An approach to Acute Decompensated Heart failure

ADHF is a medical emergency. Clinical, ECG and bedside imaging are key to early diagnosis.

1. Acute Decompensated Heart Failure Dr Dipankar Ghosh Dastidar Associate Professor, Cardiology Burdwan Medical College, Burdwan

2. Data from National Heart Failure Registry The National Heart Failure Registry [ NHFR] is a multi- centre [53 tertiary care hospitals in 21 states of India] clinical registry of consecutive ADHF patients with prospective follow-up. In total, 10,851 consecutive patients were recruited (mean age: 59.9 years, 31% women). Ischaemic heart disease was the predominant aetiology for HF (72%), followed by dilated cardiomyopathy (18%). Isolated right HF was noted in 62 (0.6%) participants. In eligible HF patients, 47.5% received GDMT. The 90 day mortality was 14.2% (14.9% and 13.9% in women and men, respectively) with a re-admission rate of 8.4%. Patients with HF with reduced ejection fraction and HF with mildly reduced ejection fraction who did not receive GDMT experienced higher mortality (log-rank  P  < 0.001) than those who received GDMT. Baseline educational class, body mass index, New York Heart Association functional class, ejection fraction, dependent oedema, serum creatinine, QRS > 120  ms , atrial fibrillation, mitral regurgitation, haemoglobin levels, serum sodium, and GDMT independently predicted 90 day mortality. Sivadasanpillai Harikrishnan ,  Ajay Bahl ,  Ambuj Roy ,  Animesh Mishra ,  Jayesh Prajapati ,  C.N. Manjunath ,  Rishi Sethi ,  Santanu Guha ,  Santhosh Satheesh ,  R.S. Dhaliwal ,  Meenakshi Sarma et al. Clinical profile and 90 day outcomes of 10 851 heart failure patients across India: National Heart Failure Registry. ESC Heart failure. Volume9, Issue6 , December 2022, Pages 3898-3908.

3. Definition and Clinical Presentation Heart failure (HF) is a clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood. The clinical presentation of symptoms and signs of congestion and poor organ perfusion due to HF requiring urgent, usually intravenous therapy is called acute decompensated heart failure [ADHF]. Physical exam findings include pulmonary crackles, pulmonary edema and pleural effusions, peripheral edema , ascites, elevated jugular venous distension, abdominojugular or hepatojugular reflux, third heart sound, and worsening mitral or tricuspid regurgitation murmurs. Signs of end-organ dysfunction secondary to congestion include aforementioned pulmonary edema , gastrointestinal edema , hepatocellular damage, and cardiorenal syndrome. Additionally, in the presence of decreased cardiac output, reduced organ perfusion can contribute to end-organ damage. Increased ventricular pressures and neurohormonal compensatory mechanisms to augment chronotropy and inotropy can trigger tachycardia, arrhythmias, and increased myocardial strain and ischemia.

4. Pathophysiology Intravascular Congestion Systemic – sodium retention due to renal dysfunction, dietary indiscretion, or medical nonadherence. Pulmonary -  increased left ventricular filling pressures or by rapid central redistribution of intravascular volume from peripheral or splanchnic venous circulation. Reduced Inotropy Extreme forms may present as cardiogenic shock commonly defined as hypotension <90 mm Hg, cardiac index <2.2 L/min per m 2 , and signs of end-organ hypoperfusion, including decreased urine output, cool extremities, altered mental status, and serum lactate elevation.

5. Pathophysiology Venous and Arterial Vasoconstriction Venous vasoconstriction - increases in peripheral and splanchnic venous vasoconstriction can result in marked volume redistribution to the central venous system. Arterial vasoconstriction – Due to reflex sympathetic activation , it leads to dramatic increases in afterload resulting in rapidly developing pulmonary congestion or flash pulmonary edema. Neurohormonal Signaling and Circulating Biomarkers RAAS, Endothelin 1, BNP, ST2, Galectin 3 are elevated. Role of Inflammation TNF, TGF-β, IL-6 and IL-1 are elevated.

6. Comorbidities Hypertension (70%) C oronary artery disease (50%–60%) A trial fibrillation (30%–40%) C linically significant atrial or ventricular arrhythmias. Anemia (50%) D iabetes (40%) Renal dysfunction (20%–30%) C hronic obstructive pulmonary disease (20%–30%) A nemia (15%–30%)

7. End-Organ Damage Lung - P ulmonary edema , Pleural effusions, alveolar stiffness and pulmonary fibrosis, Pulmonary hypertension (WHO Group II). Kidneys - Cardiorenal syndrome . Liver – Transaminitis, coagulopathies and biliary cholestasis . GI - gut edema causing decreased absorption affecting nutrition and medication absorption and bioavailability Heart – Myocardial injury (↑ Troponin) Brain - altered mental status, somnolence, and obtundation.

8. Sodium (<3g/day) and fluid restriction (<1.5 – 2L/day). IV Loop diuretics. [No difference between continuous versus bolus administration of furosemide; Dyspnea relief more with high dose vs low dose] Diuretic resistance - sequential nephron blockade with addition of a thiazide or aldosterone antagonist to the loop diuretic. Opiates - reduce patient anxiety and decrease the work of breathing . NICE study found no evidence of benefit and some evidence of harm with use of opiates in ADHF. The 2013 ACC/AHA guidelines do not mention morphine therapy as part of the management of ADHF. INITIAL SYMPTOM MANAGEMENT

9. Vasodilators - natriuretic peptides Nesiritide is an exogenous recombinant BNP developed to increase vasodilation and augment natriuresis in patients with ADHF. VMAC (2002) – Nesiritide vs Placebo (S); vs NTG (NS) ASCEND HF (2011) - Nesiritide vs Placebo; Dyspnea (S) but death / rehospitalisations (NS) C arperitide (human ANP) – higher in-hospital mortality, prolonged length of stay, and greater hospital costs - used in Japan. Ularitide [ANP analogue] TRUE AHF (2017) – Ularitide vs Placebo; NT ProBNP ↓ (S) but Cr ↑ Cenderitide , a chimeric CD-NP (c-terminus dendroaspis natriuretic peptide) TACTICS HF (2016) -

10. Vasodilators - soluble guanylate cyclase activators V ericiguat decreased HF hospitalizations in patients with chronic HF and reduced EF in the VICTORIA trial – Not tested in ADHF. C inaciguat development program for ADHF was discontinued due to increased hypotension.

11. Vasodilators - endothelin receptor antagonists Tezosentan is an intravenous mixed endothelin receptor antagonist specifically developed as a therapy for ADHF. VERITAS (2007) – Tezosentan vs Placebo; Negative results.

12. Vasodilators – Vasopressin antagonists EVEREST (2007) – Tolvaptan vs Placebo; Composite of changes in global clinical status and body weight (S); CV death or HF hospitalization (NS)

13. Vasodilators - R elaxin-2 analogues Serelaxin is a vasodilatory agent, a recombinant form of human relaxin-2 which has vasodilatory, antifibrotic, and anti-inflammatory effects. RELAX-AHF ( RELAXin in Acute Heart Failure) trial - lower incidence of worsening HF and significantly decreased cardiovascular mortality in patients admitted with ADHF, as well as evidence of renal, hepatic, and cardiac end-organ protection [ ↓ troponin release] . RELAX-AHF-2 trial did not confirm a decreased cardiovascular mortality at 6 months in patients treated with serelaxin compared with placebo.

14. Inotropes Both the ACC/AHA and the ESC support the use of continuous intravenous inotrope infusion (dobutamine, dopamine, milrinone, and epinephrine) as a temporizing measure in the setting of severe LV systolic dysfunction with diminished peripheral perfusion and end-organ dysfunction (hypotension, oliguria, confusion) until definitive therapy (coronary revascularization, mechanical circulatory support, or heart transplantation) or resolution of the underlying pathology. Inotropic drugs increase myocardial oxygen consumption and may provoke ischemia, particularly in patients with ischemic heart disease, and may precipitate atrial and ventricular tachyarrhythmias, The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure–OPTIME-CHF (OPTIME-CHF) trial showed Milrinone therapy to be associated with significant increases in hypotension and arrhythmias and a nonsignificant increases in mortality during the hospital stay (3.8 versus 2.3 percent) and at 60 days (10.3 versus 8.9 percent) as compared to placebo.

15. Inotropes – β agonists Dopamine < 2.5 μ g/kg/min - dopaminergic type 1 and type 2 - vasodilation of the splanchnic, coronary and renal vasculature - ↑ renal perfusion – no significant clinical benefit. DAD-HF [2014] and ROSE AHF – negative trials. 3–5 μ g/kg/min – β 1 - ↑ chronotropic and inotropic effects but ↑ PCWP > 5 μ g/kg/min – α1 – Vasoconstriction - ↑ afterload Dobutamine <5 μ g/kg/min - ↑ inotropy and ↓ afterload – Myocardial β 1 and peripheral β 2 > 5 μ g/kg/min - ↑ afterload – Peripheral α vasoconstriction. Problems – Development of tolerance with long term use, effects blunted with chronic beta blockade. Norepinephrine 0.01–0.03 μ g/kg/min - β 1 (inotropic) and α 1 (Vasoconstrictor) Epinephrine 0.01 μ g/kg/min – β 2 mediated vasodilatation >0.2 μ g/kg/min - β 1 (inotropic) and α 1 (Vasoconstrictor) Problems - ↑ incidences of of lactic acidosis, tachycardia, arrhythmia and gastric mucosal hypoperfusion.

16. Inotropes – Phosphodiesterase III inhibitors Milrinone [ inodilator ] PDE3i - ↑ CAMP - ↑ PrKA - ↑ Ca - ↑ Actin myosin cross bridges = ↑ inotropy Vasodilation of the peripheral and pulmonary vasculature. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure–OPTIME-CHF (OPTIME-CHF) trial showed Milrinone therapy to be associated with significant increases in hypotension and arrhythmias and a nonsignificant increases in mortality during the hospital stay (3.8 versus 2.3 percent) and at 60 days (10.3 versus 8.9 percent) as compared to placebo . D ata from the Acute Decompensated Heart Failure National Registry (ADHERE) registry point towards the direction of increased mortality for dobutamine and milrinone compared with IV nitroglycerin or nesiritide . The Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial concluded that the use of milrinone in symptomatic HF patients, despite optimal medical therapy, was associated with increased mortality and readmission rates compared with placebo.

17. Drawbacks With continued use, conventional inotropic agents—including catecholamines, phosphodiesterase-3 inhibitors, sodium-potassium adenosine triphosphatase (ATPase) inhibitors, and mixed-mechanism calcium sensitizers and phosphodiesterase-3 inhibitors—detrimentally alter myocardial energetics, decrease the adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio, and have been associated with clinical outcomes that are at best neutral and at worst deadly, including malignant arrhythmias. The underlying Ca 2+ -centric mechanism of these agents may be the dual-edged sword that causes both their inotropic and detrimental effects. 

18. Novel Inotropes C alcitropes , which alter intracellular calcium concentrations; M yotropes , which affect the molecular motor and scaffolding; M itotropes , which influence energetics

19. Inotropes – Calcium sensitisers Levosimendan [ Inodilators ] It exerts its effects by acting on troponin C, rendering the cardiomyocyte more sensitive to the already existing levels of intracellular calcium, thereby increasing its contractility. As its effects are not a result of influx of calcium in the myocyte, its arrhythmogenic potential is significantly limited. It also causes peripheral vasodilation via the opening of ATP-sensitive potassium channels on smooth muscle cells of the vasculature. The Efficacy and Safety of Intravenous Levosimendan Compared with Dobutamine in Severe Low-Output Heart Failure (LIDO) study found that levosimendan was superior to dobutamine in terms of haemodynamic profile and mortality. The 180-day mortality rate in the Levosimendan versus Dobutamine for Patients with Acute Decompensated Heart Failure (SURVIVE) trial was comparable in both arms and in the Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy (REVIVE-II) trial, despite a documented improvement in HF symptoms, levosimendan failed to prove beneficial in terms of mortality reduction and led to more cases of arrhythmias and hypotension.

20. Optimizing Inotropy: Novel Calcitrope Therapies

21. Optimizing Inotropy: phosphodiesterase III inhibitors Levosimendan is a calcitrope that inhibits phosphodiesterase III and amplifies troponin C activity resulting in increased calcium sensitivity to augment contractility. It also has a potent peripheral vasodilatory effect due to activation of K ATPase  channels. In the REVIVE (Randomized EValuation of Intravenous leVosimedan Efficacy) I and II trials, it was found to reduce HF symptoms but increased early mortality, did not improve morbidity or mortality, and had increased adverse cardiac events, including atrial and ventricular arrhythmias and hypotension.

22. Optimizing Inotropy: Nitroxyl donors C imlanod - Nitroxyl donors – Cause post-translational modifications of target proteins, including SERCA2a, phospholamban , ryanodine receptors, and myofilament proteins in cardiomyocytes thereby increasing calcium transients and sarcomere calcium sensitivity thereby augmenting myocardial contractility and relaxation. Nitroxyl also has peripheral vasodilatory effects without inducing tachycardia. The STAND-UP AHF (Study Assessing Nitroxyl Donor Upon Presentation with Acute Heart Failure) study demonstrated multiple markers of improved end-organ decongestion with cimlanod , although without a clear increase in urine output or decreased weight.

23. Optimizing Inotropy: sarcolemmal Na + /K +  pump and augmentation of the SERCA2a pump activity Istaroxime is a novel drug with a dual mechanism of action involving the inhibition of the sarcolemmal Na + /K +  pump and augmentation of the SERCA2a pump activity. These effects are mediated by the displacement of phospholamban from SERCA2a resulting in enhanced calcium reuptake by the sarcoplasmic reticulum, independently of intracellular cyclic AMP concentrations. In an early study, a 6-hour infusion of istaroxime in patients with worsening HF and HFrEF improved both systolic and diastolic left ventricular function with a mild increase in systolic blood pressure.

24. Optimizing Inotropy: Novel Myotrope Therapies

25. Optimizing Inotropy: Novel Myotrope Therapies cardiac myosin activators. It exerts its effect by binding on an allosteric site on myosin itself thereby priming it and making increased number of myosin heads available to cross-bridge with actin generating increased contractile force It is important to note that the mechanism of action of OM is independent from calcium and cAMP and independent of adrenergic pathway In the ATOMIC-AHF trial (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure), - IV Omecamtiv mecarbil dose cohort experienced significant dyspnea relief compared with those treated with placebo. GALACTIC-HF trial - oral omecamtiv mecarbil caused significant dyspnea relief with no serious adverse arrhythmic or ischemic events.

26. Novel Mitotrope Therapies

27. Novel Mitotrope Therapies Cardiac mitotropes increase cardiac function by improving myocardial energetics.  Perhexiline prevents fatty acid transport into the mitochondria via blockade of carnitine palmitoyl transferase and seems to improve myocardial ATP production. It has been studied in chronic HF and found to improve VO 2  max, left ventricular EF, and HF symptoms. Trimetazidine inhibits thiolase thereby preventing mitochondrial oxidation of fatty acids to similarly shift cellular metabolism to glucose utilization . Elampretide is a mitochondrial membrane protective agent that decreases reactive oxygen species with promising effects on cellular energetics and resultant cardioprotective effects in ischemia and reperfusion injury in animal models

28. Novel Mitotrope Therapies - Ranolazine Ranolazine causes inhibition of the late sodium current responsible for sodium influx during left ventricular repolarization, as well as acting as a partial fatty oxidase inhibitor. No large clinical studies exist evaluating the effects in humans with HF, however, subgroup analyses of the 6560 patient MERLIN (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes) trial demonstrated improved composite cardiovascular death, myocardial infarction, and recurrent ischemia specifically in patients with HF and elevated BNP. More data are necessary in a larger cohort to investigate the potential clinical utility of ranolazine in ADHF.

29. SGLT2 inhibitors and Other antidiabetic agents SGLT2 (Sodium-glucose cotransporter 2) inhibitors inactivate the SGLT2 receptor of the proximal convoluted tubule preventing glucose reabsorption resulting in glucosuria and sodium excretion associated with increased natriuresis, decreased blood pressure, renal protection, and improved myocardial energetics. The Phase 3 EMPULSE trial ( EMPagliflozin in patients hospitalized for acUte heart faiLure who have been StabilizEd ) is evaluating the clinical benefit and safety of the SGLT2 inhibitor, empagliflozin, in ≈500 patients with or without diabetes hospitalized for AHF (both de novo and decompensated). The results of the SGLT2 inhibitor trials have markedly increased interest in the role of ketone bodies as therapy for ADHF. SOLOIST-WHF Trial - S otagliflozin vs placebo in ADHF. M etformin and GLP-1 (glucagon-like peptide 1) agonists, are often held in the inpatient setting to avoid hypoglycemia and lactic acidosis, but reinitiation should not be forgotten before discharge because of long-term benefits including improved remodeling, improved myocardial glucose utilization, and cardiac fibrosis. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Voors AA, Metra M,  et al ; SOLOIST-WHF Trial Investigators.  Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med . 2021; 384:117–128. doi : 10.1056/NEJMoa2030183

30. SERCA 2 SERCA2a Gene Therapy  intracoronary administration of an adeno-associated virus type 1 encoding sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a). This gene therapy strategy initially proved to have an acceptable safety profile in and was tested in terms of efficacy in phase II trials. The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial included 39 patients with AHF in total. It was documented that gene delivery was superior to placebo in terms of symptomatic improvement, exercise tolerance, biomarkers and haemodynamic profile in the 6-month follow-up period. However, the larger CUPID II trial that followed, with 250 HF patients, could not replicate the results from the initial CUPID trial, as the administration of AAV1/SERCA2a did not significantly reduce HF-related endpoints, such as HF hospitalisations and worsening HF compared with placebo

31. Treating Iron deficiency Moderate-to-severe anemia (hemoglobin <12 g/dL in men or <11 g/dL in women) is an independent predictor of death in patients with AHF. AFFIRM-AHF trial - (Ferric Carboxymaltose in Iron-Deficient Patients Discharged FCM in CHFAfter Acute Heart Failure) - decreased the risk of HF hospitalizations within up to 52 weeks.

32. Oxygen therapy and Noninvasive ventilation Supplemental oxygen therapy in normoxemic patients results in increased reactive oxygen species and paradoxical oxidative stress as a result of hyperoxia-mediated coronary and systemic vasoconstriction. Supplemental oxygen therapy in normoxemic patients results in increased reactive oxygen species and paradoxical oxidative stress as a result of hyperoxia-mediated coronary and systemic vasoconstriction. In HF cohorts, hyperoxia secondary to oxygen supplementation in normoxemia was associated with impaired diastolic function, increased left ventricular filling pressures, and increased systemic vascular resistance resulting in decreased cardiac output. The 3CPO trial (three interventions in Cardiogenic Pulmonary Oedema) randomized 1069 patients with acute cardiogenic pulmonary edema to standard oxygen therapy, continuous positive airway pressure, or noninvasive intermittent positive pressure ventilation. Although there was no difference in 7-day mortality between the treatment groups, patients treated with NIV had greater dyspnea relief and other improved metabolic markers. Physiologically, NIV can cause decreased preload and afterload and reduced intrapulmonary shunting, although it is unclear if there are short- or long-term survival benefits. It should be used with caution in patients with isolated right ventricular dysfunction.

33. ADHF- Device therapy - IABP The IABP is inserted percutaneously via the femoral artery with the balloon placed in the proximal descending aorta. Inflation of the balloon is synchronized with diastole producing diastolic aortic pressure augmentation that increases coronary artery pressure as well as mean arterial pressure and thus improves coronary, cerebral, and peripheral perfusion. Deflation then occurs before systole to lower aortic end-diastolic and systolic pressures with a resulting reduction in ventricular afterload and myocardial oxygen consumption and improvement in cardiac output (CO). The Intra-Aortic Balloon Counterpulsation in Acute Myocardial Infarction Complicated by Cardiogenic Shock (IABP-SHOCK II) trial showed no mortality reduction of IABP compared with medical therapy in the setting of AMI complicated by cardiogenic shock.

34. ADHF- Device therapy - Impella The Impella is a percutaneous VAD placed across the aortic valve that provides non-pulsatile blood flow by unloading the left ventricle (LV) and delivering blood to the ascending aorta through a trans-axial pump. It works independent of cardiac rhythm. Results from PROTECT II trial showed that the 30-day incidence of major adverse events was not statistically different for patients with IABP or Impella 2.5 (35.1% with Impella vs. 40.1% with IABP, p=0.227) although a trend for decreased adverse events at 90 day with Impella use was noted. Several other registries have shown greater survival with pre-PCI Impella insertion compared with pre-PCI IABP and/or pharmacotherapy alone. The use of Impella in PCI with cardiogenic shock and in cardiogenic shock with multiorgan failure is a class I indication according to the 2013 ACCF guidelines

35. ADHF- Device therapy - ECMO The Extracorporeal Life Support Organization (ELSO) registry reported 27% survival to hospital discharge with ECMO to support CPR in adults after cardiac arrest. More recent studies have shown 49% survival with either mechanical support devices or ECMO in cardiogenic shock.

36. ADHF – Device therapy - LVADs Durable left ventricular assist devices (LVADs) have become the most commonly used surgical therapy for advanced heart failure, and their use is now uncoupled from transplant candidacy. 128  Historically LVADs were indicated only as a so-called bridge-to-transplantation (BTT) to ensure survival until a donor organ became available. 129  Since publication of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial in 2001 that demonstrated improved survival in advanced HF patients ineligible for transplantation treated with LVAD vs. optimal medical therapy, LVADs have become increasingly approved as a more permanent ‘destination therapy’ (DT). 128  With the advent of continuous flow devices, the 1-year survival of patients with LVADs is now in excess of 80%. 130  The vast majority of modern LVADs are continuous-flow (CF) devices. These pumps may be either centrifugal ( HeartWare HVAD, Medtronic; HeartMate III, St. Jude Medical) or axial-flow (HeartMate II, St. Jude Medical). Modern LVADs are driven electrically via a percutaneous driveline connected to a portable controller and external power source, typically batteries that are replaced every 4–18 h, and last >10 years. 131  Currently, >2500 pumps are implanted in the U.S. every year, and it is clear that a linear increase has taken place since 2006. 132  Early referral for evaluation in an LVAD or transplant center is essential. Physicians should strongly consider patients who remain in NYHA III despite optimal medical therapy; other factors that may guide decision-making include inability to walk one block, hyponatremia, significant renal dysfunction, frequent HF admissions, or lack of response to CRT

37. When to discharge patients of ADHF ? Hemodynamically stable – no inotropic support and stable oral dose of diuretics. Can tolerate GDMT BNP < 200 pg /ml [REDHOT trial - BNP < 200 pg /ml associated with 90 day mortality of <2%]. Adverse factors - hyponatremia, worsening renal function, hypotension (particularly intolerant of GDMT), anemia , persistently elevated BNP, and ventricular dyssynchrony .

38. Joyce N. Njoroge. Circulation Research. Pathophysiology and Therapeutic Approaches to Acute Decompensated Heart Failure, Volume: 128, Issue: 10, Pages: 1468-1486, DOI: (10.1161/CIRCRESAHA.121.318186) © 2021 The Authors. Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

39. Pathophysiology of ADHF

40. ACUTE DECOMPENSATED HEART FA I LURE ACUTE HEART FAILURE Acute heart failure (AHF) is a relevant public health problem causing the majority of unplanned hospital admissions in patients aged of 65 years or more. AHF was historically described as a pump failure with downstream hypoperfusion and upstream congestion. AHF remain poor with 90-day rehospitalization and 1-year mortality rates reaching 30% U nd e r s tandin g a c ut e h e art failur e : patho1lh ys i o l ogy and dia g no s i s . E ur H e art J S uppl ( 201 6)

41. There are over 1 million hospitalizations per year for HF in the United States and Europe with an astounding 24% readmission rate within 30 days and 50% within 6 months. 3–5  Patients with readmission for cardiovascular disease within 90 days of discharge for HF hospitalization have a higher risk of mortality independent of the exact amount of time from discharge. 6  One in 6 patients admitted for HF die within 30 days of hospitalization. 7 , 8  These grim statistics for ADHF in contrast to the promising future of chronic HF management prompt the need for a better understanding of the distinct entity of ADHF. Additionally, suboptimal medical management of ADHF often results in persistent congestion upon hospital discharge and subsequent increased risk of recurrent hospitalization, morbidity, and mortality. 9

42. Common Factors Precipitating HF Hospitalization With Acute Decompensated HF ACS Uncontrolled hypertension AF and other arrhythmias Additional cardiac disease (eg, endocarditis) Acute infections (eg, pneumonia, urinary tract) Nonadherence with medication regimen or dietary intake Anemia Hyper- or hypothyroidism Medications that increase sodium retention (eg, NSAID) Medications with negative inotropic effect ( eg , verapamil)

43. ACUTE DECOMPENSATED HEART FAILURE SYSTOLIC AND DIASTOLIC HEART FAILURE Heart failure occurs when the heart is either unable- -to Pump blood during systole (HFrEF) or - to Fill with blood during diastole (HFpEF) Sy1to l k Hurt F.allu,e Hotma l Hf.art Oia,to l ic HHrt F.ailu r e

44. ACUTE DECOMPENSATED HEART FAILURE CIRCLING THE DRAIN Btood o I

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46. ACUTE DECOMPENSATED HEART FAILURE BEDSIDE TEST - ECG I· I i/\_, . .- - l " ' ''" - - r- - "' • . - - n --- . "- '- - . avt.,...., I"' ;,- ..,; ,......h I fl I

47. ACUTE DECOMPENSATED HEART FA I LURE ECG - INFERIOR STEMI WITH RV INFARCTION , ST elevation In V1 - the on l y standard ECG lead that looksdirectly at the right ventricle. ST elevation in leadIll > lead II - use lead Ill i s more " rig h twar d lac i ng " than lead II andhence more sensitive to the injury currenl produced by lhe right ventric l e . R i ght ven lr lcu l ar I nfarction complicates up to 40% of I nferior STEMls. Pat i ents wilh RV infarction are very pre l oad sensitive (due to poor RV contractility) and can develop severe hypotenslon In response t . o nitrates or other preload • reduclngagents . Hypotension In right ven t ricu l ar i n farc tion is treated with cautious fluid l oading , and nitrates are contraindicated.

48. Eugenio Picano et al. J Am Coll Cardiol Img 2018; 11:1692-1705.

49. ACUTE DECOMPENSATED HEART F/°1JLURE IMAGING IN AHF CXR ECHOCARDIOGRAPHY LUNG ULTRASOUND {heart failure)

50. - -

51. ACUTE DECOMPENSATED HEART FAILURE INITIAL EVALUATION - LABORATORY TESTING BNP Troponin FBC U/E's Supplementary Testing

52. ACUTE DECOMPENSATED HEART FA I LURE BNP BNP Cutoff of 100 ng/ I , BNP had a sens i tivity 90%, spec i ficity 76% , negat i ve predictive 79% , and positive predictive value of 89%. In th i s capacity , BNP is highly useful to exc l ude AHF negative like l ihood ratio of BNP at 100 pg/ml is 0. 1 3 -L R < 100 ng/1 strongly suggestive against AHF >400ng/l suggestive of AHF exacerbation However may be falsely elevated in – renal disease, atrial fibrillation, pulmonary HTN May be falsely low in – obese patient, HFpEF High BNP increased Mortality in men

53. ACUTE DECOMPENSATED HEART FAILURE TROPONIN Useful for risk stratification ? underlying primary cause of AHF (cardiac strain, ischaemia, infarction) elevated trop = increased in hospital mortality 8% versus 2.7 % if Neg Trop increased re-hospitalisation rate increased risk at death at 90 days

54. ACUTE DECOMPENSATED HEART FA ILURE FBC, U/E,S + SUPPLEMENTAL TESTS Anaemia- HB under 8 (in IHD under 10)- improve Oxygen carrying capacity by transfusion Sodium and Renal function (AKl?-end organ damage) Liver function (end organ damage) Thyroid function (cause of failure?) Calcium - low? improves cardiac contractility amyloidosis, pheochromocytoma etc as rare causes.

55. ACUTE DECOMPENSATED HEART FAILURE MANAGEMENT OF PRELOAD Diuretics Fluid restriction Venodilators Aldosterone agonists Beta- blockers Maintenance of sinus rhythm and atrial systolic contribution Pacing to maintain AV synchrony

56. ACUTE DECOMPENSATED HEART FAILURE MANAGEMENT OF AFTERLOAD Left ventricle Vasodilators ACE- inhibitors Beta- blockers Right ventricle Normoxia Normocapnea Avoidance of excessive postive respiratory pressures Pulmonary vasodilators

57. ACUTE DECOMPENSATED HEART FA I LURE MANAGEMENT OF CARDIAC CONTRACTILITY Ionotropes Dobutamine Levosimendan Digoxin Card i ac resychronisation Support i ve hormones and micronutrients (cort i so l , insu l in, calcium, glucagon, t h yroxine, thiamine etc

58. ACUTE DECOMPENSATED HEART FAILURE DIAGNOSIS AND INITIAL PROGNOSTIC EVALUATION - BE A CHAMP

59. ACUTE DECOMPENSATED HEART FAILURE 5 DISTINCT TREATMENT GROUPS Acute heart failure syndrome (AHFS) spectrum can be divided into 5 groups as regards therapeutic management: Dyspnoea +/.congestion with elevated systolic blood pressure (SBP)>140 mmHg, usually with abrupt onset APO (most frequent type) Dyspnoea + /- congestion with normal SBP 100-140 mmHg , usually with gradual onset predominant systemic oedema and milder APO Dyspnoea +/-congestion with low SBP <100 mmHg, with predominant cardiogenic shock or end-stage cardiac failure (most fatal type) Dyspnoea + /- congestion with signs of ACS such as chest pain Isolated RV failure usually without APO

60. ACUTE DECOMPENSATED HEART FA I LURE

61. ACUTE DECOMPENSATED HEART FA I LURE VASODILATORS Safety of high dose initia l GTN: 800 mcg(2x0.4mg sl tab) GTN sl if BP>180mmHg 1200 mcg(3x0.4mg sl Tab) for BP>200 mmHg only 3/75 incidence of Hypotension Initial GTN dose iv 50-100mcg/min up to 400mcg/min for 2 min max with Physician in attendance Vasodilators should be used with extreme caution in patients with significant mltral or aortic stenosis. A CE inbitors are currently not recomended

62. ACUTE DECOMPE N SATED HEART FA I LURE VASODILATORS No robust evidence confirming their beneficial effects. They have d u a l benefit by decreas i ng venous tone (to op ll mize preload) decreas , ng arteria l tone (decrease alterload). they may a l so increase sttoke volume. Vasodilators are especially useful in pat i ents with hypertensive A HF , whereas In SB P <90 mmHg (or with

63. ACUTE DECOMPENSATED HEART FAILURE INOTROPIC AGENTS Oigoxin • no lmprovemenl over p l acebo In one (older) study Dopamine was compared withn0<epinephrine In the treatment of various shock patients. lncteased Mortality A subgroup analysis suggesled that norepinephrine would have fewer side effects and lower mortallty Norepinephrine 1stchoice bu1 increasing Oxygen demand In Heart 0e 8ackef O • BlsklnP, Oovriendt J. MadiC, Cllochrad0 , AkJGooa C.BtM&eur A, Dofranoo P , Goltlgni,es P, Vlncec,t J • L Comparison of dopafflif'le andnorep,,inephrine in metreatmen1of shock., N EngJJ Mod 2010:362 nS-789 ,

64. ACUTE DECOMPE N SATED HEART FA I LURE INOTROPES

65. ACUTE DECOMPENSATED HEART FAILURE DIGOXIN Digoxin is if at all indicated in patients with AF and rapid ventricular rate (>110 bpm) boluses of 0.25-0.5 mg i.v. if not used previously

66. ACUTE DECOMPENSATED HEART FAIL URE Pharmacologic therapy aims to improve organ perfusion by increasing cardiac output and blood pressure. fluid challenge, inotropic agent (Dobutamine)and a vasopressor (noradrenaline) as needed. immediate Coronary Angiogram recommended

67. ACUTE DECOMPENSATED HEART FA I LURE DIURETICS Diuretics are a cornerstone in the treatment or patients with AHF and signs or fluidoverload and congestion. Diuretics increase renal salt and waler excretion and have some vasod1latory effect. In patients with AHF and signs or hypoperfusion, diuretics should be avoided before adequate perfusion 1s attained. The inihal approach to congestion management invo l ves i.v. diuretics with the addition or vasodilators for dyspnoea re l ief If blood pressure allows . Options include dual nephron blockade by loop diuretics (i.e. furosem1de or torasem1de) with th1az1de diuretics or natriurellc doses of MRAs Administration of furosemlde at 2.5times theprevious oraldose resulted in greater improvement 1n dyspnoea, larger weight change and fluid loss at the cost of transient worsening In renal function. patients with new-onset AHF or those with chronic HF without a history of renal failure and previous use of diuretics may respond to I.v. boluses of 20-40 mg

68. ACUTE DECOMPENSATED HEART FAILURE FURUSEMIDE In Patient with Evidence of Fluid overload Diuretics to be started early in ED stay In the ' high-dose' arm of the DOSE study, administration of furosemide at 2.5 times the previous oral dose resulted in greater improvement in dyspnoea, larger weight change and fluid loss at the cost of transient worsening in renal function i.v. Furusemide should be given at least the same or larger the daily po dose to improve outcomes. starting does for Furusemide in de move patients 20-40mg iv Felke r GM , LeeKl, Eklll DA. Rectlleld MM,SteVenSOn LW, GoldsmrlhSR.LeWinter MM, OOfvl · ,!il A. Roul011111JL . orm EO.A11,$1tom KJ, Horn.ancloz AF,McN\llfySE.Vo&ll:equ,oz EJ . Kklury AG,CoonHH.GivertzMM,SemlgranMJ,San.BA,Mcts.cette AM,Braunwald E. O'Connoir CM. OiutObC Mr3 1 og In pabents Vffll'I .teutO docompenso l od hOlli!t f.31fu r o . N Engl J Med 2011 · 3&1 : 797--80S ,

69. ACUTE DECOMPENSATED HEART FA I LURE OXYGEN In AHF, oxygen should not be used routinely in non­ hypoxaemic patients, as it causes vasoconstriction and a reduction in cardiac output. In COPD, hyperoxygenation may increase ventilation­ perfusion mismatch, suppressing ventilation and leading to hypercapnia. During oxygen therapy, acid-base balance and transcutaneous Sp02 should be monitored. Pal1t JH , Balmaln S , Beny C, Motl«I JJ , M e Mutray JJV. Potootlaly detrlrnenlll l can:llo9fr9'1s o, oltY9'(1f'l in p;allen15wilh c.h lol\ ventric:\Aat t:Y$10llc dy&f\l lon, Heart 201ct96 · S33-538.

70. ACUTE DECOMPENSATED HEART FA I LURE OPIATES ... RATHER USE BENZO ' S Opiates relieve dyspnoea and anxiety. In AHF, routine use of opiates is not recommended and they may only be cautiously considered in patients with severe dyspnoea, mostly with pulmonary oedema. Dose-dependent side effects include nausea, hypotension, bradycardia and respiratory depression (potentially increasing the need for invasive ventilation). There are controversies regarding the potentially elevated mortality risk in patients receiving morphine Peacock WF , Holatl<ler JE,CMefeks 08. Lo,,at#\ M , Fonarow G, Emerman CL Mofpttine and OUIQOmOS In DCVIO docomponsotod h0.,1'1 t ivre ' ;,n ADI- I ERE al\lltys i s. Elfllflf9 Mod J 2008 · 25 · 205- 209.

71. ACUTE DECOMPENSATED HEART FA ILURE LEVOSIMENDAN "Calcium-sensitiser" works by increasing myocardial contractility by sensitising the cardiac myocytes to calcium In the REVIVE study levosimendan, when added to standard therapy, resulted in a more rapid symptomatic improvement when compared to placebo with standard therapy; increased risk of hypotension and dysrhythmias associated with its administration

72. ACUTE DECOMPENSATED HEART FAILURE VENTILATORY ASSISTANCE Non-invasive ventilation (NIV) refers to CPAP ; or bilevel positive airway pressure (BiPAP) non-invasive pressure support ventilation (NIPSV), where IPAP - EPAP (:PEEP) reflects the amount of pressure support delivered. CPAP reduces mortality (RR 0 . 64) and need to intubate (RR 0 . 44) , with no effect on incidence of new Ml. BiPAP reduces need to intubate (RR 0.54) , but not mortality or new Ml. Thus CPAP preferred in APO due to AMI/ ischaemia. Note 3CPO trial findings showed negative effect of NIV compared to standard medical therapy alone , but may be explained by sickest patients were excluded, low overall rates of intubation, ischaemia and mortality (i.e. their patients were different) , and considerable treatment group crossover after first 2 hours.

73. ACUTE DECOMPENSATED HEART FAILURE Non-invasive positive pressure ventilation includes both CPAP and bi-level positive pressure ventilation (PPV). Bi-level PPV also allows inspiratory pressure support that improves minute ventilation and is especially useful in patients with hypercapnia , most typically COPD patients. Non-invasive positive pressure ventilation includes both CPAP and bi-level positive pressure ventilation (PPV). Bi-level PPV also allows inspiratory pressure support that improves minute ventilation and is especially useful in patients with hypercapnia , most typically COPD patients. Non-invasive positive pressure ventilation reduces respiratory distress and may decrease intubation and mortality rate In one study (Emerg Med J 2004 ; 21 : 155-161) survival to hospital discharge was improved with CPAP (1O mm/Hg) over BiPap (lpap 15 Epap 5) and conventional therapy NIV

74. ACUTE DECOMPENSATED HEART FA I LURE EARLY REVASCULARISATION THERAPY IN ISCHAEMIC ECG The SHOCK Tria l showed a 67°/ci relative improvement in l ong-term survival, measured at 6 years, for pat i ents managed wit h rapid revasc u larization. Ro l e of revasculariza t io n is not clear for patients presenting wit h fai l ure without obvious acute ischemia.

75. ACUTE DECOMPENSATED HEART FAILURE ULTRAFILTRATION Ultrafiltration is similar to hemodialysis; however, it focuses on fluid removal rather than solute exchange. can be accomplished through a smaller-diameter catheter than hemodialysis, but it generally requires a peripherally inserted central catheter (PICC) line The UNLOAD trial evaluated ultrafiltration versus IV diuretic therapy in patients with functioning kidneys, and it demonstrated that ultrafiltration removes a larger volume of fluid and is associated with a greater reduction in 90-day resource utilisation compared to diuretic therapy.

76. ACUTE DECOMPENSATED HEART FAILURE BRIDGING THERAPY TO HEART

77. ACUTE DECOMPENSATED HEART FAILURE OPIATES Opiates relieve dyspnoea and anxiety. In AHF, routine use of opiates is not recommended only be cautiously considered in patients with severe dyspnoea, mostly with pulmonary oedema. Dose-dependent side effects nausea , hypotension , bradycardia and respiratory depression (potentially increasing the need for invasive ventilation). There are controversies regarding the potentially elevated mortality risk in patients receiving morphine

78. ACUTE DECOMPENSATED HEART FA I L URE DEVICE THERAPY - R RT Renal Replacement Therapy - routine use of u l trafi l tration is not recommended Criteria for initiation of rena l rep l acement therapy in patients w i th refractory vo l ume overload: o li guria unresponsive to fluid resuscitation measures, severe hyperkalaemia (K+ >6.5 mmol/L) , severe acidaemia (pH <7.2) , serum urea level >25 mmo l /L (150 mg/dl) and serum creatinine >300 µ mol/L (>3.4 mg/dl)

79. ACUTE DECOMPENSATED HEART FA I LURE DEVICE THERAPY - MECHANICAL ASSIST DEVICES Intra - aortic ba ll oon pump i n cardiac shock otherwise no good ev i dence IABP did not i mprove outcomes in pat i ents suffer i ng from AMI and cardiogenic shock - ( I ABP-SHOCK II t r ia l ) L eft Ventricu l a r assist dev i ces (LVAD) (MCS) may be used as a ' b r idge to decision ' or longer ter m in se l ected pat i ents

80. ACUTE DECOMPENSATED HEART FA ILURE OTHER INTERVENTIONS In patients with AHF and pleural effusion, pleurocentesis with fluid evacuation may be considered if feasible in order to alleviate dyspnoea. In ascites, ascitic paracentesis with fluid evacuation may be considered in order to alleviate symptoms. reduction in intra-abdominal pressure, partially normalizes the transrenal pressure gradient, thus improving renal filtration.

81. ACUTE DECOMPENSATED HEART FAILURE DISPOSITION The criteria for ICU/CCU admission include any of the following: need for intubation (or already intubated) signs/symptoms of hypoperfusion oxygen saturation (SpO2) <90% (despite supplemental oxygen) use of accessory muscles for breathing, respiratory rate >25/min heart rate <40 or >130 bpm, SBP <90 mmHg.

82. ACUTE DECOMPENSATED HEART FA I LURE CLINICAL VIGNETTE - OUTCOME OF YOUR PATIENT The middle-aged man with hypertensive decompensated heart failure with acute pulmonary oedema, was started immediately on BiPAP to support his breathing, and he responded well. Bedside pulmonary ultrasound showed 8-lines, confirming the diagnosis of pulmonary oedema. He was started on a high-dose nitroglycerin drip, which resulted in a significant improvement in his respiratory symptoms. He received IV diuresis and was admitted to the ICU for further management.

83. The prevalence of HF was 37.7 million cases As per estccording to GBD team in 2010 of prevalent HF worldwide, leading to an average of 4.2 years lived with this disability for each patient, but data on the global incidence of AHF were not reported 14 . Data on annual hospitalizations for HF are only available for the USA and Europe and exceed 1 million in both regions 4 , 5 . Among these hospitalizations, >90% were due to symptoms and signs of fluid accumulation (indicating AHF). In addition, up to one in four patients (24%) are readmitted within 30 days, readmission rates in the first 3 months after hospitalization for AHF may reach 30% in the USA and in other countries 4  and one in two patients (50%) are readmitted within 6 months 4 , 5 . Recurrent fluid accumulation in patients with HF has uniformly been associated with worse outcomes independent of age and renal function 15 . In multiple studies of the 30-day to 90-day post-discharge period, ~25–30% of patients with AHF are readmitted during this time frame 16 , 17 , 18 , 19 , 20 . However, a substantial proportion of these patients are readmitted for a non-HF-related cause 21 , 22 . Medical comorbidities precipitate rehospitalization and, when poorly managed, contribute to worsening HF over time 22 . Psychosocial factors such as anxiety, depression, cognitive impairment and social isolation also confer increased risk of unplanned recurrent readmission or death of patients following hospitalization for AHF 23 .