phd acc talk - gemoq.ca

PERIPARTUM CARDIOMYOPATHY

CA N D I CE S I LV E RS I D ES , M D

M I LES N A DA L CH A I R I N P R EG N A N CY A N D HEA RT

D I S EA S E

U N I V E RS I T Y OF TORON TO P REGNA NC Y A ND H EA RT

D I S EA S E P ROG RA M

Case

• 40-year-old G3P1 at 36 weeks gestation

• African American

• No medical history

• Sister with “heart problems” after a pregnancy who was told never to get pregnant

• Gestational diabetes

Case

• Presented with shortness of breath

• On exam: BP 120/85 mmHg, HR 120-130 bpm, clinical heart failure

• Echo: Moderate to severe LV systolic dysfunction

Case

Is this PPCM?

1. Yes

2. No

3. Maybe

Case

Is this PPCM?

1. Yes

2. No

3. Maybe

OBJECTIVES

Overview of PPCM

Clinical presentation

Treatment options

Prognosis

OBJECTIVES

Overview of PPCM

Clinical presentation

Treatment options

Prognosis

DEFINITION OF PPCM

Davis and Elkayam JACC 2020

DIFFERENTIAL DIAGNOSIS

Blauwet and Cooper heart 2011

INCIDENCE OF PPCM

Blauwet and Cooper Heart 2011

1 in 100 in Nigeria1 in 1,000-4,000 in US1 in 200,000 in Japan

OVERVIEW

Davis and Elkayam JACC 2020

Blauwet and Cooper Heart 2011

VASCULOTOXIC HYPOTHESIS

Vasculotoxic hormones are released from the placenta and pituitary during late gestation and early postpartum periods

Damage the Cardiac Microvasculature

Cardiomyocyte Dysfunction

Contractile Failure

• One of these potentially toxic hormones is prolactin

• Prolactin can be cleaved by extracellular proteases to yield a 16-kDa peptide that is profoundly vasculotoxic

PATHOGENESIS

Arany and Elkayam Circ 2016

VASCULOTOXIC HYPOTHESIS

Arany and Elkayam Circ 2016

Cleaved 16-kDa prolactin molecule triggers endothelial and cardiomyocyte damage

Soluble Fms-like tyrosine kinase 1 (sFlt1) inhibits the VGEF pathway and triggering PPCM

GENETICS: TTN GENE

Ware et al NEJM

• 172 women with PPCM underwent targeted sequencing of DCM genes

• 15% prevalence of high impact variants

• Majority of variants were in the TTN gene, a critical structural component of sarcomeres in cardiac and skeletal muscle

OBJECTIVES

Overview of PPCM

Clinical presentation

Treatment options

Prognosis

CLINICAL PRESENTATION

Asymptomatic

Pulmonary edema

Cardiogenic shock

Cardiac arrest

Thromboembolic complications

Death

CLINICAL PRESENTATION

Asymptomatic

Pulmonary edema

Cardiogenic shock

Cardiac arrest

Thromboembolic complications

• LV thrombus on echo reported in 10-17% of pregnancies

Death

Elkayam JACC 2011

TIMING OF PRESENTATION

Bauersach et al EJHF 2019

Outcomes of Women with PPCM in the US

Author (year) NMean Follow up Period

Mortality Heart Transplant

Witlin 1997 28 FU not reported 18% 11%

Felker 2000 42 FU 8.6 years 7% 7%

Chapa 2005 32 FU not reported 9.6% 6.5%

Amos 2006 55 43 +/- 43 months 0 10%

Mielniczuk 2006 16,296 FU No reported In hospital 2.5 % NA

Brar 2007 60 4.7 years 3.2% NA

Goland 2009 182 19 months 7% 6%

Modi 2009 40 54 months 15.9% 0

Elkayam JACC 2011

Prospective cohort study of 100 women with PPCM followed for 1 year

4 deaths over the course of a year

6 women had died, undergone transplant or were on an LVAD

6 had severe (LVEF < 35%) chronic cardiomyopathy

Timing of Mortality After Diagnosis in PPCM

Elkayam JACC 2011

OBJECTIVES

Overview of PPCM

Clinical presentation

Treatment options

Prognosis

Case

• PPCM, heart failure and moderate to severe LV systolic dysfunction

• Which medications would you consider for therapy in this patient?

1. Lasix

2. ACEI

3. Beta-blocker

4. Brompcriptine

Case

• Started on Lasix

• Oxygen 2L by nasal prongs

Bauersach et al EJHF 2019

Regitz-Zagrosek et al EHJ 2018

It is recommended to treat women with HF during pregnancy according to current guidelines for non-pregnant patients, respecting contraindications for some drugs in pregnancy

I B

Medications

Heart Failure Medications Potential Adverse Effects

Βeta-blockers IUGR; fetal bradycardia and hypoglycemia

Lasix Caution for hypovolemia or hypotension that may lead to decreased placental perfusion

Hydralazine + Nitrates Caution with hypotension

Digoxin No associated congenital defects

ACEI or ARB Anuria, oligohydramnios, fetal limb contractures, craniofacial deformation, pulmonary atresia, fetal hypocalvaria, intra uterine growth restriction, prematurity, patent ductus arteriosus, stillbirth, neonatal hypotension and death

Sacubitril-valsartan Same as ACE-I/ARB

Spironolactone Spironolactone has been associated with antiadrenergic activity, feminization of male rat fetuses and permanent changes in reproductive tract in both sexes

Ivabradine Scant data in humans, animal data suggest risk

Modified from Davis and Elkayam JACC 2020

PEACE REGISTRY(PEripArtum Cardiomyopathy in NigEria)

PPCM PROFILES IN DIFFERENT STUDIES

Koczo et al JACC 2019

Koczo et al JACC 2019

Stop BreastfeedingBromocriptine

Bromocriptine

Proof of concept; 10 women in each arm Sliwa et al Circ 2010

8 weeks bromocriptine

treatment

Bromocriptine

• 96 women in Burkina Faso

• Women were on HF therapy with ACEI/Lasix

• Randomized to 4 weeks of bromocriptine

• LVEF higher in women receiving bromocriptine at 2 weeks, 3/6/12 months

• Mortality lower in women receiving bromocriptine (17% vs 29%, p=0.0001)

Yameogo et al J Cardiol Clin Res 2017

Bromocriptine

• Multicentre trial of 63 women with PPCM + LVEF ≤ 35% + standard heart failure therapy: • Short-term (1week: bromocriptine 2.5mg) • Long-term (8 week: 5 mg for 2 weeks followed by 2.5mg for 6weeks)

• Bromocriptine started 1.6 +/- 1.6 months after delivery

• Left ventricular ejection fraction • 1 week: 28% to 49% - ΔLVEF 21% • 8 weeks: 27% to 51% - ΔLVEF 24% Delta-LVEF: P = 0.381

Hilfiker-Kleiner et al EHJ 2017

Bromocriptine

Hilfiker-Kleiner et al EHJ 2017

Full-recovery (LVEF ≥ 50%) was present in 52% of the 1W- and in 68% of the 8W-group

Bromocriptine

Hilfiker-Kleiner et al EHJ 2017

• No differences in secondary end points between groups • 3/62 had thromboembolic complications (2 venous embolism,1 peripheral

artery embolus) – all women had prophylactic anticoagulation

Regitz-Zagrosek et al EHJ 2018

In patients with PPCM, bromocriptine treatment may be considered to stop lactation and enhance recovery

IIb B

Regitz-Zagrosek et al EHJ 2018

Bromocriptine treatment should be accompanied by prophylactic (or therapeutic) anticoagulation

IIa C

PREGNANCY MANAGEMENT

Davis and Elkayam JACC 2020

DELIVERY

Davis and Elkayam JACC 2020

Case

• Presented at 36 weeks gestation with PPCM and moderate to severe LV systolic dysfunction

• What is your recommendation for the mode of delivery?

1. Vaginal delivery

2. Cesarean delivery

Case

• Presented at 36 weeks gestation with PPCM and moderate to severe LV systolic dysfunction

• What is your recommendation for the mode of delivery?

1. Vaginal delivery

2. Cesarean delivery

Regitz-Zagrosek et al EHJ 2018

Vaginal delivery is recommended as the first choice in most patients

I C

Cesarean delivery should be considered for obstetrical indications or for patients with ….. severe heart failure

IIa C

Case

• Induced at 37 weeks

• Arterial line

• Epidural

• Assisted vaginal delivery

• Oxytocin

Case

• Is it safe to breastfeed?

1. Yes

2. No

3. Unknown

Case

• Is it safe to breastfeed?

1. Yes

2. No

3. Unknown

Regitz-Zagrosek et al EHJ 2018

Due to the high metabolic demands of lactation and breastfeeding, preventing lactation may be considered in patients with severe heart failure

IIb B

In patients with PPCM, bromocriptine treatment may be considered to stop lactation and enhance recover

IIb B

Breastfeeding

Decisions on whether to inhibit lactation and terminate breastfeeding should be decided jointly with the patient on a case-by-case basis factoring in the health of the mother and the benefit of breastfeeding for the infant

Case

• Any other postpartum recommendations?

Regitz-Zagrosek et al EHJ 2018

It is recommended to treat women with HF during pregnancy according to current guidelines for non-pregnant patients, respecting contraindications for some drugs in pregnancy

I B

Medications during Breastfeeding

Heart Failure Medications

Lactation

Βeta-blockers Yes

Lasix Yes, but over-diuresis can lead to decreased milk production.

Hydralazine + Nitrates Yes, but ACE-I/ARB typically chosen post-partum

Digoxin Yes

ACEI or ARB Enalapril and captopril can be used

Spironolactone Spironolactone can be used

Sacubitril-valsartan No information in human, present in rat milk

Ivabradine No information in human, present in rat milk

Modified from Davis and Elkayam JACC 2020

ANTICOAGULATION

• Therapeutic anticoagulation is recommended in women with intracardiac thrombus or atrial fibrillation

• ESC Guidelines on the Management of Cardiovascular Disease in Pregnancy do not provide recommendations about prophylactic anticoagulation

• ESC Position Statement on PPCM recommended prophylactic anticoagulation because of the high rate of peripheral arterial and venous embolism Bauersachs et al EHJ 2019

Regitz-Zagrosek et al EHJ 2018

www.researchgate.net/figure/The-wearable-cardioverter-defibrillator

• 12 women with PPCM• 7 with an LVEF < 35% agreed to a use a

wearable cardioverter defibrillator (WCD)

• 2 women refused• During a medial of 81 days, there were

episodes of 4 ventricular fibrillation with appropriate and successful WCD shock in 3 women

• No deaths in the women not using a WCD

Duncker et al Eur J Heart Fail 2014

• Retrospective study in 107 women with PPC and a wearable cardioverter/defibrillator (WCD)

• Average follow up 4 months

•No shocks were delivered

•No deaths when using the WCD; 3 deaths after it was removed

Saltzberg et al J Card Fail 2012

POSTPARTUM CONSIDERATIONS

Davis and Elkayam JACC 2020

Objectives

Overview of PPCM

Clinical presentation

Treatment options

Prognosis

RECOVERY OF LEFT VENTRICULAR SYSTOLIC FUNCTION

Elkayam JACC 2011

LVEF AT PRESENTATION

AND LATE OUTCOMES

McNamara et at (IPAC) JACC 2015

OUTCOMES ACCORDING

TO LV SIZE AND

FUNCTION

•No subjects with both a baseline LVEF <30% and an LVEDD ≥6.0 cm recovered by 1 year postpartum

• 91% of subjects with a baseline LVEF ≥30% and an LVEDD <6.0 cm recovered by 1 year postpartum

McNamara et at (IPAC) JACC 2015

Poor PrognosisLower LVEF

Dilated LV

LV thrombus

Obesity

African American race

Concomitant pre-eclampsia

Biomarkers: NTBNP, troponin, sFlt1

Delayed diagnosis

Case

• PPCM and moderate to severe LV systolic dysfunction

• How long does she need to stay on her heart failure medications?

1. Indefinite

2. 1 year

3. 3 years

4. Until the LV systolic function recovers

5. Depends

Case

• PPCM and moderate to severe LV systolic dysfunction

• How long does she need to stay on her heart failure medications?

1. Indefinite

2. 1 year

3. 3 years

4. Until the LV systolic function recovers

5. Depends

Withdrawal of Medication

Women should remain on combined drug therapy for heart failure until they experience complete myocardial recovery and for at least 12–24 months after full recovery of LV function

Bauersachs et al EHJ 2019

Withdrawal of Medication

For women with full recovery of LVEF:

•Some experts recommend that all women with PPCM remain on long-term therapy

•Some experts recommend gradual withdrawn under careful surveillance with serial cardiac imaging and biomarker measurement

•A discussion between patient, family and clinicians is necessary where the pros and cons of stopping or continuing therapy are carefully considered

Case

• Full recovery of LV systolic function

• Can she have another pregnancy?

1. Yes

2. No

3. Maybe

Case

• Full recovery of LV systolic function

• Can she have another pregnancy?

1. Yes

2. No

3. Maybe

Maternal Complications with Subsequent Pregnancies

HF >20% drop Persistent Mortality

LVEF Dysfunction

Elkayam et al NEJM 2011

Red = LV recoveryGreen = persistent LV dysfunction

Regitz-Zagrosek et al EHJ 2018

In patients with PPCM and DCM, counselling for recurrence risk during subsequent pregnancy is recommended in all cases, even after recovery of LV function

I C

In patients with PPCM, subsequent pregnancy is not recommended if LVEF does not normalize.

III C

SUMMARY: DEFINITION

Davis and Elkayam JACC 2020

SUMMARY: MANAGEMENT

Davis and Elkayam JACC 2020

SUMMARY: POSTPARTUM

Davis and Elkayam JACC 2020

SUMMARY: LONGTERM OUTCOMES

Davis and Elkayam JACC 2020

Thank you