acute heart failure; BNP=B-type natriuretic peptide; i.v.=intravenous; NT-proBNP=N-terminal pro B-type natriuretic peptide; Pre-RELAX-AHF=preliminary study of RELAXin in Acute Heart Failure; RELAX-AHF=RELAXin in Acute Heart Failure; SBP=systolic blood pressure. References Clinicaltrials.gov 2009 (NCT ) Teerlink et al. Lancet 2013;381:29–39 Ponikowski et al. Am Heart J 2012;163:149–55.e1 Key communication point Inclusion criteria for RELAX-AHF were the same as for Pre-RELAX-AHF, and were set to select a patient population with AHF and normal or elevated blood pressure and mild-to-moderate renal insufficiency. Teerlink et al Lancet 2013;381:29–39; Ponikowski et al. Am Heart J 2012;163:149–55.e1

RELAX-AHF: key exclusion criteria
Treatment with any other i.v. HF therapies including mechanical support <2 hours before screening except i.v. nitrates at a dose of ≤0.1 mg/kg/h if the patient had a SBP >150 mmHg Signs of active infection Known significant pulmonary or valvular disease AHF caused by significant arrhythmias ACS diagnosed <45 days before screening Troponin ≥3 times the level indicative of myocardial infarction RELAX-AHF: key exclusion criteria Patients were excluded from RELAX-AHF if they met any of the following criteria: pregnant or breast-feeding; current (within 2 hours prior to screening) or planned treatment with any i.v. therapies, including vasodilators (e.g. nesiritide), positive inotropic agents and vasopressors, or mechanical support (intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist device), with the exception of i.v. nitrates at a dose of ≤0.1 mg/kg/hr if the patient has systolic blood pressure >150 mmHg at screening; current or planned ultrafiltration, hemofiltration, or dialysis; signs of active infection; known significant pulmonary disease; known significant valvular disease (including severe aortic stenosis, severe aortic regurgitation or severe mitral stenosis); acute heart failure due to significant arrhythmias; organ transplant recipient, or currently listed for transplant or admitted for any transplantation; major surgery within 30 days; non-cardiac pulmonary edema, including suspected sepsis; hematocrit <25% or blood transfusion in the prior 14 days or active, life-threatening gastro-intestinal bleeding; clinical diagnosis of acute coronary syndrome within 45 days prior to screening (including the present admission); troponin ≥3 times the level diagnostic of myocardial infarction. Abbreviations hr=hour; i.v.=intravenous; Pre-RELAX-AHF=preliminary study of RELAXin in Acute Heart Failure; RELAX-AHF=RELAXin in Acute Heart Failure. References Clinicaltrials.gov 2009 (NCT ) Teerlink et al. Lancet 2013;381:29–39 Ponikowski et al. Am Heart J 2012;163:149–55.e1 Key communication point Exclusion criteria for RELAX-AHF were the same as for Pre-RELAX-AHF, and were set to exclude patients with a high risk of complications and those with a current or recent treatment history that could interfere with assessment of the treatment effect of serelaxin. Teerlink et al. Lancet 2013;381:29–39; Ponikowski et al. Am Heart J 2012;163:149–55.e1

RELAX-AHF Conclusions: Key results Serelaxin may represent an important new treatment option for patients with AHF D180 Treatment LIKERT Timeline: VAS D1 D5 D14/Index DAOOH CV† or rehospitalization LoS (index/ICU) WHF D2 D60 p=0.7 In-hospital benefits Out-patient benefits D0 CV death OR=1.05 HR = 1.02 (p=0.89) RLX 48h i.v. +19.4% (p=0.0075) HR 0.70 (p=0.026) -0.9 day (P=0.039); -0.4 day (p=0.029) +0.6 day (p=0.328) HR = 0.63 (p=0.028); NNT = 29 Primary EP Secondary EP All-cause death HR = 0.63 (p=0.020); NNT = 25 Overall well tolerated - Manageable hypotension Teerlink et al. Lancet 2013;381:29–39

ESC guidelines 2012, fig.5 pag. 846

Heart failure has two distinctive subtypes

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Heart failure has two distinctive subtypes

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Presentation on theme: "Heart failure has two distinctive subtypes"— Presentation transcript:

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