Failing Right Ventricle in PAH , How to manage?

FAILING RV IN PAH HOW TO MANAGE

FAILING RIGHT VENTRICLE IN PAH

HOW TO MANAGE DR KEERTHIKA

NIMS,HYDERBAD ,INDIA


RV FAILURE DUE TO PAH• Irreversible PAH

• Idiopathic PAH • Eisenmenger's syndrome

• Reversible PAH• CHD with shunts • PTE


Natural History of Idiopathic PAH In 1980, the National Institutes of Health (NIH) established a registry on primary pulmonary hypertension (PPH) that described the clinical characteristics of the disease and its natural history over a 5-year period. The median survival was 2.8 years, with survival rates of 68%, 48%, and 34% at 1, 3, and 5 years, respectively. Based on the data from this registry, an equation incorporating the pulmonary artery pressure, right atrial pressure, and cardiac index was developed to predict survival. Observed survival with epoprostenol therapy at 1, 2, and 3 years was 87.8%, 76.3%, and 62.8% and was significantly greater than the expected survival of 58.9%, 46.3%, and 35.4% based on historical data. Baseline predictors of survival included exercise tolerance, functional class, right atrial pressure, and vasodilator response to adenosine. Predictors of survival after the first year of therapy included functional class and improvement in exercise tolerance, cardiac index, and mean pulmonary artery pressure.


Natural History of Idiopathic PAH 1. Rich S, Dantzker R, Ayres S, et al. Primary pulmonary hypertension: a national prospective

study. Ann Intern Med. 1987; 107: 216–223.

2. D’Alonzo G, Bart R, Ayres S, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med. 1991; 115: 343–349.

3. Rich S, McLaughlin V. The effects of chronic prostacyclin therapy on cardiac output and symptoms in primary pulmonary hypertension. J Am Coll Cardiol. 1999; 34: 1184–1187.

4. McLaughlin, Vallerie V., Alicia Shillington, and Stuart Rich. "Survival in primary pulmonary hypertension the impact of epoprostenol therapy." Circulation 106.12 (2002): 1477-1482.


NORMAL RIGHT VENTRICLE

The RV pumps the same stroke volume of LV but with 25% of the stroke work because of the low resistance offered by pulmonary

vasculature.

Therefore, by virtue of the Laplace relationship, the right ventricle is more thin walled and compliant.

Longitudinal shortening is a greater contributor to right ventricular stroke volume than short-axis (circumferential)

shortening

Geometry of chamber is complex consisting of an inlet (sinus) portion and outlet (conus) sepatated by crista supraventricularis.


PHYSIOLOGY OF RV vs. LV

• RV filling normally STARTS BEFORE and FINISHES AFTER LV.• RV IVRT, filling velocities (E and A) and the E/A ratio are LOWER but • Respiratory Variations In Filling Velocities Are More Pronounced.• Compared with the LV, the RV demonstrates a HEIGHTENED

SENSITIVITY to afterload change


IT IS LINKED TO LEFT VENTRICLE BY

Shared wall (septum) ,

By mutually encircling epicardial fibers

By attachment of RV free wall to anterior and posterior septum

By sharing pericardial space


Perfusion of the RV

• (1) its lower oxygen consumption,• (2) its more extensive collateral

system, especially from• the moderator band artery, a

branch of the first septal perforator that originates from LAD,

• (3) its ability to increase oxygen extraction.

The relative

resistance of the RV

to irreversible

ischemic injury

explained by :

RV AND PAH

The right ventricle is exposed to pressure overload by chronic pulmonary hypertension from any cause .

In PAH initial adaptive response is that of MYOCARDIAL HYPERTROPHY followed by progressive contractile dysfunction and then chamber dilation

Chamber dilatation ensues to allow compensatory preload and maintain stroke volume despite reduced fractional shortening.(FRANKS STARLING)



DECOMPENSATED RIGHT VENTRICULAR FAILURE IS CHARACTERIZED BY

clinical evidence of rising filling pressures,

diastolic dysfunction

diminishing cardiac output,

tricuspid regurgitation

due to annular dilatation and poor leaflet coaptation.


• The right ventricle in severe idiopathic pulmonary arterial hypertension assumes a spherical shape with a greater cross-sectional area than the left ventricle (LV).

• The more spherical-shaped right ventricle results IN ABNORMAL SEPTAL FUNCTION that also impairs left ventricle performance.


Norbert F. Voelkel et al. Circulation. 2006;114:1883-1891

Copyright © American Heart Association, Inc. All rights reserved.


VENTRICULAR INTERDEPENDENCE

• Ventricular interdependence is the phenomenon in which the size shape compliance of one ventricle may affect the size , shape & pressure volume relationship of other ventricle through direct mechanical interaction.

• Systolic ventricular interdependence mediated mainly through interventricular septum , pericardium in diastolic ventricular interdependence.

• About 20 – 40 % of RV systolic pressure and volume outflow results from LV contraction


In the presence of RV scarring also RV output is by septal interaction UNTIL RV IS DILATED .

• shifts the IVS to left , • alters LV geometry • increases pericardial constraint • results in decrease in LV compliance

leads to decreased LV preload • increased LV end diastolic pressure

or low cardiac output state.

In acute RV

pressure and

volume overload & dilation of

RV


Assessment of Ventricular Interdependence

Ventricular interdependence may be clinically assessed by considering

(1) The degree of reciprocal respiratory change in ventricular filling profiles,

(2) Ventricular coupling (in dimension or pressure), or(3) Abnormal septal motions (SEPTAL BOUNCE)


•RV FUNCTION IS THE MOST IMPORTANT DETERMINANT OF LONGTERM SURVIVAL IN PATIENTS WITH PAH


RV FAILURE

RV failure is a complex clinical syndrome that can result from any structural or functional cardiovascular disorder that impairs the ability of RV to fill or to eject blood


Right ventricular failure is the main cause of death in patients with PAH, the ability of the right ventricle to ADAPT to the progressive increase in PVR is the main determinant of a patient’s functional capacity and survival

Despite heterogeneous underlying aetiologies, all forms of PAH SHARE SIMILAR clinical and haemodynamic findings and identical pathological changes in the pulmonary vasculature.


• Vasoconstriction• Cell proliferation with in smooth muscle

cells and endothelial cell proliferation causing obstructive remodelling of the pulmonary blood vessal walls .

• Inflammation• In situ thrombosis

PATHOPHYSIOLOGY OF RV FAILURE


Figure 4. Postulated pathobiology of right ventricle failure in pulmonary hypertension.

Norbert F. Voelkel et al. Circulation. 2006;114:1883-1891

Copyright © American Heart Association, Inc. All rights reserved.


DETERMINANTS OF RV FUNCTION

RV SYSTOLIC FUNCTION IS A REFLECTION OF

Contractility Afterload Preload.


• HEART RHYTHM, • SYNCHRONY OF VENTRICULAR

CONTRACTION, • RV FORCE INTERVAL RELATIONSHIP &• VENTRICULAR INTERDEPENDENCE

RV PERFORMANCE influenced

by :


• Intravascular volume status, • Ventricular relaxation,• Chamber compliance, • Heart rate• Passive and active atrial characteristics,• LV filling,• Pericardial constraint & the filling period.

Factors influencin

g RV FILLING


Assessment of RV structure

• A change in RV shape and volume can be the FIRST SIGN of RV dysfunction, pressure or volume overload.


Assessment of RV Function

ECHO

RADIONUCLEOTIDE ANGIOGRAPHYMRI


RV contractility most commonly assessed : RVEF• highly dependent on loading conditions and • may not adequately reflect contractility.

• MRI : most accurate method for measuring RVEF

• Radionuclide angiography : gives RVEF free of geometric assumptions.

• 3D echo has also shown promising but variable correlations with RVEF.


ECHO: for RV Function

• 2D-RVEF : (SIMPSON METHOD) show moderate correlation with radionuclide /MRI-derived RVEF (correlations 0.65-0.80)

• RV fractional area change : the ratio of systolic area change to diastolic RV area.(n>32%), good correlation with RVEF


Tricuspid annular plane systolic excursion (TAPSE)

Longitudinal M mode systolic excursion of the lateral tricuspid valve annulus toward the apex in A4C view


RV myocardial performance index ( MPI )Ratio of isovolumic time intervals to ventricular ejection time.

Tei C et al, JASE 1996


RV pressure overload• Dilated pulmonary artery • RV enlargement ( RV ~2/3 of LV & doesn't form apex)• RV hypertrophy (RV free wall > 0.5 cm) • Decreased RV systolic function• Right atrial enlargement• Interventricular septal flattening (D-shaped LV)Rapid early systolic correction of diastolic septal flattening suggests RV volume overload, whereas failure of this suggests RV pressure overload


Eccentricity Index

A measure of septal displacement in systole or diastole

• Eccentricity Index EI = D2/D1

D1= minor axis diameter perpendicular to IVS

D2= minor axis diameter parallel to IVS

Ryan, T. et al. J Am Coll Cardiol 1985;5: 918-24


Doppler findings of increased Right sided pressure

• Best validated Doppler technique for PASP is - modified Bernoulli equation

ΔP = 4 TR Vmax2 • Change in RVOT Doppler velocity curve from rounded to rapid

acceleration• Short RVOT Doppler time of onset to peak velocity ( PAT< 90 ms)


OTHER TDI METHODS• Systolic signal of the tricuspid annulus (St) <11.5 cm/s identifies presence of

RV dysfunction with a sensitivity and specificity of 90% and 85%

• IVA( isovolumic myocardial accelaration ) : new TDI parameter of systolic performance calculated by dividing the maximal isovolumic myocardial velocity by the time to peak velocity


RV Diastolic Parameters and Estimation of Preload

The different parameters used include (1) RV end-diastolic or RA pressures, (2) RV volumes, (3) RV filling profiles.

2D-ECHO findings of elevated RAP• Enlarged RA & coronary sinus• Leftward bowing of IAS• Enlarged IVC (> 20 mm) with <50% diameter change with

inspiration (caval respiratory index)


Mean RAP (mmHg) IVC ∅ (mm) IVC Collapse 0 – 5 < 15 Complete5 – 10 15 – 25 > 50%10 – 15 15 – 25 < 50 %15 – 20 > 25 < 50 % > 20 >25 No change

Ommen SR. et al. Clin Proc 2000;75: 24-9.


Doppler findings of elevated RAP

Short RV rIVRT <60 ms

Tricuspid E/Ea >6 suggests mean RAP>10


ECHO ESTIMATION OF PVR

PVR = 10 x (TR Vmax m/s/ RVOT-VTI cm) + 0.16 wood units i.e. PVR TR VMAX/RVOTVTI∝

Abbas AE. et al. J Am Coll Cardiol 2003;41:1021-1027.


PREDICTORS OF RV FUNCTION IN 2D ECHO


Biomarkers of RV Failure

• BNP : useful in diagnosing RV failure associated with pulmonary hypertension & associated with worse survival.

• Elevated TROPONIN Levels have also been associated with worse outcome in pulmonary embolism and PAH.


MANAGEMENT OF Chronic and Acute RV Failure in PAH


GENERAL &SUPPORTIVE• DIEURETICS• DIGOXIN• ANTICOAGULATION

AFTERLOAD REDUCTION• PDE5 INHIBITORS• PROSTANOIDS• ENDOTHELIN

RECEPTOR ANTAGONIST

PREPARE FOR TRANSPLANTATION



Goals of Therapy

The goals of treating chronic right ventricular failure due to PAH are to

• 1) Relieve Symptoms, Improve Exercise Capacity, And Quality Of Life; • 2) Reduce Morbidity And Mortality • 3) Improve Cardiopulmonary Hemodynamics To Prevent Worsening

Of Right Heart Failure & Delay Disease Progression.


Acute Decompensated RV Failure

• The immediate goals of treating acute decompensated right ventricular failure (ADRVF), especially with hemodynamic compromise, are to

• 1) Restore Oxygenation;• 2) Treat Volume Overload; And • 3) Restore Vital Organ Perfusion.


ADRVF: Identification and Correction of Precipitating Factors

• Factors That Precipitate ADRVF In Patients With Chronic Right Ventricular Failure Are

• Dietary Indiscretion, • Intercurrent Infection, • Anemia/Erythrocytosis, • Thyroid Disorders, • Concomitant Pulmonary Embolus, And• Dysrhythmias. • Infection Must Be Considered In Patients With An Indwelling Central Venous

Catheter For Epoprostenol Infusion


infection

• Infection is poorly tolerated in patients with right ventricular failure .• The increase in right ventricular work associated with reduction in

SVR will result in systemic hypotension. • In this scenario, beta- and alpha- agonists such as dopamine or

norepinephrine are indicated as initial therapy to stabilize hemodynamics.


In the acutely decompensated PAH,

• The Most Useful Agents1. Inhaled Nitric Oxide,2. Intravenous Or Inhaled Epoprostenol,3. Iloprost, And4. Inotropic Support



Strategies

• To Prevent And Treat Chronic Right Ventricular Failure Are Aimed At

1. Reducing Right Ventricular Wall Stress,

2. Minimizing Myocardial Oxygen Consumption And Ischemia,

3. To Improve The Inotropic State Of The Right Ventricle.


Reduce wall stress

• Lower right ventricular afterload with chronic pulmonary arterial vasodilators:

1. O2 therapy,2. Endothelin receptor antagonists,3. Prostanoids4. Phosphodiesterase V inhibitors • Calcium channel blockers should be avoided in patients with marginal

blood pressure and• significant right heart failure right atrial pressures greater than15

mmHg and low cardiac index (less than 2.0 L/min/m2).



Combination therapy

• Describes the simultaneous use of more than one PAH-specific class of drugs, e.g. ERAS, PHOSPHODIESTERASE TYPE-5 INHIBITORS, PROSTANOIDS, AND NOVEL SUBSTANCES.

• Standard of care in many PAH centres.




The Relatively Small BREATHE-2 Study Showed A Trend To A Better Haemodynamic Effect Of The Initial Combination Of Epoprostenol-bosentan As Compared To Epoprostenol Alone.

The STEP-1 Study Addressed The Safety And Efficacy Of 12 Weeks Therapy With Inhaled Iloprost In Addition To Bosentan And Found A Marginal Increase In The Post-inhalation 6 Min Walk Distance.


Chronic anticoagulation

• Recommended To Prevent Pulmonary Arterial Thrombosis In Situ, • Which Contributes To Narrowing And Remodeling Of The Pulmonary

Arterial Bed,• Consequently Increasing Right Ventricular Outflow Impedance.


Preload optimisation

• Challenging :• May Differ In The Acute And Chronic Settings.

• Excessive volume loading may increase pericardial constraint and decrease LV preload and cardiac output through the mechanism of ventricular interdependence.

• Hypovolemia decrease RV preload and cardiac output.• Reduction in right ventricular preload and tricuspid regurgitation to reduce

right ventricular wall stress can be accomplished with diuretics.


Preload optimisation

• Chronic therapy with loop diuretics (furosemide, bumetanide, torsemide) alone or in combination with intermittent potent thiazide diuretics (ie, metolazone) and/or aldosterone antagonists (spironolactone, eplerenone) are effective at controlling volume overload.

• Right ventricular failure and hepatic congestion are associated with aldosterone activation. Use of aldosterone antagonists in appropriate doses and with close monitoring of electrolytes can potentiate diuresis in patients treated with loop diuretics.


• As aldosterone activation is associated with sodium/fluid retention, potassium/ magnesium wasting, increases in ventricular mass and fibrosis, and endothelial dysfunction, even nondiuretic neurohormonal blocking doses of the aldosterone antagonists (spironolactone or eplerenone at 12.5 to 50 mg daily) often exert beneficial effects in patients with right ventricular failure due to PAH.


Diuretics

• Although there are no RCTs of diuretics in PAH, clinical experience

shows clear symptomatic benefit in fluid-overloaded patients treated

with this therapy

• The addition of aldosterone antagonists should also be considered


alternative strategy

• When attempts to decrease right ventricular wall stress by pharmacologically manipulating right ventricular preload and afterload are inadequate, an alternative strategy is to improve right ventricular inotropy.


Contractility enhancemnt

• Dobutamine is the most commonly used inotrope in RV failure.

• The combination of dobutamine and nitric oxide in PH also has been shown to be beneficial. Vizza CD, Crit Care. 2001;5:355–361.

• Other inotropes used are dopamine, milrinone & digoxin.• Digoxin can produce a modest increase in cardiac output and it has

been shown to decrease circulating catecholamine levels.


DIGOXIN

• Digoxin has been shown to improve cardiac output acutely in IPAH

• It may be given to slow ventricular rate in patients with PAH who develop atrial

tachyarrhythmias.



Neurohormonal Modulation

• ACE-I & Beta blockers• In patients with biventricular failure, ACE-I have been shown to

increase RVEF and to reduce RVED volume and filling pressures. Massie B et al :Circulation. 1982;65:1374 –1381.

• Small studies have demonstrated that carvedilol or bisoprolol improves RV systolic function

Quaife RA et al :Am J Cardiol. 1998;81:247–250.

• The role of nesiritide is still not defined.


Atrial Septostomy

• It was first proposed by RICH and LAM in 1983 as palliative treatment of pulmonary hypertension

Current indications for BAS in PAH

1. Failure Of Medical Therapy 2. Persisting Right Heart Failure 3. Recurrent Syncope4. Bridging To Transplantation5. Absence Of Other Therapeutic Options


Hemodynamic impact of BAS in PAH

• Mean RA pressure falls at least 5mmhg • PA pressure - no significant impact expected• Tricuspid regurgitation regresses• Marginal reduction of RA,RV sizes • Cardiac output increases by 750 ml to 1 litre• Fall of systemic saturation should not be more than

10%


Follow up following BAS in PAH

• Greatest relief is from syncope.• Functional class improvement in >50% .• One year survival benefit is substantial (75-90%) • Late deterioration can occur as ASD gets closed in few cases


GOAL OF BALOON ATRIAL SEPTOSTOMY

• Goal of procedure is palliation and restoration of clinical stability until a transplant can be performed .

• Reported success rates for bridging patients to transplantation with septostomy range from 30- 40 %.

• Procedural mortality is around 15 %


Contraindications to BAS in PPH • Critical RV failure – BAS is not a procedure for dying

patients of PAH

• Mean RA pressure > 20mmhg

• Pulmonary vascular resistance index> 55 Wood units / sq.meter


iabp

• CIRCULATION


RV Assist Device

In patients with acute RVF refractory to medical treatment, mechanical support with an RV assist device may be used as

1. bridge to transplantation 2. Destination therapy


RV Assist Device


ecmo

• Venovenous Extracorporeal Membrane Oxygenation In patients with large PFO or ASD

• Venoarterial ECMO• Pulmonary Artery to Left Atrium ECLS


HEART LUNG TRANSPLANTATION

• NORMAN SHUMWAY , JOHN WALLWORK , BRUCE REITZ • in 1981 did first successful heart lung transplantation.

• JOEL COOPER reported first single lung transplant in pulmonary fibrosis 1986


• WHO functional class III & IV• Mean right atrial pressure >10 mm of hg• Mean PAP more than 50mm of hg• Cardiac index <2.5L/min/m2• Failure to improve despite maximal

medical therapy• Rapidly progressive disease

Guidelines to refer a

patient for transplant EVALUATIO

N


Single lung transplant

• ADVANTAGEOUS• Favourable in older patients and those with comorbidities due to

shorter time under anesthesia• Native lung may help patient sustain through early graft reaction• Two patients can be helped with single donar

• DISADVANTAGES• Monitoring of PFT in COPD will be unreliable


DOUBLE LUNG TRANSPLANT

• Survival is increased• Post transplant PFT monitoring is easy

• Longer duration of anesthesia increases risk


HEART LUNG TRANSPLANTATION

• ADVANTAGES• Patients with RV & LV dysfunction will not benefit from single or

double lung transplant

• DISADVANTAGES• Long waiting period• Poor survival


CONCLUSION

• RV physiology & function are different from LV• PAH with RV failure has worst prognosis and difficult to

manage• ECHO with Doppler & TDI is now the mainstay of routine RV

assessment• No convencing evidence to treat NYHA class I • Combination therapy is the standard of care in NYHA class II

& III .BREATHE 2 &STEP1 showed a trend to better hemodynamic effect


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Failing Right Ventricle in PAH , How to manage?