Prof. U. C. SAMAL provides an overview of acute decompensated heart failure and what is new in the field. He discusses similarities and differences between acute myocardial infarction and acute heart failure syndromes. Mortality rates are high for both conditions, though clinical benefits of interventions are greater for acute MI based on published clinical trials. The document then discusses definitions and classifications of acute heart failure syndromes, as well as guidelines for diagnosis and treatment from ESC and ACC/AHA. Biomarkers that can help with diagnosis, prognosis, and guiding therapy are also summarized.
The two major causes of acute right ventricular (RV) failure in ICU patients are acute cor pulmonale (ACP) during acute respiratory distress syndrome (ARDS) and ACP during acute massive pulmonary embolism (PE).
The increase in pulmonary vascular resistance (PVR) in ARDS can be secondary either to « structural » mechanisms related to lung injury per se and to « functional » mechanisms related to the effects of mechanical ventilation with positive end expiratory pressure (PEEP). The latter mechanism is enhanced when PEEP overdistends more than it recruits lung volume and when tidal volume (VT) is high. The recommended protective ventilation with low VT and PEEP adjusted to driving pressure can also reduce the RV afterload. A reduced central blood volume can also play a role in the increase in PVR (extension of the West’s zone 2). In this case, volume administration can reduce the PVR and improve the RV function. Finally, prone positioning also exerts a beneficial effect on RV afterload through a decrease in PVR (lung recruitment, decrease in hypoxic vasoconstriction, increase in central blood volume with decrease in the extent of zone 2).
In acute PE, RV dysfunction is associated with poor outcome. Thrombolytic treatment, which is indicated in cases of severe PE with shock, prevents hemodynamic decompensation in patients with intermediate risk PE, but also results in increased risk of severe hemorrhage and stroke. In the case of PE with low cardiac output and no RV dilatation, fluid administration can be indicated to improve cardiac output. In cases of systemic arterial hypotension, vasopressors such as norepinephrine can be indicated to restore adequate RV perfusion pressure. Indication of inotropic agents such as dobutamine, which improves the RV-pressure artery coupling should be evaluated individually. Surgical pulmonary embolectomy can be indicated when the thrombolytic therapy is contra-indicated in acute PE with shock.
The two major causes of acute right ventricular (RV) failure in ICU patients are acute cor pulmonale (ACP) during acute respiratory distress syndrome (ARDS) and ACP during acute massive pulmonary embolism (PE).
The increase in pulmonary vascular resistance (PVR) in ARDS can be secondary either to « structural » mechanisms related to lung injury per se and to « functional » mechanisms related to the effects of mechanical ventilation with positive end expiratory pressure (PEEP). The latter mechanism is enhanced when PEEP overdistends more than it recruits lung volume and when tidal volume (VT) is high. The recommended protective ventilation with low VT and PEEP adjusted to driving pressure can also reduce the RV afterload. A reduced central blood volume can also play a role in the increase in PVR (extension of the West’s zone 2). In this case, volume administration can reduce the PVR and improve the RV function. Finally, prone positioning also exerts a beneficial effect on RV afterload through a decrease in PVR (lung recruitment, decrease in hypoxic vasoconstriction, increase in central blood volume with decrease in the extent of zone 2).
In acute PE, RV dysfunction is associated with poor outcome. Thrombolytic treatment, which is indicated in cases of severe PE with shock, prevents hemodynamic decompensation in patients with intermediate risk PE, but also results in increased risk of severe hemorrhage and stroke. In the case of PE with low cardiac output and no RV dilatation, fluid administration can be indicated to improve cardiac output. In cases of systemic arterial hypotension, vasopressors such as norepinephrine can be indicated to restore adequate RV perfusion pressure. Indication of inotropic agents such as dobutamine, which improves the RV-pressure artery coupling should be evaluated individually. Surgical pulmonary embolectomy can be indicated when the thrombolytic therapy is contra-indicated in acute PE with shock.
Heart Transplantation in India, Delhi by expert surgeon Dr. Kewal Krishan. If you have know more information visit us www.kewalkrishan.com or call 91-9650300500 . Patients should receive maximal medical therapy before being considered for transplantation. They should also be considered for alternative surgical therapies including CABG, valve repair / replacement, cardiac septalplasty, etc
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
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Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
1. Prof. U. C. SAMAL
MD, FICC, FACC, FIACM, FIAE, FISE, FISC, FAPVS
Ex- Prof. Cardiology & Ex-HOD Medicine
Patna Medical College, Patna, Bihar
Past President, Indian College of Cardiology
Permanent & Chief Trustee, ICC-Heart Failure Foundation
National Executive Member, Cardiological Society of India
President, CSI Bihar
Acute Decompensated Heart Failure :
What Is New ?
1
2. AHFS : NOT VERIFIED
Similarities and differences between acute MI & AHFS in
hospitalization in the US
Incidence 1 million per year 1 million per year
Mortality
Pre hospitalization
In hospital
After discharge [ 60-90 d]
High
3-4%
2%
?
3-4%
10%
Myocardial injury Yes Likely
Pathophysiological target Clearly defined
[coronary thrombosis]
Uncertain
Clinical benefits of
interventions in published
clinical trial
Beneficial Minimal / no benefit or
deleterious compared with
placebo
ACC / AHA recommendation LEVEL A NONE
2
3. Acute Heart Failure Syndrome(s)
• Acute heart failure (AHF) is defined as a rapid
onset or change in the signs and symptoms of
HF, resulting in the need for urgent therapy.
• Symptoms are primarily the result of severe
pulmonarycongestion due to elevated left
ventricular (LV) filling pressures(with or without
low cardiac output).
• AHFS can occur in patientswith preserved or
reduced ejection fraction (EF).
• Concurrentcardiovascular conditions such as
coronary heart disease (CHD),hypertension,
valvular heart disease, atrial arrhythmias, and/or
noncardiac conditions (including renal
dysfunction, diabetes,anemia) are often present
and may precipitate or contributeto the
pathophysiology of this syndrome 3
ESC Guidelines
5. Proposed classification for patients who present with acute
heart failure syndromes
ACCF/AHA
stage
Explanation of stage
Worsening
chronic HF
(75%)
Stage C C: structural heart disease with
prior or current symptoms of
HF
Advanced HF
(5%)
Stage D D: refractory HF requiring
specialized interventions
De novo HF
(20%)
Stage B most
common, but
also Stage A
Also neither A
nor B
B: structural heart disease but
without signs or symptoms of
HF
A: at high risk for HF but
without structural heart disease
or symptoms of HF
5
Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793
6. • diuretics
• ultrafiltration
Vasodilators
• nitroglycerin
• nesiritide
• nitroprusside
INOTROPES
• dobutamine
• dopamine
• levosimendan
• nitroprusside
Fluid retention or redistribution ?
“dry out” “warm up & “dry out”
Assessment of hemodynamic profile : therapeutic
implications
Adapted from Stevenson L W, Eur Heart j
6
7. HF Management:
Principal changes from the 2008 guidelines
o An expansion of the indication for mineralocorticoid
receptor antagonists (MRAs)
o A new indication for the sinus node inhibitor
Ivabradine
o An expanded indication for cardiac resynchronisation
therapy (CRT)
o New information on the role of coronary
revascularisation in HF (PCI / CABG)
o Recognition of the growing use of ventricular assist
devices (LVAD)
o The emergence of transcatheter valve interventions
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure
7
8. Linking Short- term intervention with long-term benefit:
What is needed?
Better understanding of Acute Heart Failure pathophysiology
MORTALITY
• Myocardial injury [Tn
release]
• Renal dysfunction [CRS]
• Liver dysfunction
PREVENTION OF END-
ORGAN DAMAGE
Congestion
Viable but
dysfunctional
myocardium
Neurohormonal
& inflammatory
activation
Mechanisms which
can be targeted
Metabolic
factors
Hemodynamic
deterioration
[↑LVFP,↓ CO, ↓ PERFUSION]
Vascular resistance
/stiffness ↑
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 Reviewed by Ponikowski
9. Neurohormones
Norepinephrine
Renin
Angiotensin II
Copeptin
Endothelin
Vascular system
Homocysteine
Adhesion molecules
(ICAM, P-selectin)
Endothelin
Adiponectin
C-type natriuretic
peptide
Inflammation
C-reactive protein
sST2
Tumor necrosis
factor
FAS (APO-1)
GDF-15
Pentraxin 3
Adipokines
Cytokines
Procalcitonin
Osteoprotegerin
Myocardial stress
Natriuretic
peptides
Mid-regional
pro-adrenomedullin
Neuregulin
sST2
Myocardial injury
Cardiac troponins
High sensitivity cardiac troponins
Myosin light-chain kinase 1
Heart-type fatty acid binding
protein
Pentraxin 3
Matrix and cellular
remodeling
Galectin-3
sST2
GDF-15
MMPs
TIMPs
Collagen
propeptides
Osteopontin
Cardio-renal syndrome
Creatinine
Cystatin C
NGAL
ß-Trace protein
Oxidative stress
Oxidized LDL
Myeloperoxidase
Urinary biopyrrins
Urinary and plasma
isoprostanes
Plasma malondialdehyde
HF as a systemic illness & organ cross-talk
9
Nature Review Cardiology
Vol.9 June 12 pg 349
And organ
cross talk
10. Using Biomarkers across the ARC of Heart Failure Hospitalisation
Therapy
decisions
Measure delta
change
Look for
decline
Obtain
baseline
Monitor
therapy
Present to
ED
Decisions
on triage
Determine
prognosis
In-hospital
treatment
Discharge
Outpatient
follow-up
Therapy
decisions
Nov 1, 2013 - Dr Yancy interviews Drs Pang and Januzzi on the use of biomarkers ... Cardiac
Intensive Care Unit, Massachusetts General Hospital, Boston,
11. BNP Status
This pilot study demonstrates that home BNP testing is feasible and that trials using
home monitoring for guiding therapy are justifiable in high-risk patients. Daily weight
monitoring is complementary to BNP, but BNP changes correspond to larger changes
in risk, both upward and downward. (Heart Failure [HF] Assessment with B-type
Natriuretic Peptide [BNP] In the Home [HABIT]; NCT00946231)
12. Clinical RELEVANCE of promising novel biomarkers(AHFS)
Biomarker Diagnosis Prognosis Therapy guidance Cardiac
Production
NT-proBNP and
BNP
++++ ++++ ++ Solely
Serum Sodium + +++ ++ No
Serum Creatinine - +++ ++ No
MR-proANP +++ ++++ Likely similar to NT-
ProBNP/BNP
Solely
sST2 + ++++ ? Not Exclusively
Hs troponin-I
[EFFECT]
+ ++++ ? Solely
MR-proADM - ++++ ? No
Cystatin C - ++++ ? No
NGAL - ++++ ? No
GDF-15 - +++ ? Not Exclusively
β- Trace protein - +++ ? No
Gal-3 - +++ ? Not exclusively
CRP - ++ ? No
TNF-α - ++ ? No
IL-6 - ++ ? No
PTX3 - ++ ? Unknown
MPO - ++ ? Not exclusively
ET-1 - ++ ? Not exclusively
Copeptin - ++ ? No
PCT ++ ++ ++ No
12
Clinical Chemistry 58:1 127–138 (2012)
13. Pulmonary congestion evaluated by lung ultrasound
predicts admission in pts with HF
•97 HF outpts followed up during a
period of 106 ± 12 days
•21 hospitalizations for acute
pulmonary edema
•Multivariate analysis showed that
pulmonary congestion assessed by
lung ultrasound is strongest
predictor of hospital admission
Conclusion – in a HF outpt setting, B-lines assessment by lung
ultrasound may help to identify pts who are most likely to decompensate
14. The four chest areas per side considered for complete eight
zone lung ultrasound examination. These areas are used to
evaluate for the presence of interstitial syndrome. Areas 1 and
2 denote the upper anterior and lower anterior chest areas,
respectively. Areas 3 and 4 denote the upper lateral and basal
lateral chest areas respectively. 14
Echo windows
15. Multiple reflections
of ultrasound beams
ultrasound
beams
ultrasound
beams
Comet-tails
echographic
image
Normal
echographic
image horizontal
lines
Regular
intervalReverberations
Transducer Transducer
Edematous
Interlobular Septa
Normal Interlobular
Septa
Ultrasound Comet-Tail Images: A Marker Of Pulmonary Edema
A: Typical comet-tail artifacts: hyperechogenic, coherent
vertical bundles with narrow basis spreading from the
transducer to the further border of the screen. This
artifact is composed of multiple microreflections of the
ultrasound beam.
A B
B: Normal subject, with regular, parallel,
roughly horizontal hyperechogenic lines due to
the lung-wall interface.
Chest. 2005;127(5):1690-1695.
doi:10.1378/chest.127.5.1690
15
16. HF: Monitoring to predict/ prevent ADHF
admissions
• Devices: Externally applied Impedance Cardiography
(PREDICT study 211 pts)
• Internally placed devices measuring intra thoracic
impedance(PARTNER 2HF: CRT device with Impedance
monitoring): predicted subsequent admission for ADHF
• PA / LA/ LVEDP monitoring devices
Usefulness uncertain for mortality benefit
16
17. Heart Failure Risk Scores
Circ HF 2013
End point: Death/ transplant/ Assist device
• Heart Failure Survival Score(200pts):
– IHD, QRS>120ms, LVEF, Resting HR, mean BP, O2
consumption, ser Na
• Seattle Heart Failure model: (1100pts)
– Age, LVEF, NYHA class, SBP, Diuretic dose, Na+, uric
acid, ser. Chol., lymph. count
- Sex, IHD, QRS >120ms, ICD, CRT, betablockers, ACEI,
Statins, Allopurinol,
• SHOCKED predictor: (900pts):
Age>75, NYHA>II, AF, COPD, CKD, LVEF<20%, DM
• PACE: (900 pts) PVD, Age >70, Creatinine >2, EF < 20%,
• ADHERE registry( for acute mortality): SBP, Ser creatinine
and BUN
• Frankenstein: BNP , 6′WT
18. … We found that in a large, diverse contemporary HF
population, risk assessment was strikingly similar across all
LVEF categories. These data suggest that, although many HF
therapies are uniquely applied to patients with reduced
LVEF, individual prognostic factor performance does not seem
to be significantly related to level of left ventricular systolic
function.
(Circ Heart Fail. 2013;6:635-646.)
19. AHF Treatment Goals
Immediate [ED/ICU/CCU]
•Treat symptoms and restore oxygenation
•Improve hemodynamic and organ
perfusion
•Limit cardiac and renal damage
•Prevent thromboembolism
•Minimize length of ICU stay
Intermediate [in –hospital]
• stabilise pt and optimize treatment
strategy
•Initiate and up-titrate disease modifying
pharmacologic therapy
•Consider device therapy in appropriate
pts
• identify etiology and relevant
comorbidities
Pre-discharge and long term management
•Plan follow up stratergy
•Enroll in ds management programme,
educate and initiate life style adjustments
•Plan to up-titrate / optimise disease
modifying pharmacologic therapy
•Ensure assessed for appropriate device
therapy
•Prevent early readmission
•Improve symptoms
Http://www.Peerviewpress.Com/01/r286
20. 20
While pharmaceutical innovation has been highly successful in reducing mortality in chronic heart
failure, this has not been matched by similar success in decompensated heart failure syndromes.
Despite outstanding issues over definitions and end points, we argue in this paper that an
unprecedented wealth of pharmacologic innovation may soon transform the management of these
challenging patients. Agents that target contractility, such as cardiac myosin activators and novel
adenosine triphosphate-dependent transmembrane sodium-potassium pump inhibitors, provide
inotropic support without arrhythmogenic increases in cytosolic calcium or side effects of more
traditional agents. Adenosine receptor blockade may improve glomerular filtration and diuresis by
exerting a direct beneficial effect on glomerular blood flow while vasopressin antagonists promote
free water excretion without compromising renal function and may simultaneously inhibit myocardial
remodeling. Urodilatin, the renally synthesized isoform of atrial natriuretic peptide, may improve
pulmonary congestion via vasodilation and enhanced diuresis. Finally, metabolic modulators such as
perhexiline may optimize myocardial energy utilization by shifting adenosine triphosphate production
from free fatty acids to glucose, a unique and conceptually appealing approach to the management of
heart failure. These advances allow optimism not only for the advancement of our understanding and
management of decompensated heart failure syndromes but for the translational research effort in
heart failure biology in general.
22. Some new therapeutic agents for acute heart
failure and their potential targets
Agent For patients with these
clinical features
Diuretics, vasopressin
antagonists,
adenosine antagonists
Patients with signs of fluid
overload, high BNP
Vasodilators Normal to high SBP, high BNP
Inotropes Low SBP, signs of
Hypoperfusion
Renal preservation agents Renal dysfunction
Myocardial protection agents CAD, or ongoing ischaemia
22
23. Short- and long-term novel therapies for AHF syndromes
Short term Long term Both
Levosimendan [LIDO, CASINO, SURVIVE] ? ?
Nesiritide[ ASCEND-HF, ROSE-AHF]
Relaxin [RELAX-AHF]
Myosin Activators Omecamtiv Mecarbil
[ATOMIC-AHF]
RyR2 stabilizers/ rycals
Cinaciguat (UIT)
Adenosine regulating agents
Stresscopin
Istaroxime [HORIZON-HF]
Ularitide [TRUE-AHF, SIRIUS II, URGENT]
Urocrotins [UNICORN]
Hypertonic Saline
Ultrafiltration [RAPID-CHF, UNLOAD]
IABP
EECP [PEECH]
CAFA
IMT
Direct renin
Inhibitors (DRI)
[ASTRONAUT]
Macronutrients
Micronutrients
CRT/AICD
Adenosine Antagonists
[PROTECT, REACH UP rolofylline]
Vasopressin Antagonists
[EVEREST, TACTICS-HF]
Digoxin [DIG]
CD-NP
Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793 modified 2013
23
24. Newer Drugs/Devices and
targeted Therapy
Group A
• Managing fluids
• Preserving renal function
Group B
• Contractility
• Diastole/ Vascular Resistance
Group C
• Vasomotion
24
26. • Loop diuretics are an essential component of therapy for patients with acute decompensated
heart failure, but there are few prospective data to guide their use.
• In a prospective, double-blind, randomized trial, we assigned 308 patients with ADHF to
receive furosemide administered intravenously by means of either a bolus every 12 hours or
continuous infusion and at either a low dose (equivalent to the patient’s previous oral dose) or
a high dose (2.5 times the previous oral dose).
• DOSE Trial: Among patients with ADHF, there were no significant differences in patients’
global assessment of symptoms or in the change in renal function when diuretic therapy was
administered by bolus as compared with continuous infusion or at a high dose as compared
with a low dose.
• Low dose dopamine increases GFR and RBF. DAD-HF investigated 60 pts randomized to low
dose furosemide (continuous infusion 05 mg/hr) and 5 µg/kg/min per eight hours was found
effective in terms of dyspnoea relief with improved renal function. High dose combination
though was equally effective caused WRF . 20 mg/hr F + 5µg/kg/min Dopamine.
Furosemide
26
27. • The study tests the hypothesis that in patients admitted with acutely decompensated heart failure
(ADHF), achievement of adequate body hydration status with intensive medical therapy, modulated by
combined bioelectrical vectorial impedance analysis (BIVA) and B-type natriuretic peptide (BNP)
measurement, may contribute to optimize the timing of patient’s discharge and to improve clinical
outcomes.
• 300 ADHF pts underwent serial BIVA and BNP measurement. Therapy was titrated to reach a BNP
value of 250 pg/ml, whenever possible.
• Our study confirms the hypothesis that combined BNP/BIVA sequential measurements help to achieve
adequate fluid balance status in patients with ADHF and can be used to drive a ‘‘tailored therapy,’’
allowing clinicians to identify high-risk patients and possibly to reduce the incidence of complications
secondary to fluid management strategies.
27
28. Ultrafiltration
28
• UNLOAD(200pts):
• superior to diuretics as it reduces volume at a rate
more than 500 ml/hr which is Isotonic ultrafiltrate
(both salt and water)
• UF leads to a lower plasma renin, norepinephine
and aldosterone levels as compared to diuretics.
• CARESS study: High risk ADHF pts.: Similar outcome
for weight reduction, but higher rise in ser creatinine,
need for dialysis, and other adverse events…. UF a
new therapy as primary beyond diuresis resistance in
ADHF??
• AVOID HF: Ongoing trial (to be completed in 2016)
J Am Coll Cardiol 2012:59:2145-53
29. Investigational drugs in ADHF
Adenosine A1 receptor antagonist:
Rolofylline
• A1 receptor blockade results in afferent arteriolar
vasodilation which leads to improved GFR and enhanced
diuresis and natriuresis without activation of
tubuloglomerular feedback.
• Preserve GFR, improve diuresis, increase sodium
excretion by kidney.
• Phase 2 trial: better relief of dyspnoea and lesser renal
dysfunction.
• Phase 3 trial: PROTECT:2033 pts.: negative trial with
none of the primary end points significant and safety was
questioned due to neurological side effects: seizure and
stroke.
29
30. • Small studies have indicated that adenosine A1
receptor antagonists enhance diuresis and may
improve renal function in patients with chronic heart
failure or AHF.
• 2,033 AHF pts, volume overload, eCrCl 20 - 80
ml/min, and elevated BNP randomized (2:1) within 24
h of hospital presentation to rolofylline 30 mg/day or
intravenous placebo for up to 3 days.
• In this large, phase III clinical trial, the adenosine A1
receptor antagonist rolofylline did not prevent
persistent worsening renal function in AHF patients
with volume overload and renal dysfunction.
Rolofylline
30
SCr↑
BUN↑
31. •Effects of rolofylline on endpoints in relation to baseline renal function.
•The secondary morbidity/mortality endpoint, the risk of death or cardiovascular or renal
rehospitalization through day 60, was lower in the rolofylline group compared with the
placebo group only in patients with a baseline eCrCl 30 ml/min (hazard ratio: 0.64; 95% CI:
0.43 to 0.95), but not in the other subgroups
Rolofylline
31
33. Levosimendan enhances contractility by increasing responsiveness of myofilaments to calcium. The
cardiac myosin activator Omecamtiv mecarbil stimulates myosin adenosine triphosphatase
(ATPase), thereby increasing force generation. Istaroxime inhibits activity of plasma membrane
sodium-potassium ATPase and increases the activity of sarcoplasmic/endoplasmic reticulum
calcium ATPase (SERCA).
Mechanism of action of novel contractility-enhancing
medications.
Omecamtiv mecarbil
(Modified from Tavares M, Rezlan E, Vostroknoutova I, et al. New pharmacologic therapies for acute heart failure. Crit Care Med
2008; 36[Suppl]:S112-S120.)
33
Istaroxime
Levosimendan
34. Omecamtiv Mecarbil (OM) is a Novel Selective
Cardiac Myosin Activator
Malik Fl, et al. Science 2011; 331:1439-43
Teerlink JR, et al. Lancet 2011; 378:667-75; Cleland JGF, et al. Lancet 2011; 378:676-83
Mechanochemical Cycle of Myosin
•
• Increases duration of systole
• Increases stroke volume
• No Increase in myocyte calcium
• No change in dp/dtmax
• No increase in MVO2
ATOMIC-AHF Phase 2; 613 pts .X 48 hrs
random IV dose 115; 230; 310 ng/ml.
ATOMIC-AHF Phase 2; 613 pts .X 48 hrs
random IV dose 115; 230; 310 ng/ml.
COSMIC-HF chronic oral therapy;
oral alone or IV to oral transition.
COSMIC-HF chronic oral therapy;
oral alone or IV to oral transition.
Omecamtiv mecarbil increases the
entry rate of myosin into the tightly-
bound, force-producing state with
actin
“More hands pulling on the rope”
34
36. ATOMIC –AHF Omecamtiv Mecarbil Dyspnea Response
Teerlink J R ESC 2013, Symposium 4503
Response rate
ratio
1.02 1.02 1.41
95% CI [0.74 -1.42] [0.76 – 1.37] [1.02 -1.93]
Response rate ratio : ratio of response rate to placebo with each cohort
37. Omecamtiv Mecarbil : time dependent changes in
echocardiogram measures
Http://www.Peerviewpress.Com/01/r286
38. • Efficacy
– OM did not meet the 1° endpoint of dyspnoea relief
– Appeared to improve dyspnoea in Cohort 3
– Trends towards reduction of worsening HF
• Safety
– Overall SAE profile and tolerability similar to placebo
– Increase in troponin; no clear relationship to OM concentration
– Numerical imbalance in MIs in Cohort 3
– No evidence of pro-arrhythmia
• Pharmacology
– PK similar to healthy volunteers and stable HF patients
– Systolic ejection time significantly increased consistent with MOA
– Small fall in heart rate & rise in systolic BP at higher doses
ATOMIC- AHF Summary
Though at present investigational the drug of the future in AHF
Janccin B: New Heart failure inotrope could be ‘Holy Grail’. IMNG Medical Media September 5, 2013
John J. V. McMurray et al, on behalf of the ATOMIC-AHF Investigators and Patients
39. • Istaroxime is a novel intravenous agent with inotropic and lusitropic properties
related to inhibition of Na/K adenosine triphosphatase (ATPase) and stimulation
of sarcoplasmic reticulum calcium ATPase.
• 120 AHF pts and reduced systolic function. Three sequential cohorts of 40
patients each were randomized 3:1 istaroxime:placebo to a continuous 6-h
infusion. The first cohort received 0.5 g/kg/min, the second 1.0 g/kg/min, and the
third 1.5 g/kg/min istaroxime or placebo.
• In patients hospitalized with HF, istaroxime improved PCWP and possibly
diastolic function. In contrast to available inotropes, istaroxime increased SBP
and decreased HR.
Istaroxime
Mihai Gheorghiade et al JACC 2008:03;015
39
[HORIZON-HF Trial]
40. •Urocortins are a recently discovered group of peptide hormones of the corticotropin
releasing factor family. They bind with a strong affinity to the CRH-R2 receptor, which
is highly expressed in the myocardium and in the vascular endothelium.
•Urocortins exhibit potent inotropic and lusitropic effects on rat and sheep hearts and
activates a group of myocyte protective pathways collectively known as ‘reperfusion
injury salvage kinase’.
•In healthy humans show that brief intravenous infusions of urocortin 2 in healthy
humans induce pronounced dose-related increases in cardiac output, heart rate, and
left ventricular ejection fraction while decreasing systemic vascular resistance;
similar effects were seen in HF patients.
Urocortins
40
41. Stresscopin
Human stresscopin is a corticotropin-releasing factor type 2 receptor
selective agonist and a member of the CRF peptide family. Stimulation of
CRFR2 improves cardiac output and LVEF.
62 pts with HF and LVEF ≤ 35% were instrumented with a pulmonary
artery catheter and randomly assigned (ratio 3:1) to receive an
intravenous infusion of stresscopin or placebo. The main study was an
ascending dose study of three doses (5, 15, and 30 ng/kg/min) of study
drug or placebo administered in sequential 1 h intervals (3 h total).
Statistically significant increases in CI and reduction in SVR were
observed with both the 15 ng/kg/min (2 h time point) and 30 ng/kg/min (3
h time point) doses of stresscopin without significant changes in HR or
SBP. No statistically significant reductions in PCWP were seen with any
dose tested in the primary analysis, although a trend towards reduction
was seen.
In HF patients with reduced LVEF and CI, ascending doses of stresscopin
were associated with progressive increases in CI and reductions in SVR
without significant effects on PCWP, HR, or SBP.
41
43. Vaso active drugs in ADHF
Relaxin: Serelaxin
• A recombinant human relaxin -2- a naturally occurring peptide that
regulates maternal adaptations
• RELAX AHF:1160 pt. of ADHF with preserved SBP >115 mmHg.
• Serelaxin 30 ug/kg/day x48 hrs or Placebo
• Significant improvement in dyspnoea scale
• No impact on short term mortality/ HF readmission at 60 days,
though 180 day mortality was significantly lower.
• Hypotensive episodes higher but renal dysfunction less than
placebo group
• No limitation: dobutamine milrinone (increase intercellular calcium
in myocytes leading to tachycardia and arrhythmias, levosimendon
calcium sensitiser causes atrial and ventricular arrhythmias, and
like milrinone may be limited by hypotension.
• FDA grants Breakthrough Therapy designation to Novartis'
serelaxin (RLX030) for acute heart failure.
43
44. Biology of Relaxin and Potential Beneficial Effects in HF
Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M - Curr Heart Fail Rep (2010)
Endogenous peptide
associated with
pregnancy, and acts
through relaxin receptor:
reduce inflammation,
decrease fibrosis,
attenuate ventricular
remodeling, increase
vasodilation, promote
renal blood flow,
increase vascular
endothelial growth
factor, and angiogenesis.
↓Inflammation↓Inflammation ↓Fibrosis↓Fibrosis ↑Vasodilation↑Vasodilation Renal effectsRenal effects AngiogenesisAngiogenesis
Relaxin ReceptorRelaxin Receptor
RelaxinRelaxin
Pregnancy associated endogenous peptide
Relaxin ReceptorRelaxin
44
45. Pre-RELAX-AHF : Rapid dyspnea improvement through
24 hours [Likert Scale]
Teerlink J R Lancet 2009,373:1429-1439
48. RELAX-AHF
• 1161 pts with AHF
• 19% improvement in dyspnea
• Decreases in worsening HF
• Improvement of in-hospital signs and symptoms of HF
• Decreased length of hospital stay
• No significant difference in second primary efficacy endpoint of the
proportion of pts with dyspnea relief
• No significant effect on secondary endpoints of cardiovascular death
or hospital readmission for HF or renal failure [RELAX –AF was not
powered as a mortality trial]
Teerlink J R Lancet 2013, 381:29-39
49. Seralaxin
• Increased renal function
• Improved vascular compliance
• Improved cardiac output
Beneficial effects on dyspnea and post-discharge clinical outcomes
50. • Cinaciguat (BAY 58-2667) is a soluble guanylate cyclase (sGC, second messenger that internalizes the
message carried by intercellular messengers such as peptide hormones and NO) activator that is
being developed as a first-in-class treatment for acute decompensated heart failure (ADHF). It acts
independently of the sGC ligand nitric oxide.
• Cardioprotective effects in animal models, and pilot clinical studies found that it was well tolerated,
unloaded the heart and increased cardiac output.
• This placebo-controlled, randomized, double-blind, multicenter, international phase IIb study
investigated the safety and efficacy of intravenous cinaciguat (per-protocol) as add-on to standard
therapy in 139 patients with ADHF (NYHA functional class III and IV; pulmonary capillary wedge
pressure [PCWP] ≥ 18 mmHg).
• Cinaciguat rapidly and significantly reduced PCWP and PVR and increased cardiac output in patients
with ADHF, without impairing cardiac or renal function. Hypotension occurred in some patients;
further dose titration studies are therefore required to establish the optimal dosing strategy for this
promising new therapy.
Cinaciguat
JACC Mar 9,2010 Vol:55 issue 10A
50
51. These molecules have been engineered to combine the beneficial aspects of different
natriuretic peptides into a single molecule while minimizing potentially negative
actions.
CD-NP is a combination of C-type natriuretic peptide (CNP) and Dendroapsis NP
(DNP).
Although lacking natriuretic effects, CNP is a more selective venodilator than BNP,
thus reducing the risk of significant hypotension. On the other side, DNP possesses
significant natriuretic activity, at the expense of possible hypotensive effects.
The chimeric peptide CD-NP combines the favourable natriuretic effects of DNP with
the venodilatory profile of CNP, reducing the risk for harmful side effects.
Preliminary studies in AHFS patients are ongoing.
Chimeric natriuretic peptides
51
52. Adenosine regulating agents
•This new class of drugs, whose prototype is represented by acadesine, has been
developed to mimic the protective effects of adenosine during ischaemia.
•Acadesine exerts its pharmacological actions by increasing adenosine bioavailability
and by activating 50adenosine monophosphate (AMP) signalling cascade via its
metabolite 5-aminoimidazole-4-carboxamide riboside (ZMP).
•The first mechanism leads to multiple anti-ischaemic effects (maintenance of
endothelial function and vasodilation, inhibition of platelet aggregation and neutrophil
activation), whereas the latter ameliorates glucose uptake and free fatty acid
oxidation thus increasing ATP synthesis. Importantly, acadesine exerts its actions
only in areas undergoing net ATP catabolism (such as ischaemic tissues) thereby
avoiding potentially harmful peripheral vasodilator effects.
Acadesine
52
53. • Nesiritide is approved in the United States for early relief of dyspnea in patients with acute
heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the
mortality associated with this agent.
• We randomly assigned 7141 patients [ASCEND-HF trial]
• Co-primary end points were the change in dyspnea at 6 and 24 hours, and the composite end
point of rehospitalization for heart failure or death within 30 days.
• Nesiritide was not associated with an increase or a decrease in the rate of death and
rehospitalization and had a small, nonsignificant effect on dyspnea when used in
combination with other therapies.
• It was not associated with a worsening of renal function, but it was associated with an
increase in rates of hypotension. On the basis of these results, nesiritide cannot be
recommended for routine use in the broad population of patients with acute heart failure.
Nesiritide
53
54. Ularitide
• Synthetic form of Urodilantin: human natriuretic
peptide produced in kidney: induces natriuresis
and diuresis. Also potent vasodilator( increases
intracellular cyclic GMP) and increased renal
blood flow) : Two double blind studies have
shown favorable outcome in ADHF by symptom
improvement and hemodynamics.
• Phase 3 trial(TRUE-AHF >2110 pts) - ongoing
study.
54
55. Summary• AHFS is a complex condition with heterogenous pathophysiology
and varied etiology with unpredictable and often stormy course.
• Present management rests on therapeutic optimisation of
congestion, perfusion & protection against kidney injury & finally
myocardial preservation and enhancement. Needless to point out,
too much reliance on inotropics and pressor amines could be
ominous.
• Simplistic biometrics like HR, B.P. and eGFR are inexpensive and
dependable. Measures of clinical assesment while BNP and other
monitoring devices may be superior but often unaffordable and
expensive and make HF management imposible.
• The safe path on part of ED Physician is to follow updated guideline
pathways till future breakthrough and safe newer drugs are
available.
• All stabilised discharged pts must have GDMT/ Devices/
revascularisation as could be indicated. Multi disciplinary care
approach is inevitable at all stage.
• Serelaxin, Omecamtiv Mecarbil , Istaroxime & Ularitide appear to be
new drugs of the near future.
• … Future trials conducted in aHFs must abandon the ‘one-sizefits-
all’ approach in favor of an approach that takes into account the
varied and distinct pathophysiologies of aHFs.
55
59. (1) Symptom relief.
(2) Measures of congestion relief (i.e. improvement in
clinical signs).
(3) Index hospitalization data (e.g. length of stay).
(4) Prevention of end-organ damage (heart and
kidney).
(5) Post-discharge: death and rehospitalization data.
Federal Drug Administration (FDA) Study Group as a general
guide for choosing the components of the endpoints to be
included when testing different types of drugs in different patient
subgroups, although not all of them would be necessary in a
single trial
Position Statement European Journal of Heart Failure (2011)
59
Editor's Notes
In HF patients with reduced LVEF and CI, ascending doses of JNJ-39588146 were associated with progressive increases in CI and reductions in SVR without significant effects on PCWP, HR, or SBP
Furosemide is conventional volume reducing drug. There are some newer observation depicted by DOSE trial: High Vs Low / Bolus Vs continuous infusion. Further DAD- HF tells us High vs Low dose furosemide with low dose of dopamine equal effect in diuresis and dysponea relief but high dose furosemide causes WRF.
In optimization of monitoring volume reduction a targeted approach with bio-electrical vectorial impedence anaysis with BNP measurement give us precise message as against regular clinical observation of fluid status, perhaps this will provide clinicians a drive for “ Tailor Therapy”
Ultrafiltration though used in state of diuretic resistance and refractory Heart Failure, UNLOAD experience there is optimising , this may be first line application. With newer versions of equipment and easy peripheral venovenus connection this is apt to be used as OPD procedure with cardiac small need for anticoagualants.
Rolofylline was identify as a drug which improves GFR enhance diuresis and natriuress without activation of TGF i.e. with afferent glomerular arteriolar vasodilation. In phase 3 trials drugs was questioned in 2033 patients failing to address none of the primary end points and loss of safety with neurological side effects like seizure and stroke it turned out to be a Negative trial.
Obviously it shows secondary morbility and mortality endpoint as the risk of death and rehospitalisation due to cardiac or renal not favourable expect at sub-group the pts. With eGFR 30ml/min.
This is a unified model to demonstrate the myo contractility enhancing mechanism of three principal drugs : Levosimendan judiciously used in Europe and Asia though not approved by FDA, USA. Two others are in pipeline:- Omecamtiv mecarbil amd Istaroxime.
Omecamtiv mecarbil exerts a novel chemical mechanism to generate force and enhance contraction while istaroxime leads to SERCA activation leading into myocardial enhancement and contraction.
None of the above drugs increase intracellular calcium nor oxygen demand by the myocyte i.e constractingly unique to conventional Inotropics agents which lead to ischemia arrhythemia and hypotension eminently the dobutamine milrinone
So, dyspnoea response only significant in cohort 3 while though better not more significant in cohort 1 or 2.
Echocardiographic evidence of improvement of myocardial performance in terms of systolic ejection time (SET) which is the characteristic therapeutic effect of OM. There is appreciated beneficial, in terms of systolic value change LVESV AND LVEDV.
Finally in terms of relief of dysponea a reduction of worsening HF and myocardial enhancement without significant adverse effects OM is the future drugs of the HF as McMurray says this is a cloud with silver lining believably the star of the future in AHF care and as per IMNG Medical Media Observation an inotrope , no less a Holy Grail.
Istaroxime as shown in the confluent diagram a having convincing mode of action. This is a unique drug which causes reduction of PCWP and possibly diastolic function in the contrast of available inotrope it shown a trend of increased SVB and decrease of HR which are the clinical marker of Heart Failure benefit. By ATPase inhibition and SERCA ATPase stimualation it exerts inotropic and lusitropic.
Urocortins is a peptide harmone of CRH Family which is highly express in myocardial and vascular endothelial with I.V. Infusion in a healthy human it enhances Cardiac Output HR and LVEF while decrease in SVR. It pronounced Inotropic and lusitropic effects in the experimental animals and found interestingly activates a group of myocyte protective pathways known as the reperfusion injury salvagekines
This is similar to Urocortin . This drug is studied by PaC monitoring with the graded dose by IV infusion in pts. Of reduced ejection fraction and Cardiac Index it causes progressive increased in CO & CI. With reduction in SVR. There is no effect on PCWP, HR or SBP. This study is small but very encouraging.
This is considered to be a promisingly physiological therapy against the ADHF. Relaxin is pregnancy associated harmone which protect pregnant women against volume expansion with advancing pregnancy. Serelaxin is a recombinant, relaxin analog developed by Novartis. This is the only drug which has been given breakthrough status by FDA in AHF therapy.
This is anti inflammatory anti fibrotic and renoprotective and enhances the vasomotion by angiogenese. This picture depicts the intricate pathways culminating in unique renoprotective action which is the considered to independent predictor of prognosis and outcome AHFS. Though it contributes a severally volume homeostatis.
Proportion of the pts. At the dose of 30 mg/ day shows the benefit in dyspones relief in Likert scale which confirm to the conviction a similar administration of the single dose in ADHS in ED department would be very beneficial would suffice.
In comparison to placebo benefits is seen in terms of myocardial injury / troponin – Myocardial stretch NT-proBNP- Acute Kidney injury Cystatin C . The graph is expressed in terms of comparative applicacy to bring it to down basal level.
To read it out.
Soluble guanylate cylase in smooth muscle cells is converted to CGMP with causes vasodilation.
At high doses, a substantial decreases in SBP was noted, not associated with adverse effects on renal function, rehospitalisation or mortality.