HF THERAPEUTICS Flashcards
recent advances and long-term challenges: cell therapy
- Demonstration of marked capacity of neonatal mammalian heart for regeneration
- Demonstration of residual capacity of adult human heart for minor regeneration
- Continued demonstration of small clinical improvements in clinical trials
- Mainly transient clinical improvements with limited evidence of retention of exogenous cells
- Mismatch between improvements in animal models and those observed in clinical trials
- Continuing debate about correct cell type and mode of delivery
- Uncertain therapeutic mechanisms
- Possible arrhythmia risk
- Potential need to modulate immune response if non-self cells used
recent advances and long-term challenges: gene therapy
- Targeted therapy of Ca2+ handling genes shows remarkable benefits in animal models
- Evidence that multiple levels of the same regulatory axis can be targeted using gene therapy
- Potential to harness much of our knowledge of cellular pathophysiology
- Some evidence that gene therapy is clinically safe and has some efficacy
- Largely clinically untested
- Long-term effects unknown
recent advances and long-term challenges: LVADs
- Recovery has been demonstrated in multiple patient populations at a rate of between 5%-10% and up to 73%.
- Left ventricular assist devices appear to induce reverse remodeling in multiple systems
- Reverse remodeling is long-lasting
- Complications are becoming less important in newer generations
- Complications remain serious
- Requires major operation
- Debate as to how common cardiac recovery is
- Centers may be reluctant to explant devices in fear of recurrence of heart failure
- Mechanical unloading may have deleterious effects such as atrophy and fibrosis
recent advances and long-term challenges: CRT
- Improves contractility acutely
- Reverse remodeling of left ventricular structure
- Improved mitochondrial function
- Improved subcellular remodeling
- Safe
- Unknown how long-term improvements are
- What is the role in early heart failure without major dysynchrony?
CARE-HF trial demonstrated:
CRT significantly greater proportion of patients alive and well.
CRT significantly increased the remission rates for NYHA I/II and improved ventricular function in NYHA III/VI
main points re Curing of HF and how to increase cure rates for HF
• Fundamental Premise
• Heart Failure is malignant (‘cancer of the heart’)
• Like cancer
○ It can be / is being beaten
○ It is heterogeneous
□ More likely that we will ‘cure’ some types before others
□ Matching type to intervention will be important
○ Is associated with ageing
□ Treatment that improves HF may also retard ageing and/OR Treatment that retards ageing may treat/prevent HF
• Prevention (Delaying) Strategies • Whole Population • Targeted ○ Age & CV Risk Factors ○ Early Evidence of CV Dysfunction • Treatment Strategies • Early Detection • Effective Treatment ○ Generic ○ Phenotype Specific ○ Individual Patient
HOW TO INCREASE CURE RATES FOR HF?
• Early Identification
• Increases prevalence! –> should we do it before we have really effective treatments??
• Phenotype & Stratify
• Know what you are treating
• Pick types of heart failure off one at a time
• Intervention & Adjuvant
• Heart failure is rarely due to one thing going wrong
• Isolated approach is ineffective in such multifactorial and complex problem as HF
○ A Treatment with one drug might fail but combining several might well act synergistically
• Don’t Get Trapped by Pre-conceptions
Check if what you know is really true – and keep checking!
cardiac remission of ESTABLISHED DISEASE
• Spontaneous • Beta-Blockers • Ivabradine • Cardiac Resynchronization Therapy • Revascularisation • Valve Repair & Replacement ○ Probably not with treatments focussed on congestion § ACEi § ARB § MRA § Diuretics ○ Certainly not with
ICD
what is cure for HF? how is it defiend?
Remission and • Withdrawal of All Treatments for Heart Failure Without • Recurrence And • Normalisation of life expectancy
how is HF remission defined?
• Resolution of Symptoms And • Restoration of Cardiac Function And • Withdrawal of Diuretics And • No Cardiac Events = Remission
RAAS system: implications and therapeutics
multiple pathways affected by ACE inhibitors. The most widely recognized action of angiotensin-converting enzyme is the conversion of angiotensin I to angiotensin II. ACE inhibitors block this dominant pathway of angiotensin II synthesis and thereby can prevent most of the actions of angiotensin II.
However, as illustrated in this slide, angiotensin converting enzyme, which is also known as kininase II, is the major enzyme responsible for the breakdown of bradykinin. Thus, ACE inhibition also increases tissue levels of bradykinin, which is a major stimulant of nitric oxide and prostaglandin synthesis. The degree to which increased prostaglandin synthesis plays an important role in reducing the benefits of ACE inhibitors is unknown, but inhibition of prostaglandin synthesis by aspirin would potentially block these effects. The hemodynamic effects of prostaglandins may be more important in patients with heart failure than in other conditions, making an interaction with aspirin more apparent and relevant in the setting of heart failure.
mechanisms of action of RAAS inhibitors
MECHANISMS OF ACTION: • Renal?: • Electrolyte & Water Metabolism ○ Offloading of heart (decrease water and vasodilating) may bring all the secondary beneficial effects • Vasodilator:- • Arterial • Venous • Direct Effects on Cardiac Function • Remodelling of CV Structure
potassium in HF
Potassium and Risk of death in HF: mortality increases when K goes either up or down from the norm and HF patients seem particularly sensitive to K+ changes because the HF patients are intracellularly dehydrated even though extracellularly there is fluid overload -affects electrolyte balance.
LCZ696
Arb (valsartan) combined with Nep-inhibitor
Inhibits breakdown of BNP but not nt-proBNP(but it’s not the active one anyway)
renin and prorenin
Renin and prorenin bind to a specific (pro)renin receptor which enhances their catalytic activity, activates MAPKs and induces RGF-beta, which in turn increases plasminogen activator inhibitor 1, fibronectin and collagen production, independently of Angiotensin II production. Thus direct renin inhibition may provide additional protection over other RAAS inhibitors.
SERCA21 gene therapy effects in animals
- AAV9.SERCA2a gene therapy normalises SR Ca2+ content
- Spontaneous SR Ca2+ spark frequency unchanged in failing myocytes after SERCA2a gene transfer
- SERCA2a Gene Therapy Reduces Spark-mediated SR Calcium Leak
- SERCA2a Gene Therapy Reduces the Frequency of Ca2+ Waves in Failing Cardiomyocytes
OVERALL: SERCA2a gene therapy is antiarrhythmic
•
SR load is restored, but buffering of Ca release decreases overall spark mass
•
SR leak/load ratio is therefore decreased
•
Large long-lasting sparks are particularly decreased
•
Conversion of sparks to waves is less likely
► Significantly positive Effect of SERCA2a Gene Transfer on Survival in Rats with Pressure-Overload Hypertrophy in Transition to Heart Failure
