a case report of a rare cause for postpartum heart failure

Predominant causes for newly diagnosed postpartum heart failure are preeclampsia and peripartum cardiomyopathy. Being an anatomical variant of Takotsubo syndrome (TTS) reverse TTS in this period is rare. We present a 36 year old patient, who had delivered triplets by cesarean section. Because of postpartum bleeding she was administered sulprostone. Later she was transferred to the Intensive Care Unit with sudden development of dyspnea, tachypnea and tachycardia. Clinical symptoms, laboratory findings and chest radiograph showed signs of acute heart failure. Transthoracic echocardiography (TTE) revealed reverse TTS with moderately reduced left ventricular ejection fraction (LVEF 39%). The patient stabilized with loop diuretic, angiotensine-converting enzyme inhibitors and beta-blockade. Breast-feeding was discouraged and bromocriptine administered. Left ventricular function normalized (LVEF 60%) within four weeks. TTS should be considered in patients with early postpartum development of heart failure. Rapid cardiac recompensation after the start of adequate therapy and complete resolution of clinical symptoms and TTE findings are typical for postpartum TTS.


Introduction
Heart failure during and after pregnancy can be caused by e.g. preexisting cardiovascular disease, hypertensive complications (e.g. preeclampsia, HELLPsyndrome), pulmonary embolism, peripartum cardiomyopathy (PPCM), previously unrecognized genetic forms of cardiomyopathies, myocarditis. 1 Pregnancy related takotsubo syndrome (TTS) as cause of acute heart failure has been described in rare cases, with e.g. 18 cases identified by Minatoguchi et al. in 2014. 2 We present a case of a rare variant of postpartum TTS, with a hyperkinetic cardiac apex and wall motion abnormalities at the base of the left ventricle, also known as Reverse TTS. Only few cases with this rare anatomical variant of TTS related to pregnancy have been described. [3][4][5][6][7][8]

Patient information and physical examination
We present a 36 year old patient, who delivered triplets by cesarean section at week 32+5 of pregnancy (secundigravida, 1 missed abortion) ( Table 1). During cesarean section a Bakri® Balloon had been placed to prevent postpartum hemorrhage and tranexamic acid was given. Yet because of insufficient uterus-contraction and postpartum bleeding additionally sulprostone (approximately 500 µg) was administered, followed by nasal oxytocin (4 units four times a day) for 3 days.
On the third day after cesarean section the patient developed dyspnea, tachypnea and tachycardia. Respiration rate was 20/min, pulse oximetry showed 90% oxygenation, heart rate was 145 beats per minute and blood pressure was 133/84 mmHg. General examination was significant for a patient in distress with intermittent expiratory stridor. Physical examination showed slight peripheral pitting edema without distended jugular veins, hepatojugular reflux was negative. Auscultation of the lungs revealed bilateral basal rales, cardiac auscultation was normal.

Diagnostic assessment and interventions
Electrocardiography showed sinus tachycardia with no ST-segment elevation or depression, but T-inversion in aVL and I. A chest radiograph revealed pulmonary congestion, bilateral pleural effusions and cardiomegaly. High-sensitivity cardiac Troponin T was elevated at 33 ng/L (cut-off value 14 ng/L), Creatine Kinase-MB 3.8 µg/L (cut-off value 5 µg/L), D-Dimer at 1.18 µg/mL (cut-off value 0.5 μg/mL) and NT-proBNP at 9254 ng/L (cut-off value 177 ng/L), hemoglobin was 82 g/L (lower cutoff value 100 g/L). CT-angiography of the chest showed no signs of pulmonary embolism.
A transthoracic echocardiography (TTE) showed a moderately reduced left ventricular ejection fraction (LVEF) of 39%. Contractility of the apex was hyper dynamic with a hypo-to akinesia of all basal segments (link to sequence for online publication). A small pericardial effusion was seen near the right atrium. We presumed postpartum heart failure due to reverse TTS with the differential diagnosis of PPCM. Two days later cardiac magnetic resonance imaging ( Figure 1) confirmed an apical hyperkinesia with basal to midventricular hypokinesia and akinesia without evidence of myocardial edema in T2 mapping sequences. Bilateral pleural effusions were still present. A myocardial edema in the areas of wall motion abnormality was not found. There was no evidence of myocardial late gadolinium enhancement ( Figure 2). By the cardiac MRI, we were able to exclude myocardial infarction or myocarditis as the cause of her acute heart failure. 9 The initial therapy for acute heart failure was intravenous loop diuretic (furosemide 40 mg) and 30 mg of labetalol because of tachycardia. Another 40mg of furosemide were administered when clinical benefit from the first dose was insufficient, which then led to a diuresis of 2 L over 2 h. Patient received non-invasive ventilation and was transferred to the Intensive Care Unit (ICU). Treatment was adapted with a short acting beta-blocker (propanolol 10 mg three times daily), ACE-I (enalapril 5 mg) and intravenous loopdiuretic (furosemide). Because the patient wished to stop breast-feeding and the initial differential diagnosis of PPCM bromocriptine 2.5 mg twice a day was started according to current recommendations. 10 Beta-blockade was changed to carvedilol (6.5 mg/day) and we interchanged enalapril to ramipril (5 mg/day). Receiving a total of 120 mg furosemide the resulting diuresis of 5 L in the first 24 h led to complete clinical stabilization and decrease of NT-proBNP to 7904 ng/L.
During her stay on ICU, clinical situation improved, ACE-I and betablockade could be increased, loop-diuretics were decreased and changed to an oral form (torasemide). Patient could be transferred to regular ward after 3 days.

Follow-up and outcomes
Before hospital discharge 14 days after admission to the ICU there were no signs of heart failure in the physical examination anymore. Accordingly, no pleural effusions were found with ultrasound anymore. The patient was discharged from the hospital. 4 weeks after discharge, the global and regional left ventricular function was normalized in TTE. LVEF was measured at 60%. Accordingly, NT-proBNP reached normal level (85 ng/L).
Over the next months the ACE-Inhibition and beta-blockade was tapered due to low blood pressure and orthostatic hypotension and stopped completely after 7 months. TTE and NT-proBNP still remained normal after 9 months.

Discussion and Conclusions
In the presented case, the patient showed a sudden development of symptoms of postpartum heart failure three days after delivery of triplets by cesarean section. TTE findings were leading us to the diagnosis of reverse TTS.
For diagnosis we followed the revised Mayo-criteria of the Takotsubo Italian Network and Heart Failure Association of the European Society of Cardiology diagnostic criteria for Takotsubo syndrome. 11,12 Following these criteria, we did not exclude an acute coronary plaque rupture, dissection, thrombosis or spasm by coronary angiography. Yet we found Tinversion in ECG without ST-segment elevation or depression supporting our diagnosis. In the laboratory results we saw a significant and completely reversible elevation of NT-proBNP. Creatine-Kinase-MB never exceeded the above mentioned 3.8 µg/L and high-sensitivity Troponin T never exceeded 33 ng/L, also supporting the diagnosis of TTS. Yet it is possible that the increase seen for Troponin could be explained by the postpartum state alone. Late gadolinium enhancement in the MRI was negative, which is considered typical for TTS, further strengthening our diagnosis by imaging and also excluding myocarditis. 13 But the MRI missed proof of myocardial edema in the areas of wall motion abnormality as is common in TTS. Under therapy with beta-blockade, ACE-I and loop diuretics we achieved a rapid recovery during 48 h and complete recovery of left ventricular function after 4 weeks, as confirmed in TTE. Cesarean section and birth were viable stressful events preceding the development of the first symptoms.
Considering other possible diagnoses for this patient there were no signs of myocarditis. A genetic form of a cardiomyopathy was improbable, as a complete recovery was seen after 9 months. Also there were no findings for preeclampsia. Acute heart failure due to peripartum cardiomyopathy (PPCM) would differ in the evolution of the disease and left ventricular dysfunction, as well as NT-proBNP would not normalize within four weeks. 1 A systematic review by Citro et al. led to the conclusion that peripartum TTS should be considered a clinical entity different from PPCM. 14 A sudden onset of symptoms with a rapid worsening of the clinical presentation requiring immediate therapy is considered typical for TTS. In contrast to TTS a complete normalization of left ventricular function was only observed in a minority of patients with PPCM and clinical symptoms were increasing over time. 12 Physical and emotional stress, as wells as administration of catecholamines/ vasoconstrictive substances during cesarean section have been discussed to cause pregnancy related TTS, with the majority of cases developing symptoms at time of cesarean section up to 6 days later. 2,12 The main risk factor for development of TTS in the postpartum period seems to be the cesarean section itself, which often comprises stress, emotionally and physically, as well as the administration of adrenergic stimulants and anticholinergics. 12,15 In our case the administration of sulprostone after the cesarean section can be discussed as an additional cause for the development of TTS, as sulprostone has been associated with TTS before. 16,17 Diffuse coronary spasm alone due to the sulprostoneadministration as a theoretical cause for TTS is possible. Still, the administration was stopped before the patient developed the first clinical symptoms of acute heart failure.

Clinical and Experimental Cases/Hypothesis
We did not exclude a pheochromocytoma as requested in above mentioned diagnostic criteria.
Following the above mentioned criteria we miss proof for the absence of acute coronary plaque rupture, dissection, thrombosis or spasm as coronary angiography was not done. The clinical and diagnostic follow up nevertheless showed no signs for a coronary heart disease. We also miss myocardial edema in the areas of wall motion abnormality in the MRI, as it is present in approx. 80% of TTS cases. 18 Yet we saw no late gadolinium enhancement and no signs for myocarditis or myocardial infarction. MRI was performed when the patient had already stabilized, while TTE was performed while she was still in acute heart failure. The remaining criteria were fulfilled following either the revised Mayocriteria of the Takotsubo Italian Network or the Heart Failure Association of the European Society of Cardiology diagnostic criteria for Takotsubo syndrome. 11,12 Meanwhile new international criteria the InterTAK Diagnostic Criteria and Diagnostic Score/Algorithm were published (Tables 2 and 3). 19,20 Following these new criteria, pheochromocytoma no longer have to be excluded as the findings during a catecholamine storm are considered indistinguishable from TTS. 19,20 With the new InterTAK Diagnostic Score our patient scores 74 points (Female Sex 25 points, Emotional Stress 24 points, Physical Stress 13 points, No ST-segment depression 12 points), which gives a high probability for TTS (cut off 70 points). The TTE and MRI findings as well as the clinical development we saw in our patient further support our diagnosis following these new diagnostic score and algorithm. Yet again we miss the exclusion of coronary artery disease with coronary computed tomography 4 weeks before admission ICU Admission to hospital because of shortened cervical length during pregnancy with dichorial-triamniotic triplets 3 days before admission to ICU Caesarean section, with Bakri Balloon placement and due to atone uterus with postpartum bleeding administration of sulprostone followed by oxytocin At admission to ICU Acute heart failure presenting with dyspnea, tachycardia, pleural effusions, slight peripheral edema, NT-proBNP 9254 ng/L TTE showed wall motion abnormalities, LVEF 39% Loop-diuretic, beta-blockade and ACE-inhibition were started 2 days after admission to ICU MRI without typical edema Patient stabilized, NT pro BNP at 6421 ng/L Bromocriptine was started, patient stopped breast feeding 14 days after admission to ICU Patient still stable, left hospital 4 weeks after presentation TTE showed no regional wall motion abnormalities with LVEF 60% and NT-proBNP 85 ng/l. No pleural effusions or other signs of heart failure Therapy: Beta-blockade and ACE-Inhibition 9 months after presentation Medication was stopped, TTE and NT pro BNP remained normal angiography, as it is recommended in this algorithm.

Online videos
The sequence of online videos shows cine loops of the first echocardiography performed in the intensive care unit showing hyperkinetic apex and wall motion abnormalities in the basal segments: Video 1) 4-chamber view; Video 2) 2-chamber view; Video 3) 3-chamber view.