ABSTRACTPeripartum cardiomyopathy is an idiopathic cardiomyopathy that most commonly affects women in the third trimester of pregnancy or in the first five months of the postpartum period. It has been associated with a myriad of different findings on electrocardiograms and arrhythmias. This review discusses these electrocardiogram changes and arrhythmias in regards to prevalence, genetic landscape, screening and prognostication implications, and management. Keywords: Cardiology, electrophysiology, peripartum, cardiomyopathy, arrhythmia, pregnancy INTRODUCTIONPeripartum cardiomyopathy (PPCM) in the United States has an incidence rate of 1 in 1,000 to 1 in 4,000. (1) The most commonly used definition for PPCM was developed by the 2010 European Society of Cardiology Working Group on Peripartum Cardiology, which described it as 1. an idiopathic cardiomyopathy with the absence of other identifiable causes of HF, 2. left ventricular ejection fraction (EF) less than 45%, 3. within the 3rd trimester of pregnancy or five months following the pregnancy in the postpartum period. (2) Patients with PPCM are at a high likelihood of recurrent hospital readmissions. Half of these admissions are cardiac-related, and approximately 15% of these cardiac-related admissions are secondary to arrhythmias. (3) Arrhythmias are not uncommon in this population and have been associated with increased maternal mortality. (4,5) In a retrospective study published in 2017 that used the Healthcare Utilization Project Nationwide Inpatient Sample database, there was a prevalence of 18.7% of arrhythmias in patients hospitalized with PPCM from a total of 9841 patients. (6) Within this population, 4.2% of the arrhythmias were characterized as ventricular tachycardia, followed by atrial fibrillation (AF) at 1% and ventricular fibrillation (VF) at 1%. (6) The remaining burden of arrhythmias were classified as “unspecified arrhythmias”. Among these 9,841 patients, 6.8% of them had implantable cardioverter-defibrillator (ICD) placement, permanent pacemaker (PPM) placement in 3.4%, catheter ablation in 1.9%, and electrical cardioversion in 0.3%. Genetic Landscape of PPCMPeripartum cardiomyopathy and its genetic underpinnings remains poorly described in literature. Multiple genetic variants have been historically associated with peripartum cardiomyopathy, including TTN, FLNC, DSP and BAG3. (7) These genetic variants are often seen in dilated cardiomyopathy, supporting a similar genetic predisposition. In a study of 172 patients with PPCM, about 15% of them harbored bore truncating loss-of-function variants in TTN (TTNtvs), similarly to a group of patients with dilated cardiomyopathy. (8) The significance of TTN genetic mutations remains unknown, however a post hoc analysis of the Investigations of Pregnancy Associated Cardiomyopathy (IPAC) cohort showed that patients with TTNtvs have worse cardiac outcomes compared to patients without TTNtvs at 1 year follow up. (8) Patients with these TTN truncating variants often have lower ejection fractions, conferring more aggressive disease since ejection fraction is a strong predictor of clinical outcomes in PPCM. (7) Patients with truncating variants in FLNC have higher rates of malignant arrhythmias and may warrant aggressive antiarrhthmyic management. (9,10) These findings suggest the importance of genetic-phenotypic manifestations, which has therapeutic implications. For example, gene-specific therapies in dilated cardiomyopathy have led to lower thresholds for considering placement of defibrillator devices in patients with the truncated FLNC variant. In a article by Goli et al., this same approach is recommended to patients with PPCM who harbor a truncated FLNC variant. (7) These findings are summarized in Table 1. Further studies are warranted to investigate the diagnostic and therapeutic implications of these genetic variants in the setting of PPCM, especially from an arrhythmogenic standpoint. ELECTROGRAM FINDINGS In patients with PPCM, normal ECGs are rare. (11) Common ECG findings include sinus tachycardia, ST-segment changes, Q waves primarily in the anterior precordial leads, prolonged PR and QRS intervals, T wave inversions, and QTc interval prolongation. (13-15) A few of the most common abnormalities on the initial ECG at the time of diagnosis were T-wave changes (59% of patients), sinus tachycardia (45% of patients), QTc changes (44% of patients), P wave abnormalities (29% of patients), and QRS axis deviation (25% of patients). (13-16) Many cases of dilated cardiomyopathy that are not PPCM have a prevalence of bundle branch blocks in about 25-30% of patients. (17,18) However, in patients with PPCM, QRS complexes are often wider but do not usually meet the criteria of being >120 msec, and seldom have left or right bundle branch blocks. (13-15) Only about 1% to 5% of patients have a either a right or left bundle branch block. (13,15) QRS duration in patients with PPCM has been shown to be moderately correlated (r=0.4; p<0.003) with left ventricular end-systolic dimension (LVESD), left ventricular end-diastolic dimension (LVEDD), and left ventricular end-systolic volume index (LVESVI). (14) Honigberg et al. found that patients with an initially abnormal ECG at the time of diagnosis (those with a bundle branch block, ventricular hypertrophy, ST-segment elevation/depression, or atrial abnormalities) were more likely to have a larger left ventricular end-diastolic dimension (58 vs. 54 mm, P= 0.002). (13) Sinus tachyardia is also associated with an ejection fraction <35% (P= 0.006), and QRS, LBBB, and LVH were all associated with LVEDD >55 mm (P= 0.018, 0.017, and 0.017, respectively). (19) PROGNOSTICATION OF ECG FINDINGS An increase in incidence of sinus arrhythmia during follow-up visits is associated with an event-free survival, including no death or readmissions. (16) Major T wave changes on the initial ECG are associated with a lower ejection fraction at the time of diagnosis and during the 6-month follow-up. (15,16) However in a study by Honigberg et al., T wave inversions were not associated with worse outcomes. (13) Another PPCM cohort study published in 2019 showed that positive T waves in aVR were associated with adverse cardiac outcomes. (20) ST-segment elevation and depression are associated with a decreased EF at 6-month follow-up. (15) Sinus tachycardia was found to be an independent predictor of poor outcomes. (16,21) Prolonged QTc was also found to be associated with adverse cardiac outcomes. (16) Left atrial abnormalities were associated with a lower EF at 6 and 12 month follow up, and predicted decreased event-free survival at 1 year follow-up compared to those with no left atrial abnormalities (75% vs 97%, P= 0.008). (13) These left atrial abnormalities on ECG are 96% specific for left atrial enlargement seen on echocardiogram, however only 38% sensitive. Left ventricular hypertrophy (LVH) identified on baseline ECG using the Cornell voltage criteria or the Sokolow-Lyon criteria was associated with a lower EF at initial time of diagnosis, compared to those without LVH on ECG (27% versus 35%, P= 0.03). Normal ECGs at baseline during initial diagnosis are associated with complete recovery of EF (EF > 50%) in about 84% of patients as compared to 49% of patients who had abnormal ECGs at baseline. (13) Also, event-free survival was found in 100% of patients who had normal ECGs at baseline versus 85% in patients with abnormal ECGs (p= 0.01). (13) Patients with an abnormal ECG at baseline (those with a bundle branch block, ventricular hypertrophy, ST-segment elevation/depression, or atrial abnormalities) are more likely to require inotropic therapy. (13) As for patients who present with PPCM and persistent bradyarrhythmia, approximately 7% of these patients will require permanent pacing. (22) These findings are summarized in Table 2. ARRHYTHMIAS IN PPCMThe true prevalence of brady- and tachyarrhythmias may be underdiagnosed since an ECG only screens at one point in time. (13-15) The majority of patients who are diagnosed with PPCM and undergo ECG testing are found to be in sinus rhythm, often including sinus tachycardia. (14,15,21) Patients that present in sinus tachycardia often have decreasing heart rates on subsequent visits. (16,23) There was a mean reduction of 27 beats/minute on 6-month follow-up appointments in one study. (15) About 25% of patients have normalization of these ECG abnormalities on follow-up appointments 6-months post-diagnosis. (15) Ambulatory ECG monitoring can extend the recording time to screen for arrhythmias while also allowing for more accurate monitoring during everyday activities. A study done by Diao et al. showed that the Holter monitor was able to diagnose a greater frequency of premature atrial and ventricular contractions as compared to a 10-second ECG in patients diagnosed with PPCM. (21) In this study, premature atrial contractions were seen in 21% of all patients, premature ventricular contractions in 36.8% of patients, and sinus tachycardia in 89.4% of patients. A recent clinical trial recruited 40 pregnant patients that had symptoms of arrhythmia and/or structural heart disease, and were randomized to a 24-holter ECG monitor versus a 24-holter ECG monitor plus an implantable loop recorder (holter-ILR group). (37) The holter monitor detected arrhythmias in 13% of patients in the holter monitor only group, and 24% of patients in the holter-ILR group. In the holter-ILR group, the ILR detected arrhythmias in 53% of patients. Seven patients were missed by the holter monitor in the holter-ILR group which included 4 patients with SVT, 1 with premature ventricular complexes, and 2 with paroxysmal AF. (37) External and implantable loop recorders are the preferred method of cardiac recording when infrequent arrhythmias are suspected. 1. Ventricular arrhythmias Ventricular arrhythmias may occur in up to 20% of all patients with PPCM. (21) Cases of peripartum polymorphic ventricular tachycardia such as Torsades de pointes, monomorphic ventricular tachycardia, and ventricular fibrillation has been described. (25-27) Ventricular tachyarrhythmias are the culprit in 25-39% of all-cause mortality and are an independent predictor of in-hospital mortality, increased hospital costs, and longer length of hospitalization. (22,28,29) Severely reduced EF significantly increases the risk of non-life-sustaining arrhythmias, which may still occur even after normalization of EF. A study done by Duncker et al. reported that 3 out of 12 women with PPCM were found to have a total of 4 episodes of ventricular fibrillation over a 2.5 year period. (30) One patient developed the episode of VF after her EF was found to have improved to 45%. Although this study has a poor sample size, equating the risk of VT/VF with the EF as a sole factor is not a reliable method of risk stratification. Included within the subset of ventricular arrhythmias, it is important to be aware that frequent premature ventricular contractions (PVCs) can further induce cardiogenic dysfunction and systolic failure. This is highly dependent on the frequency of the PVCs, as a PVC burden that is at least 24% of all beats has a high sensitivity and specificity in determining whether there is a dysfunctional left ventricle. (31-33) Long-term recurrence of ventricular arrhythmia is highly dependent on recovery of the ventricular tissue. 2. Supraventricular arrhythmias and atrial fibrillationSupraventricular arrhythmias are not common in patients diagnosed with PPCM and are found in less than 1% of patients. (16) Similarly, only 1% to 3% of patients with PPCM have atrial fibrillation. (6,34) On the contrary, supraventricular tachycardia (SVT) in pregnant patients without diagnosed PPCM is seen in about 24 per 100,000 admissions, making it the most common arrhythmia in pregnancy. (35) MANAGEMENT AND PREVENTIONManagement of Peripartum CardiomyopathyThe management of PPCM is dependent on the timeframe of PPCM. In the antepartum period, not all contemporary guidelines of treating heart failure apply as many of the mineralocorticoid receptor antagonists (MRA), ACE-inhibitors (ACE-I), and angiotensin receptor blockers (ARBs) have toxic effects on the fetus and should be avoided during pregnancy. Nitrates and hydralazine are the preferred treatment as a form of afterload reduction. Loop diuretics including furosemide can also be considered in cases where acute pulmonary vascular congestion is suspected. Beta-blockers should be initiated with caution. In the postpartum period, guideline-directed medical therapy (GDMT) guidelines for heart failure with reduced ejection fraction apply to the treatment of PPCM patients. (38) This includes beta-blockers, ACE-I/ARBs, MRAs and SGLT-2 inhibitors. Given that elevated prolactin level in PPCM has been hypothesized to be pathogenic in PPCM, bromocriptine was proposed as a option for theapy. (39-41) However, the use of bromocriptine therapy in PPCM remains controversial. (1) If a patient is started on bromocriptine, concomitant anticoagulant therapy should be considered to decrease risk of thromboembolic complications. (42) A study conducted in South Africa reported improved outcomes in patients diagnosed with PPCM who had elevated inflammatory markers and were treated with pentoxifylline, however further investigation is warranted. (43) Management of Supraventricular TachycardiaTreatment is dependent on patient hemodynamics. During both the ante- and postpartum periods, patients that are hemodynamically stable should undergo vagal maneuvers to terminate the rhythm. If unsuccessful, adenosine can be considered. Beta-blockers can also be considered, especially for prophylactic purposes. If none of these pharmacological agents are successful in controlling the SVT, or if hemodynamic instability ensues, next best step would be to utilize direct current cardioversion (DCCV). In the setting of pre-excitation, prevention therapy should include the use procainamide, while avoiding AV nodal blocking agents. Table 3 provides more guidance on the associations of certain anti-arrhythmic medications in the antepartum and postpartum periods that can be considered for the management of such arrhythmias. (42,44-54) Finally, catheter ablation may be warranted in difficult to control or refractory SVTs. Electroanatomic mapping systems are preferred in this population, especially during the antepartum period, to reduce exposure of fluoroscopy. (55) Radiation exposure during a fluoroscopy-utilized procedure is unlikely to cause fetal harm given that the uterus is not within the field of view. For example, when the field of view is the chest from a posterior-anterior or lateral view, the mGy dose that the fetus is exposed to is <0.002. Most fetal adverse effects typically occur when mGy is at least 50-100, hence a non-concerning amount of radiation absorption. (56) Nonetheless, there has been great enthusiasm for electroanatomic mapping systems and this is the preferred option in capable centers to avoid radiation exposure. Management of Atrial Fibrillation or FlutterAtrial fibrillation or flutter should be managed with a goal of rate versus rhythm control and anticoagulation, similarly to the non-PPCM population. Beta-blocker therapy is often the initial medication class of choice for rate control. Atenolol should be avoided during the antepartum period and postpartum if breastfeeding. Sotalol can be considered for rhythm control as it is considerably safe in pregnancy and in the postpartum period. There is limited safety data on dofetilide in pregnancy. Dronedarone and amiodarone are contraindicated in pregnancy and the postpartum period as there remains a risk of neonatal toxicity with lactation. If refractory, digoxin can be considered. Due to reduced ejection fraction in PPCM, calcium-channel blockers are generally contraindicated. (57) DCCV is preferred for patients with hemodynamic instability or if symptomatic and refractory to medical therapy. Catheter ablation (zero-fluoroscopy preferred) is an option if medications fail however is often deferred until the postpartum period. (58,59) Anticoagulation with heparin products, particulary low-molecular weight heparin (LMWH), is the preferred method during pregnancy as this does not cross the placenta, and is less likely to cause bleeding, osteoporosis, or thrombocytopenia as compared to unfractionated heparin. LMWH should be discontinued about 12 hours prior to delivery, and resumed about 24 hours after cesarean delivery, 12 hours after vaginal delivery, and 2-12 hours after epidural removal. (60) Direct oral anticoagulant therapy (DOAC) should be avoided during the antepartum period given minimal data regarding its use in pregnancy and known fetal toxicity with some of the common DOAC medications. (61) However, in the postpartum period, DOACs are safe to use and often utilized. Management of Ventricular TachycardiaPatients with PPCM are at high risk of developing ventricular arrhythmias and hemodynamic instability. Medications that are commonly used within the third trimsester of pregnancy should be utilized cautiously as these medicaitons can prolong the QTc and increase the risk of ventricular arrhythmias. These medications include oxytocin, anesthetics such as sevoflurane, and anti-emetics. In both the antepartum and postpartum periods, ultimate treatment should be targeted at repleting deficient electrolytes or cessation of culprit medications. In both the antepartum and postpartum period, hemodynamically stable ventricular tachycardia can be managed with beta-blockers, lidocaine, and sotalol, as these medications are generally safe in pregnancy and in the postpartum period. These medications are also effective as prophylactic agents. During the antepartum period, procainimide and quinidine can be considered if refractory to other initial pharmacological agents, however, their use should be limited considering their risk of fetal toxicity. Quinidine should be avoided during breastfeeding. Procainamide can be considered during breastfeeding if used at the lowest dose possible. Verapamil can be considered in the setting of fascicular VT, however, should be utilized cautiously given it crosses the placenta and is secreted into breast milk. (62) Magnesium intravenous therapy can be used in the setting of polymorphic VT or torsade de pointes. (48) If hemodynamic instability ensues, DCCV should be of high priority. VT ablation is also a possible intervention in the antepartum period, however, is often deferred until the postpartum period. (63) Utilization of electroanatomic mapping systems is preferred if ablation is done during pregnancy. (64) Management of Cardiac ArrestApproximately 2.2% of patients with PPCM and arrhythmias develop cardiac arrest. (6) During cardiac arrest, medications and defibrillation should not be withheld for concerns of maternal and/or fetal teratogenicity or toxicity, done at the same doses as in the non-pregnant population. Compressions are recommended in concordance with the ACLS guidelines. In the antepartum period, manual lateral displacement of the uterus could be done to prevent aortocaval compression. Within 4 minutes of resuscitation efforts without achievement of ROSC, emergency C-section should be considered to maximize chance of fetal viability. (65) Management of Premature Ventricular ComplexesIf frequent PVCs are contributing to cardiomyopathy in PPCM, treatment is warranted. First-line therapy includes beta-blockers. Catheter ablation can also be considered for these patients if they fail medical management in both the antepartum and post-partum periods. (33) A meta-analysis of 27 cases demonstrated that ablation in the pregnant population during the antepartum period is an effective therapeutic approach regardless of ejection fraction. (55) Complications included one case of pre-eclampsia complicated by placental abruption five weeks after ablation and one case of microcephaly. Ablation modalities that use intracardiac echocardiogram and electroanatomic mapping systems are preferred, and should be completed in left lateral decubitus positioning for prevention of aortocaval compression. In the post-partum period, catheter ablation modalities are highly dependent on center specific guidelines and protocols. Direct-Current CardioversionDCCV is an efficacious modality for terminating tachyarrhythmias in patients with PPCM. (66) Infrequent complications during the antepartum period include increased uterine contractions, spontaneous preterm deliveries, fetal cardiovascular distress, and maternal death. (67-69) During the antepartum period, defibrillator pads should be placed away from the gravid uterus, positioned in the left lateral decubitus position, fetal monitoring to assess for fetal compromise, and resources available for emergency cesarean section. (69,70) The postpartum patient can undergo DCCV similarly to the non-pregnant population. Pacemaker ImplantationApproximately 7% of patients with PPCM and persistent bradycardia will require PPM placement. (22) Device implantation can be conducted using minimal fluoroscopy methods and an electroanatomic navigation guidance system. (71) One consideration for patients who are pacemaker dependent undergoing cesarean delivery is to reprogram the pacemaker into an asynchronous mode and use bipolar cautery. This is done to avoid any pacemaker inhibiton caused by noise interference. (72) Implantable Cardioverter DefibrillatorIndications for placement of an ICD in patients in the United States include those with severely reduced EF < 35% despite optimal medical therapy or as secondary prevention in those with ventricular arrhythmias. (22,73) ICD placement should be considered in patients with PPCM, however, exercised with caution. (74-76) In PPCM, about 41.5% to 57.5% of all patients undergo complete left ventricular (LV) recovery. (34) LV recovery is most often seen within the first six months after the diagnosis of PPCM, and rarely occurring past the 12-month mark. Patients with PPCM who do not undergo ventricular recovery within six months following delivery have been associated with high mortality rates, and ICD may provide benefit in these groups of patients. (77-79) ICD implantation can be done by utilizing minimal fluoroscopy, electroanatomic navigation guidance systems, and transesophageal guidance. (80-85) Cardiac resynchronization therapy can also be considered for patients with PPCM who fail to undergo complete LV recovery within a 6-month time span. (86) Specific to defibrillator therapy, an alternative option is fluoro-less implantation of a subcutaneous ICD system which is often used in patients with complex anatomy and difficult endovascular lead access. (87-89) For patients at high risk of sudden cardiac death without left ventricular recovery, a subcutaneous ICD is a safe alternative. The 2022 ESC guidelines classify the S-ICD as a class-lla recommendation for patients who require ICD without the need for cardiac resynchronization therapy or pacing for bradycardia. (90,91) However, given recent innovative advancements in cardiovascular medicine, the inability to pace may eventually be overcome with use of leadless pacemakers. Inactivation of the S-ICD may be warranted near delivery considering risk of inappropriate shock deliveries, emphasizing the importance of frequent patient monitoring and availability for manual shock delivery. A wearable cardioverter defibrillator (WCD) is also an option as a temporary measure. In a study by Duncker et al., 4 out of 7 patients with PPCM and an EF < 35% received biphasic shocks from their WCD for an episode of ventricular fibrillation. (30) Another multicenter analysis done in 16 medical centers in Germany showed that 12% of patients with newly diagnosed PPCM and EF <35% had a cumulative rate of 8 ventricular tachyarrhythmias during the period they wore a WCD (mean wear time was 120 days). (92) These tachyarrhythmias included VF, sustained VT, and non-sustained VT. CONCLUSIONPeripartum cardiomyopathy is associated with a myriad of different findings on the electrocardiogram and carries a significant risk of arryhthmias. 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