Abstract Background Natriuretic peptide (NP) receptor activation has a beneficial role in the treatment of heart failure (HF). The enzyme phosphodiesterase (PDE) 9 breaks down cGMP, the second messenger stimulated by natriuretic peptides. PDE9 inhibition may increase intracellular cGMP signaling and, potentially, have beneficial effects in HF. We examined the effects of the selective PDE9 inhibitor CRD-740 on the NP signaling pathway in HF. Purpose The objectives of this early phase 2 trial were to assess the tolerability of CRD-740 and its effects on plasma and urinary cGMP (markers of potential clinical effiacy) in patients with HFrEF, including those receving background treatment with sacubitril/valsartan. Methods Key inclusion criteria were patients with a history of HFrEF of > 6 mos, NYHA II or III, EF < 40% and NT-proBNP ≥600 pg/ml at screening (≥1000 pg/mL if in atrial fibrillation), on treatment with stable guideline-directed therapy for a minimum of 4 weeks. Patients were randomized 2:1 double-blind to CRD-740 (10mg twice daily for 2 weeks, then 25mg twice daily for 10 weeks) or placebo. Tolerability and safety were assessed. The primary pharmacodynamic endpoint was the between-group change from baseline in plasma cGMP at Week 4. Exploratory endpoints included urine cGMP levels, KCCQ and biomarkers. Results 60 patients were randomized to CRD-740 (n=40) or placebo (n=20). Baseline characteristics included age 67+13 yrs, 85% men, EF 28+7%, BMI 30+10, with 73% of patients taking sacubitril/valsartan, and 47% on SGLT2 inhibitors. The primary endpoint was positive, with placebo-corrected change in plasma cGMP significantly increased at all time points at week 4 in those treated with CRD-740 (see Table). cGMP levels were also increased on day 1 (Table) and week 2. A significant increase in urinary cGMP also was observed with CRD-740 vs placebo (Figure) in 6-hour collections at day 1 (p=0.012) and week 2 (p=0.014). In this small study, not powered for exploratory endpoints, directionally favorable placebo-corrected, baseline-adjusted changes also were seen in the KCCQ Clinical (+7.1 [95%CI, -1.6, +15.7], p=0.11) and Overall Summary Scores (+7.4 [-0.8, +15.5], p=0.075) for patients on CRD-740. No significant changes in NT-proBNP were observed between treatment groups. Adverse events (AEs) were observed in 62% and 50% of CRD-740 and placebo-treated patients, with discontinuation in 5% and 10% respectively, with no between-group difference in change in BP. There were no hypotension AEs, and no treatment-related serious adverse events. Conclusions In this early phase 2 trial, PDE9 inhibition with CRD-740 was well-tolerated and resulted in substantial elevations of plasma and urinary cGMP on top of standard care, including sacubitril/valsartan. These results support the potential of PDE9 inhibition to further activate the beneficial effects of the NP receptor-cGMP pathway incrementally to that achieved by existing HF treatments.Changes in Plasma cGMP over Time (ng/mL)Changes in Urinary cGMP over Time

Abstract Background Peripartum cardiomyopathy (PPCM) is a pregnancy-associated form of heart failure, which occurs in previously healthy women towards the end of pregnancy and in the first months postpartum. Previous reports showed a varying prevalence of PPCM across different regions and potentially a higher incidence in patients with black African ethnicity. The correct and timely diagnosis remains challenging and there is a need for novel disease-specific biomarkers. Accuracy in diagnosing PPCM can be improved by using serum-protein biomarkers such as QSOX1, adiponectin and ITIH3 in addition to NT-proBNP. However, it still needs to be ascertained whether there are ethnic differences in proteomic profiles amongst patients with PPCM with different ethnicities. Aims To delineate possible differences in serum protein biomarker profiles across different ethnic groups within the EURObservation Research Programme (EORP) multi-national cohort of women with PPCM. Methods Demographic and clinical data, as well as serum samples were collected from 84 patients with PPCM from seven EORP participating countries. Serum proteomic profiling was conducted using DIA-based label-free quantitative (LFQ) LC-MS at the time of diagnosis from depleted serum samples. Mass spectrometry data were analyzed by Spectronaut v15 using a study-specific spectral library. From the 84 patients in the EORP PPCM registry on whom we performed proteomic analyses, 82 patients self-declared their ethnicity. These 82 patients were assessed for any ethnical differences in their proteomic expression profile using unsupervised principal component analysis (PCA). Results In this cohort of 82 women with PPCM, the mean age was 30.5±6.7 years (Table 1). Three quarters of this cohort had no hypertension during pregnancy and only 13.8% had a prior diagnosis of PPCM. The mean left ventricular ejection fraction (LVEF) was 35% at time of first diagnosis, with no difference between the ethnic groups. However, women of Middle Eastern decent had more severe LV dilatation (LVEDD: 64.0 (62.0-65.0) mm). Three hundred and twenty-nine (329) proteins were identified in the serum samples. As depicted in Figure 1, PCA did not yield a distinct separation between the different ethnic groups. Principal component 1 (PC1) accounted for 15.2% of the total variability in protein expression among ethnic groups, PC2 explained a comparatively lower percentage at 12%. Conclusion The protein biomarkers identified in PPCM patients showed no discernible racial differences, demonstrating consistent performance across all ethnic groups.

Abstract Background Hypertensive disorders of pregnancy (HDP) are estimated to occur in 10% of pregnancies in the general population and preeclampsia specifically in 3–5%. HDP are suggested to be more common in and less well tolerated by women with heart disease. However, the current data are conflicting and this knowledge gap impacts clinical practice guidelines. Purpose To harness the well characterized data of the Registry of Pregnancy and Cardiac disease (ROPAC) to examine the frequency of HDP in women with structural heart disease and its impact on maternal and perinatal outcomes. Methods The ROPAC registry (n=5739) is a worldwide prospective registry on pregnancies in women with heart disease, including congenital heart disease (CHD, n=3295), valvular heart disease (VHD, n=1648), cardiomyopathy (CMP, n=438), aortopathy (AOP, n=217), ischemic heart disease (IHD, n=95), and pulmonary arterial hypertension (PAH, n=45). We defined HDP as either chronic hypertension, gestational hypertension, and/or preeclampsia (including HELLP syndrome and eclampsia) and assessed the frequency of HDP in each heart disease category. Predictors of preeclampsia were identified using multivariable logistic regression. The proportion of women with adverse maternal, pregnancy, and fetal/neonatal outcomes were described among women with preeclampsia or HDP, and compared between women with and women without HDP using chi-square tests. Results In total, the frequency of HDP and preeclampsia was 9.3% and 2.6% in CHD, 7.5% and 2.2% in VHD, 18.7% and 7.1% in CMP, 15.7% and 2.8% AOP, 35.8% and 6.3% in IHD, and 22.2% and 11.1% in PAH. Independent predictors of preeclampsia were chronic hypertension (OR 3.06, 95% CI 2–4.69), nulliparity (2.39, 1.68–3.38), HDP in a previous pregnancy (2.29, 1.11–4.7), gestational diabetes in the current pregnancy (2.13, 1.13–4.03), pulmonary hypertension (1.71, 1.08–2.7) and age (1.04, 1.01–1.07). In women with preeclampsia and heart disease, maternal mortality was 3.5% and heart failure was 29.1%. Maternal mortality (1.4% vs 0.6%, p=0.042), heart failure (18.5% vs 10.6%), Caesarean section (61.2% vs 48.4%), preterm births (27.4% vs 16.9%), low Apgar score (9.8% vs 6.6%), small for gestational age (14.6% vs 9.7%) and neonatal mortality (1.7% vs 0.4%) were higher in women with than women without HDP (all p<0.001 except maternal mortality). Conclusions The frequency of HDP is increased (>10%) in CMP, AOP, IHD and PAH, but not in CHD and VHD. The high frequency of HDP is partly due to chronic hypertension, but the incidence of preeclampsia is also increased (>5%) in CMP, IHD and PAH. Among women with cardiac disease, HDP were associated with adverse maternal and perinatal outcomes. The high maternal mortality rate of 3.5% in women with heart disease and preeclampsia warrants close clinical monitoring and a better understanding of the optimal management strategies in the complex population group. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Funding from “Zabawas Foundation” and “De Hoop Foundation” in addition to the support from EORP is greatly acknowledged. Since the start of EORP, the following companies have supported the programme: Abbott Vascular Int. (2011–2021), Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2021), Bayer AG (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance (2011–2019), Daiichi Sankyo Europe GmbH (2011–2020), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2014–2017), Edwards (2016–2019), Gedeon Richter Plc. (2014–2016), Menarini Int. Op. (2009–2012), MSD-Merck & Co. (2011–2014), Novartis Pharma AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011), Servier (2009–2021), Vifor (2019–2022). HDP in women with heart diseaseIncidence of HDP per diagnosis group

Abstract Background Cardiac disease remains an important cause of maternal morbidity and mortality globally. Peripartum cardiomyopathy (PPCM), defined as heart failure secondary to left ventricular (LV) systolic dysfunction in previously healthy women towards the end of pregnancy or up to five months following delivery, can result in cardiogenic shock due to severe LV dysfunction or arrhythmias leading to sudden cardiac death. Cardiac electrical activity and its relationship to cardiac dysfunction have not yet been interrogated in large multi-centre studies. Purpose This study aimed to identify the ECG abnormalities associated with PPCM; their relationship with echocardiographic structural and functional abnormalities and explore regional and ethnic differences in ECG features. Methods We included the first 411 patients enrolled into the EURObservational PPCM registry (EORP). Baseline demographic, clinical and echocardiographic data were collected. ECGs were analysed for rate; rhythm; QRS width, axis and morphology; and QTc interval. Results Mean age of the women (from >40 countries) was 30.7±6.4 years. More than two thirds of patients presented with NYHA class III or IV (with no regional differences). The median QRS rate was 102bpm (IQR 87–117). More than half presented with sinus tachycardia (QRS rate >100bpm), whereas atrial fibrillation was rare (2.27%). The mean QRS width was 90.1ms ±21.5, with regional differences (ESC 93.8ms ±21.7 vs. non-ESC 86.8ms ±20.8, P<0.001). Left bundle branch block (LBBB) was reported in 9.30% with no regional or ethnic differences. Left ventricular hypertrophy (LVH) was present in a quarter of the cohort, and more prevalent amongst African (59.62%) and Asian (23.17%) than Caucasians (7.63%, P<0.001). The median QTc by Bazett was 456.7ms (IQR 409–490.7) and almost half (47.11%) had prolonged QTc (>460ms). The median LVEDD was 60mm (IQR 55–65) on echocardiography. Compared with their Asian and Caucasian counterparts, African patients were more likely to have LV dilatation (LVEDD>53mm: 70.11%, 79.31% and 89.42% respectively; P=0.004). The median LV ejection fraction (LVEF) was 32.50% (IQR 25–39) with no significant regional or ethnic differences. Sinus tachycardia predicted poor systolic function (OR 1.85 [95% CI 1.20–2.85], p=0.006). LVEF <35% was associated with a significantly higher QRS rate (median rate 107 vs. 98bpm, p=0.002). Women with LVEDD ≥53mm had a longer mean QRS duration (92.0±22.4 vs. 82.4±15.4ms, p<0.001) and frequency of LBBB (11.15% vs 1.54%, p=0.016). LBBB was a predictor of LVEDD >53mm (sensitivity 11.15%; specificity 98.46%; PPV 97.14%; NPV 19.10%; OR 8.02 [95% CI 1.08–59.66], p=0.042). Conclusion Patients with PPCM commonly present with sinus tachycardia, LVH, and/or prolonged QTc interval on their ECG. Wide QRS and/or LBBB, were associated with LVEDD>53mm. Sinus tachycardia, however, was associated with LVEF<35%. Risk of arrhythmia in those with prolonged QTc remains to be ascertained. Acknowledgement/Funding Heart Failure Association of the ESC

Abstract Background Aortic Stenosis (AS) is the most common valvular heart disease in the Western world. Wild-type transthyretin amyloid (wtATTR) affects the heart, causing restrictive cardiomyopathy. Deposits can be found in up to 25% of individuals >85 years of age at autopsy. Recently several reports showed a relatively high prevalence of transthyretin cardiac amyloidosis (TTR-CA) in patients with AS. Objectives The aim of this study was to examine the clinical effects of TTR-CA in patients who have undergone aortic valve replacement therapy and evaluate the outcome of the intervention. Methods We recruited patients who underwent surgical (AVR) or percutaneous (TAVI) aortic valve intervention between 2011 and 2018. The patients underwent a Tc99m-PYP scan using SPECT technology which has been shown to be valid for the diagnosis of TTR-CA. We reviewed patient files before (time point 1) and after intervention (time point 2) and at 2 years (time point 3) follow up, and collected data on hospitalizations, laboratory, and echocardiography. Results The study included 86 patients, mean age 78±6 years, 55% women. Twenty-nine (33%) participants were diagnosed as positive (VAS 2 and 3) for transthyretin cardiac amyloidosis.There were no differences in baseline characteristics between patients with and without TTR-CA in cardiovascular risk factors and co-morbidities, laboratory parameters and nutritional status. There were no differences in baseline echocardiographic parameters including valve gradients and left ventricular hypertrophy. However, the patients with TTR CA had more advanced diastolic dysfunction compared to patients without TTR CA (P=0.03) and higher pulmonary artery pressure (44±14.75mmhg vs 30.5±11.38mmhg, p=0.06). Before the intervention, patients with transthyretin cardiac amyloidosis had 3.26 times more hospitalizations due to heart failure as compared to patients in the negative group (p=0.01). After the intervention, diastolic function remained more severely affected in the positive group at all follow-up points compared to the negative group (p=0.05). Similar observations were seen in the measurements of pulmonary arterial pressure (p=0.019 at time 2 and p=0.015 at time 3). Consistent with the echocardiographic findings, patients with transthyretin cardiac amyloidosis had 2.84 times more hospitalizations after intervention for heart failure than patients in the negative group (p=0.02). Conclusions Co-existence of transthyretin cardiac amyloidosis and aortic stenosis in the older population is associated with a more severe clinical presentation and with more advanced clinical and echocardiographic signs of heart failure. Improvement after valvular intervention might be limited in terms of symptoms and hospitalizations in this subgroup. Acknowledgement/Funding None

Abstract Introduction Aortic Stenosis (AS) is the most common valvular heart disease in the Western world. Transcatheter aortic valve implantation (TAVI) is an alternative to surgical valve replacement in medium and high-risk patients. One of the most common complications after TAVI is conduction system disturbances including bundle branch block, complete heart block and need for permanent pacemaker implantation. Transthyretin cardiac amyloidosis (TTR–CA) is an increasingly recognized cause of heart failure that almost exclusively affects older adults. Diagnosis of TTR-CA in patients undergoing valvular intervention is relevant to understand their clinical outcomes and to discuss specific management. Objectives Occult amyloid may account for the frequent need for pacemakers among TAVR patients. We aimed to assess the correlation between intervention induced conduction abnormalities and the need for a pacemaker insertion and the presence of TTR-CA. Methods The study population included patients who had aortic valve intervention between 2011–2018. The patients underwent Tc99m-PYP scan using SPECT technology which has been shown to be valid for the diagnosis of TTR-CA. We examined the rate of conduction disorders and the need for a permanent pacemaker from patient files at the time of hospitalization and during a 24-month follow-up. Results The study population included 86 patients, mean age 78±6 years, 55% women. Twenty-nine (33%) of the participants were diagnosed as positive (VAS 2 and 3) for transthyretin cardiac amyloidosis. There were no differences in baseline characteristics with regard to age, gender, risk factors, hemoglobin and renal function between patients positive and negative for TTR CA. Conduction disorders were seen in 35 (40%) patients. Patients with TTR CA had a statistically higher prevalence of conduction disorders. Forty-two percent of TTR CA positive patients underwent peri-procedural permanent pacemaker implantation compared to 28% peri-procedural pacemaker implantations in the negative group (p=0.043). Development of a new left bundle branch block during the follow-up period was observed in 14.1% of all patients. There was a statistically significant higher rate in the positive group compared to TTR CA negative group (39.1% vs 10.9% p=0.03). Conclusions We observed a high prevalence of occult TTR-CA in older adults with aortic stenosis who underwent TAVI. We also found a high prevalence of conduction abnormalities following TAVI in patients with TTR CA. These findings suggest a need for more careful observation for possible conduction abnormalities and requirement for pacemaker insertion in these patients. Acknowledgement/Funding None

Purpose of reviewTo provide recommendations for the diagnosis and management of patients with peripartum cardiomyopathy (PPCM).Recent findingsPPCM is pregnancy-associated myocardial disease that occurs during pregnancy or postpartum and is characterized by the development of heart failure due to marked left ventricular (LV) systolic dysfunction. The disease is relatively uncommon, but its incidence is increasing, and it remains an important cause of cardiac-related maternal morbidity and mortality in previously healthy young women. With early diagnosis and treatment, the majority of the patients demonstrate recovery.SummaryThe review provides information on the clinical presentation, prognosis and contemporary management of PPCM as well as the approach to subsequent pregnancies, labor and delivery and long-term psychological consequences of the disease.

AIMS:We report the maternal and foetal outcomes at birth and after 6 months in a cohort of pregnant women with hypertrophic cardiomyopathy (HCM). Although most women with HCM tolerate pregnancy well, there is an increased risk of obstetric and cardiovascular complications.METHODS AND RESULTS:All pregnant women with HCM entered into the prospective worldwide Registry of Pregnancy and Cardiac disease (ROPAC) were included in this analysis. The primary endpoint was a major adverse cardiovascular event (MACE), which included death, heart failure (HF), thrombo-embolic event, and arrhythmia. Baseline and outcome data were analysed and compared for patients with MACE vs. without MACE and for patients with obstructive HCM vs. non-obstructive HCM. Sixty pregnant women (mean age 30.4 ± 6.0 years) with HCM (41.7% obstructive) were included. No maternal mortality occurred in this cohort. In 14 (23%) patients at least one MACE occurred: 9 (15.0%) HF and 7 (12%) an arrhythmia (6 ventricular and 1 atrial fibrillation). MACE occurred most commonly during the 3rd trimester and postpartum period. In total, 3 (5.0%) women experienced foetal loss. Women with MACE had a higher rate of emergency Caesarean delivery for cardiac reasons (21.4% vs. 0%, P = 0.01). No significant differences in pregnancy outcome were found between women with obstructive and non-obstructive HCM. NYHA functional class of ≥II and signs of HF before pregnancy, were associated with MACE.CONCLUSION:Although most women with HCM tolerated pregnancy well, cardiovascular complications were not uncommon and predicted by pre-pregnancy status facilitating pre-pregnancy counselling and targeted antenatal care.

What is known and objective Carvedilol is the standard of care for heart failure (HF) patients. Carvedilol is partially metabolized by the highly polymorphic enzyme, CYP2D6. To reach an effective dose while avoiding adverse drug reactions (ADRs), testing of CYP2D6 genotype prior to carvedilol initiation may be considered. The objectives of this study were to determine CYP2D6 metabolic genotypes in an Israeli cohort of HF patients and to investigate the relationship between genotype, carvedilol dose and number of ADRs to determine the importance of CYP2D6 genotyping prior to treatment initiation. Methods Ninety-three patients with HF on carvedilol were CYP2D6 genotyped and classified as poor (PM), intermediate (IM), extensive (EM) or ultrarapid (UM) metabolizers. Carvedilol dose and ADRs were calculated and correlated with genotype using linear regression statistic analysis. Results and discussion The distribution of the CYP2D6 phenotype in the Israeli population with HF is similar to the European general population. There were no significant differences of carvedilol dose and number of ADRs among genotype groups. Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose changes. What is new and conclusion Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose during therapy for patients with HF. The Israeli CYP2D6 phenotype distribution in HF patients was consistent with the frequency in the general European population.