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Flashcards in HF THERAPEUTICS Deck (21)
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1
Q

recent advances and long-term challenges: cell therapy

A
  • 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
2
Q

recent advances and long-term challenges: gene therapy

A
  • 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
3
Q

recent advances and long-term challenges: LVADs

A
  • 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
4
Q

recent advances and long-term challenges: CRT

A
  • 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?
5
Q

CARE-HF trial demonstrated:

A

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

6
Q

main points re Curing of HF and how to increase cure rates for HF

A

• 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!

7
Q

cardiac remission of ESTABLISHED DISEASE

A
• 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

8
Q

what is cure for HF? how is it defiend?

A
Remission and
• Withdrawal of All Treatments for Heart Failure 
Without 
• Recurrence
And 
• Normalisation of life expectancy
9
Q

how is HF remission defined?

A
• Resolution of Symptoms
And
• Restoration of Cardiac Function
And
• Withdrawal of Diuretics 
And
• No Cardiac Events
= Remission
10
Q

RAAS system: implications and therapeutics

A

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.

11
Q

mechanisms of action of RAAS inhibitors

A
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
12
Q

potassium in HF

A

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.

13
Q

LCZ696

A

Arb (valsartan) combined with Nep-inhibitor

Inhibits breakdown of BNP but not nt-proBNP(but it’s not the active one anyway)

14
Q

renin and prorenin

A

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.

15
Q

SERCA21 gene therapy effects in animals

A
  • 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

16
Q

advantages and challenges of SERCA gene therapy

A

► An anti-arrhythmic positive inotrope
► Transfected SERCA2a may evade biological regulation e.g. by miR 25 (shown to down-regulate SERCA in HF, Wahlmquist, Hajjar Mercola, Nature 2014)
► Long lasting effect from a single injection
But
► Unable to “withdraw” treatment
► Prior or induced neutralising antibodies to AAV
► Larger proportion of neutralising antibody positive patients than expected
• Plasmapheresis?
• Decoys?
• Engineered capsids?
► Induction of T-cell mediated immunity – ELISPOT assay
► Effects in other tissues difficult to avoid
• Tropism is limited
• Attempts at localisation of application ineffective
• Biological targeting limits SERCA2a protein increase to muscle cells
► Quantifying gene delivery

17
Q

ASSOCIATE study

A

A large body of evidence points to high resting heart rate (HR) as a risk factor for mortality in various populations, including patients with cardiovascular disease. Elevated HR is an important pathophysiological variable that increases myocardial oxygen demand and also limits tissue perfusion by reducing the duration of diastole, during which most myocardial perfusion occurs.
Large epidemiological trials have established that elevated resting HR is a prognostic factor for cardiovascular events and mortality in healthy individuals and in patients with myocardial infarction, stable coronary artery disease and heart failure.

18
Q

what does ivabradine do?>

A

)contributes to the restoration of oxygen balance. No relevant negative effects are evidenced on cardiac conduction, contractility, relaxation or repolarization, or blood pressure.

19
Q

tirals on ivabradine

A

ivabradine treatment did not affect the primary composite outcome, it reduced the need for hospitalization due to myocardial infarction and coronary revascularization.

SHIFT:
The efficacy and safety of ivabradine is independent of SBP. This may have implications for the management of HF patients with low SBP and elevated heart rate.

BEAUTIFUL and SHIFT:
In both trials the favorable effects of ivabradine were greatest in those patients with a higher heart rate. The most striking finding of the SHIfT trial, obtained from the echocardiographic substudy, was the reversal of cardiac remodeling in the left ventricle with pronounced increase in left ventricular ejection fraction and reduced left ventricular systolic volume

20
Q

ivabradine mechanism of action

A

The mechanisms of ivabradine, however, remain controversial. Most clinical and experimental evidence points to a primary role of heart rate reduction.

the likely cause of remodeling by optimizing energy consumption while simultaneously reducing cardiac work load

there are studies showing that some of the effects may be mediated by different mechanisms. We have recently shown that the reduction in myocardial fibrosis induced by ivabradine is not due to heart rate reduction, as the β‐adrenergic blocker metoprolol did not reduce fibrosis in a rodent model of heart failure, despite a similar reduction in heart rate

the remodeling effects on arrhythmias independent of heart rate reduction by using a nonbradycardic dose of ivabradine. With this strategy they clearly demonstrated the reduction in If amplitude and occurrence of spontaneous action potentials in the presence of isoproterenol and improved survival rate in the dnNRSF‐Tg model

other Ivabradine effects : the attenuation of the renin–angiotensin aldosterone system (RAAS) through a reduction in angiotensin‐converting enzyme and angiotenisn II type I receptor (AT‐1) transcript expression.

All these studies support the notion that ivabradine can have direct effects on ventricular structure and electrophysiology independent of the sinoatrial node.

21
Q

ivabradine and LVAD

A

Ivabradine shows beneficial structural and E-C coupling effects during MU: Iva reverses myocardial fibrosis and enhances the restoration of deranged E-C coupling, displaying more beneficial effects than that of Met. These results suggest that Iva may prove effective in enhancing functional recovery in heart failure patients receiving LVAD therapy.