Early diastolic heart sounds caused by the atrial kick.

An 81-year-old male with a history of coronary artery disease, hypertension, paroxysmal atrial fibrillation and chronic kidney disease presents with asymptomatic bradycardia. Examination was notable for an early diastolic heart sound. 12-lead electrocardiogram revealed sinus bradycardia with a markedly prolonged PR interval and second-degree atrioventricular block, type I Mobitz. We review the differential diagnosis of early diastolic heart sounds and present a case of Wenckebach associated with a variable early diastolic sound on physical exam.

Intrahepatic Transcriptomics Differentiate Advanced Fibrosis and Clinical Outcomes in Adults With Fontan Circulation.

BACKGROUND: The molecular mechanisms underlying Fontan-associated liver disease (FALD) remain largely unknown. OBJECTIVES: This study aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. METHODS: This retrospective cohort study included adults with the Fontan circulation. Baseline clinical, laboratory, imaging, and hemodynamic data as well as a composite clinical outcome (CCO) were extracted from medical records. Patients were classified into early or advanced fibrosis. RNA was isolated from formalin-fixed paraffin-embedded liver biopsy samples; RNA libraries were constructed with the use of an rRNA depletion method and sequenced on an Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were performed with the use of DESeq2 and Metascape. RESULTS: A total of 106 patients (48% male, median age 31 years [IQR: 11.3 years]) were included. Those with advanced fibrosis had higher B-type natriuretic peptide levels and Fontan, mean pulmonary artery, and capillary wedge pressures. The CCO was present in 23 patients (22%) and was not predicted by advanced liver fibrosis, right ventricular morphology, presence of aortopulmonary collaterals, or Fontan pressures on multivariable analysis. Samples with advanced fibrosis had 228 upregulated genes compared with early fibrosis. Samples with the CCO had 894 upregulated genes compared with those without the CCO. A total of 136 upregulated genes were identified in both comparisons and were enriched in cellular response to cytokine stimulus or oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-ß signaling pathway, and vasculature development. CONCLUSIONS: Patients with FALD and advanced fibrosis or the CCO exhibited upregulated genes related to inflammation, congestion, and angiogenesis.

Flexible 3-D Electrochemical Impedance Spectroscopy Sensors Incorporating Phase Delay for Comprehensive Characterization of Atherosclerosis.

Background: Distinguishing quiescent from rupture-prone atherosclerotic lesions has significant translational and clinical implications. Electrochemical impedance spectroscopy (EIS) characterizes biological tissues by assessing impedance and phase delay responses to alternating current at multiple frequencies.We evaluated invasive 6-point stretchable EIS sensors over a spectrum of experimental atherosclerosis and compared results with intravascular ultrasound (IVUS), molecular positron emission tomography (PET) imaging, and histology. Methods: Male New Zealand White rabbits (n=16) were placed on a high-fat diet for 4 or 8 weeks, with or without endothelial denudation via balloon injury of the infrarenal abdominal aorta. Rabbits underwent in vivo micro-PET imaging of the abdominal aorta with 68 Ga-DOTATATE, 18 F-NaF, and 18 F-FDG, followed by invasive interrogation via IVUS and EIS. Background signal corrected values of impedance and phase delay were determined. Abdominal aortic samples were collected for histological analyses. Analyses were performed blindly. Results: Phase delay correlated with anatomic markers of plaque burden, namely intima/media ratio (r=0.883 at 1 kHz, P =0.004) and %stenosis (r=0.901 at 0.25 kHz, P =0.002), similar to IVUS. Moreover, impedance was associated with markers of plaque activity including macrophage infiltration (r=0.813 at 10 kHz, P =0.008) and macrophage/smooth muscle cell (SMC) ratio (r=0.813 at 25 kHz, P =0.026). 68 Ga-DOTATATE correlated with intimal macrophage infiltration (r=0.861, P =0.003) and macrophage/SMC ratio (r=0.831, P =0.021), 18 F-NaF with SMC infiltration (r=-0.842, P =0.018), and 18 F-FDG correlated with macrophage/SMC ratio (r=0.787, P =0.036). Conclusions: EIS with phase delay integrates key atherosclerosis features that otherwise require multiple complementary invasive and non-invasive imaging approaches to capture. These findings indicate the potential of invasive EIS as a comprehensive modality for evaluation of human coronary artery disease. HIGHLIGHTS: Electrochemical impedance spectroscopy (EIS) characterizes both anatomic features - via phase delay; and inflammatory activity - via impedance profiles, of underlying atherosclerosis.EIS can serve as an integrated, comprehensive metric for atherosclerosis evaluation by capturing morphological and compositional plaque characteristics that otherwise require multiple imaging modalities to obtain.Translation of these findings from animal models to human coronary artery disease may provide an additional strategy to help guide clinical management.

Clinical and invasively-measured predictors of high exercise capacity in Fontan patients.

INTRODUCTION: Fontan patients have variable exercise capacity. Contemporary understanding as to which factors predict high tolerance is limited. METHODS: Records from the Ahmanson/University of California, Los Angeles Adult Congenital Heart Disease Center were reviewed for adult Fontan patients who underwent CPET. Patients were considered "high performers" if their maximum oxygen uptake (VO2 max/kg)-predicted was greater than 80%. Cross-sectional clinical, hemodynamic, and liver biopsy data was gathered. High-performers were compared to control patients across these parameters via associations and regression. RESULTS: A total of 195 adult patients were included; 27 patients were considered "high performers". They had lower body mass indices (BMI, p < 0.001), mean Fontan pressures (p = 0.026), and cardiac outputs (p = 0.013). High performers also had higher activity levels (p < 0.001), serum albumin levels (p = 0.003), non-invasive and invasive systemic arterial oxygen saturations (p < 0.001 and p = 0.004), lower New York Heart Association (NYHA) heart failure class (p = 0.002), and were younger at Fontan completion (p = 0.011). High performers had less severe liver fibrosis (p = 0.015). Simple regression found Fontan pressure, non-invasive O2 saturation, albumin level, activity level, age at Fontan surgery, NYHA class, and BMI to predict significant changes in VO2 max/kg %-predicted. These associations persisted in multiple regression for non-invasive O2 saturation, NYHA class II, activity level, and BMI. CONCLUSIONS: Thin Fontan patients who exercise more had better exercise capacity, Fontan hemodynamic profiles, and less liver fibrosis.

Intrahepatic transcriptomics differentiate advanced fibrosis and clinical outcomes in adults with the Fontan circulation.

Background: The molecular mechanisms underlying Fontan associated liver disease (FALD) remain largely unknown. We aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. Methods: This retrospective cohort study included adults with the Fontan circulation at the Ahmanson/UCLA Adult Congenital Heart Disease Center. Clinical, laboratory, imaging and hemodynamic data prior to the liver biopsy were extracted from medical records. Patients were classified into early (F1-F2) or advanced fibrosis (F3-F4). RNA was isolated from formalin-fixed paraffin embedded liver biopsy samples; RNA libraries were constructed using rRNA depletion method and sequencing was performed on Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were carried out using DESeq2 and Metascape. Medical records were comprehensively reviewed for a composite clinical outcome which included decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, protein-losing enteropathy, chronic kidney disease stage 4 or higher, or death. Results: Patients with advanced fibrosis had higher serum BNP levels and Fontan, mean pulmonary artery and capillary wedge pressures. The composite clinical outcome was present in 23 patients (22%) and was predicted by age at Fontan, right ventricular morphology and presence of aortopulmonary collaterals on multivariable analysis. Samples with advanced fibrosis had 228 up-regulated genes compared to early fibrosis. Samples with the composite clinical outcome had 894 up-regulated genes compared to those without it. A total of 136 up-regulated genes were identified in both comparisons and these genes were enriched in cellular response to cytokine stimulus, response to oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-beta signaling pathway, and vasculature development. Conclusions: Patients with FALD and advanced liver fibrosis or the composite clinical outcome exhibit up-regulated genes including pathways related to inflammation, congestion, and angiogenesis. This adds further insight into FALD pathophysiology.

Outcomes of malignancy in adults with congenital heart disease: a single center experience.

BACKGROUND: Malignancy is known to be a major cause of death in adult congenital heart disease (ACHD). However, data regarding cardiovascular and cancer-related outcomes in ACHD are lacking. METHODS: We conducted a retrospective single-center cohort study comprising patients with ACHD and malignancy. The primary outcome was all-cause mortality. Key secondary outcomes included major adverse cardiovascular and cerebrovascular events (MACCE), cardiotoxicity events and consequent cancer therapy modifications. RESULTS: Sixty-eight patients with ACHD and a history of cancer were included in the study. 82% of patients had moderate or great ACHD anatomic complexity. Over a median follow-up of 5 years after cancer diagnosis, 16 (24%) patients died, with 69% of deaths being due to cancer. Univariate predictors of mortality were baseline arrhythmia (OR 3.82, 95% CI 1.15-12.67, p = 0.028), baseline diuretic therapy (OR 3.54, 95% CI 1.04-12.04, p = 0.044) and advanced cancer stage at diagnosis (OR 2.37, 95% CI 1.32-4.25, p = 0.004). MACCE occurred in 40 (59%) patients and was independently predicted by baseline diuretic requirement (OR 9.91, 95% CI 1.12-87.85, p = 0.039). A 14% incidence of cardiotoxicity was seen; 3 patients needed modification and 1 patient needed temporary interruption of cancer therapy for 2 weeks. CONCLUSIONS: Considerable mortality occurred in this cohort of patients with ACHD and cancer; most deaths were cancer-related. A high rate of MACCE was observed, yet rates of obligatory modification of cancer therapy due to cardiotoxicity were low.

Delivery Timing and Associated Outcomes in Pregnancies With Maternal Congenital Heart Disease at Term.

Background Current recommendations for delivery timing of pregnant persons with congenital heart disease (CHD) are based on expert opinion. Justification for early-term birth is based on the theoretical concern of increased cardiovascular stress. The objective was to evaluate whether early-term birth with maternal CHD is associated with lower adverse maternal or neonatal outcomes. Methods and Results This is a retrospective cohort study of pregnant persons with CHD who delivered a singleton after 37 0/7 weeks gestation at a quaternary care center with a multidisciplinary cardio-obstetrics care team between 2013 and 2021. Patients were categorized as early-term (37 0/7 to 38 6/7 weeks) or full-term (≥39 0/7) births and compared. Multivariable logistic regression was conducted to calculate the adjusted odds ratio for the primary outcomes. The primary outcomes were composite adverse cardiovascular, maternal obstetric, and adverse neonatal outcome. Of 110 pregnancies delivering at term, 55 delivered early-term and 55 delivered full-term. Development of adverse cardiovascular and maternal obstetric outcome was not significantly different by delivery timing. The rate of composite adverse neonatal outcomes was significantly higher in early-term births (36% versus 5%, P<0.01). After adjusting for confounding variables, early-term birth remained associated with a significantly increased risk of adverse neonatal outcomes (adjusted odds ratio 11.55 [95% CI, 2.59-51.58]). Conclusions Early-term birth for pregnancies with maternal CHD was associated with an increased risk of adverse neonatal outcomes, without an accompanying decreased rate in adverse cardiovascular or obstetric outcomes. In the absence of maternal or fetal indications for early birth, induction of labor before 39 weeks for pregnancies with maternal CHD should be reserved for routine obstetrical indications.

Polygenic risk scores of endo-phenotypes identify the effect of genetic background in congenital heart disease.

Congenital heart disease (CHD) is a rare structural defect that occurs in ∼1% of live births. Studies on CHD genetic architecture have identified pathogenic single-gene mutations in less than 30% of cases. Single-gene mutations often show incomplete penetrance and variable expressivity. Therefore, we hypothesize that genetic background may play a role in modulating disease expression. Polygenic risk scores (PRSs) aggregate effects of common genetic variants to investigate whether, cumulatively, these variants are associated with disease penetrance or severity. However, the major limitations in this field have been in generating sufficient sample sizes for these studies. Here we used CHD-phenotype matched genome-wide association study (GWAS) summary statistics from the UK Biobank (UKBB) as our base study and whole-genome sequencing data from the CHD cohort (n1 = 711 trios, n2 = 362 European trios) of the Gabriella Miller Kids First dataset as our target study to develop PRSs for CHD. PRSs estimated using a GWAS for heart valve problems and heart murmur explain 2.5% of the variance in case-control status of CHD (all SNVs, p = 7.90 × 10-3; fetal cardiac SNVs, p = 8.00 × 10-3) and 1.8% of the variance in severity of CHD (fetal cardiac SNVs, p = 6.20 × 10-3; all SNVs, p = 0.015). These results show that common variants captured in CHD phenotype-matched GWASs have a modest but significant contribution to phenotypic expression of CHD. Further exploration of the cumulative effect of common variants is necessary for understanding the complex genetic etiology of CHD and other rare diseases.

Cardiopulmonary Exercise Test Outcomes in Fontan Patients With Right Versus Left Single Ventricle Morphology.

Background: Congenital heart defects (CHDs) palliated with Fontan surgery often result in a functional single ventricle that is either a morphologically right or left ventricle, and much less commonly undefined. Given this departure from normal physiology, especially for systemic right ventricle Fontan patients, our study sought to compare cardiopulmonary exercise test (CPET) results of adult patients with single right ventricle (SRV) and single left ventricle (SLV) morphology. Methods: Of 237 Fontan patients from the Ahmanson/UCLA Adult Congenital Heart Disease Center database, 135 patients met the inclusion criteria and were split into 2 groups: SRV (n = 44) and SLV (n = 91). Data were collected on baseline demographics, cardiac history, and CPET results. The 2 groups were compared using unpaired t-test, Mann-Whitney, or Chi-square test. Results: Regarding baseline demographics, SRV patients underwent CPET at a slightly younger age than the SLV group (26.5 ± 6.2 vs 29.6 ± 8.5 years, P = .03). There were no significant differences in CPET parameters (including peak heart rate, oxygen saturation, and maximum VO2/kg) between the SRV and SLV groups. When evaluated subsequent CPET at 3 to 4 years, there was no difference in CPET peak heart rate, peak oxygen saturation, and maximum VO2/kg between the 2 groups. Conclusions: This single-center retrospective analysis suggests that dominant single ventricle morphology may not be associated with an appreciable difference in exercise performance in adult survivors with a Fontan palliation.

Venoarterial Versus Venovenous Extracorporeal Membrane Oxygenation As Bridge to Lung Transplantation.

BACKGROUND: Venovenous (VV) extracorporeal membrane oxygenation (ECMO) has been used as a bridge to lung transplantation with acceptable outcomes. We hypothesized that venoarterial (VA) ECMO, as part of a multidisciplinary ECMO program, yields similar outcomes as VV ECMO as a bridge in lung transplantation. METHODS: Records of all patients who had undergone ECMO with the intention to bridge to lung transplantation at University of California, Los Angeles, from January 1, 2012, to March 31, 2020, were reviewed. Baseline characteristics, in-hospital outcomes, long-term survival, and freedom from bronchiolitis obliterans syndrome were assessed. RESULTS: During this interval, 58 patients were placed on ECMO with the intention to bridge to lung transplantation: 27 on VV ECMO, and 31 on VA ECMO, with a median duration of 7 and 17 days of support, respectively (P = .01). Successful bridge to lung transplantation occurred in 21 VV patients (78%) and in 26 VA patients (84%). Incidence of primary graft dysfunction III at 72 hours in the VV and the VA cohorts was 0% and 4%, respectively (P = .99). In-hospital and 90-day survival of the VV and VA groups was 100% and 96%, respectively (P = .99). Survival of the 2 groups at 3 years was not significantly different from a contemporary cohort of lung transplant recipients not bridged with ECMO. CONCLUSIONS: VA and VV ECMO can both be used as a bridge to lung transplantation with high success, with short and medium-term survival similar to non-bridged lung transplant recipients. Both modes should be considered effective at bridging select candidates to lung transplantation.

The systemic right ventricle in adult congenital heart disease: why is it still such a challenge and is there any hope on the horizon?

PURPOSE OF REVIEW: Adult congenital heart disease patients with systemic right ventricle comprise a distinctly clinically challenging group of patients with increased morbidity and mortality. This article aims to review the different subgroups, most common complications and different treatment strategies. RECENT FINDINGS: Most commons long-term complications include heart failure and arrhythmias. Heart failure medical therapy treatments include several new agents, which show promise in systemic right ventricle patients. In addition, interventional therapies to mitigate atrioventricular valve regurgitation, baffle/conduit stenosis are discussed. Furthermore, several electrophysiological approaches to manage tachyarrhythmias as well as bradycardias are discussed. There is ongoing excitement on the new medical as well as interventional therapies that could provide benefit in additional to standard goal-directed medical therapy. SUMMARY: There is an array of medications as well as interventions aimed to treat patients with systemic right ventricle with limited benefits. A multidisciplinary approach with a prudent combination of such therapies to maximize benefit is imperative. This article reviews the data supporting such therapies.

Coronary Artery Dominance and Cardiovascular Pathologies in Patients with Bicuspid Aortic Valve.

BACKGROUND: Bicuspid aortic valve (BAV) is the most common congenital heart defect and is associated with a number of cardiac pathologies including coarctation of the aorta (CoA), aortic dilation, aortic stenosis, and premature coronary artery disease (CAD). Furthermore, BAV has been associated with left dominant coronary artery anatomy but there is still much debate regarding this association. To date, no study has investigated the association between coronary artery dominance and cardiac pathologies in patients with BAV. METHODS: A total of 45 patients with BAV who underwent coronary computed tomography angiography (CTA) and/or cardiac catheterization at a single center were included. Coronary artery dominance, presence of CAD, CoA, and aortic dilation was determined from coronary CTA and/or cardiac catheterization reports. Incidence of aortic valve stenosis and aortic valve regurgitation was determined from echo reports. RESULTS: Of the 45 patients with BAV, 80% (36) had right dominant coronary artery circulations. Patients with BAV with left dominant circulations had a significantly (p = 0.04) higher incidence of CoA compared to patients with right dominant circulations (44% vs. 14%). There was no significant difference when comparing the incidences of aortic dilation, aortic valve stenosis, aortic valve regurgitation and CAD in right and left dominant patients. CONCLUSIONS: Our study found a predominance of right dominant coronary artery circulation in patients with BAV, similar to the general population. Interestingly, left dominance was significantly associated with CoA in patients with BAV. This observation highlights the importance of further studies regarding how coronary artery dominance can be associated with other cardiovascular pathologies in patients with BAV.

Mechanical thrombectomy of COVID-19 DVT with congenital heart disease leading to phlegmasia cerulea dolens: a case report.

BACKGROUND: COVID-19 and Fontan physiology have each been associated with an elevated risk of venous thromboembolism (VTE), however little is known about the risks and potential consequences of having both. CASE PRESENTATION: A 51 year old male with tricuspid atresia status post Fontan and extracardiac Glenn shunt, atrial flutter, and sinus sick syndrome presented with phlegmasia cerulea dolens (PCD) of the left lower extremity in spite of supratherapeutic INR in the context of symptomatic COVID-10 pneumonia. He was treated with single session, catheter directed mechanical thrombectomy that was well-tolerated. CONCLUSIONS: This report of acute PCD despite therapeutic anticoagulation with a Vitamin K antagonist, managed with emergent mechanical thrombectomy, calls to attention the importance of altered flow dynamics in COVID positive patients with Fontan circulation that may compound these independent risk factors for developing deep venous thrombosis with the potential for even higher morbidity.

Orthotopic Heart and Combined Heart Liver Transplantation: the Ultimate Treatment Option for Failing Fontan Physiology.

Purpose of the Review: This is a comprehensive update on failing Fontan physiology and the role of heart and combined heart and liver transplantation in the current era. Recent Findings: Single ventricle physiology encompasses a series of rare congenital cardiac abnormalities that are characterized by absence of or hypoplasia of one ventricle. This effectively results in a single ventricular pumping chamber. These abnormalities are rarely compatible with long-term survival if left without surgical palliation in the first few years of life. Surgical treatment of single ventricle physiology has evolved over the past 60 years and is characterized by numerous creative innovations. These include the development of arteriopulmonary shunts, the evolution of partial cavopulmonary connections, and the eventual development of the "Fontan" operation. Regardless of the type of Fontan modification, the long-term consequences of the Fontan operation are predominantly related to chronic central venous hypertension and the multi-organ consequences thereof. Atrial arrhythmias can further compromise this circulation.Patients with single ventricle physiology represent a special sub-segment of congenital cardiac transplants and are arguably the most challenging patients considered for transplantation. Summary: This review describes in detail the challenges and opportunities of heart and liver transplantation in Fontan patients, as viewed and managed by the experienced team at the Ahmanson/UCLA Adult Congenital Heart Center.

Left main coronary artery compression in pulmonary hypertension.

Extrinsic compression of the left main coronary artery (LMCA) by a dilated pulmonary artery (PA) in the setting of pulmonary arterial hypertension (PAH) is an increasingly recognized disease entity. LMCA compression has been associated with angina, arrhythmia, heart failure, and sudden cardiac death in patients with PAH. Recent studies suggest that at least 6% of patients with PAH have significant LMCA compression. Screening for LMCA compression can be achieved with computed coronary tomography angiography, with a particular emphasis on assessment of PA size and any associated downward displacement and reduced takeoff angle of the LMCA. Indeed, evidence of a dilated PA (>40 mm), a reduced LMCA takeoff angle (<60°), and/or LMCA stenosis on CCTA imaging should prompt further diagnostic evaluation. Coronary angiography in conjunction with intravascular imaging has proven effective in diagnosing LMCA compression and guiding subsequent treatment. While optimal medical therapy and surgical correction remain in the clinician's arsenal, percutaneous coronary intervention has emerged as an effective treatment for LMCA compression. Given the prevalence of LMCA compression, its associated morbidity, and mortality, and the wide array of successful treatment strategies, maintaining a high degree of suspicion for this condition, and understanding the potential treatment strategies is critical.

Percutaneous edge-to-edge repair for common atrioventricular valve regurgitation in a patient with heterotaxy syndrome, single ventricle physiology, and unbalanced atrioventricular septal defect.

Congenital heart disease patients, specifically with unbalanced atrioventricular septal defects and common atrioventricular valves requiring single ventricle palliation, have substantial morbidity and mortality. Atrioventricular valve regurgitation (AVVR) is associated with poor outcomes in single ventricle patients, and many of them require surgical treatment of AVVR in their lifetimes. We describe a unique case of transcatheter edge-to-edge valve repair using the MitraClip system (Abbott, Chicago, IL) in a single ventricle patient with severe common AVVR.

Perioperative Echocardiography in the Adult With Congenital Heart Disease.

Survival of patients with congenital heart disease has significantly improved over the last 2 decades, confronting interventionalists, surgeons, anesthesiologists, cardiologists, and intensivists with often unfamiliar complex pathophysiology in the perioperative setting. Aside from cardiac catheterization, echocardiography has become the main imaging modality in the hospitalized adult with congenital heart disease. The great variety of congenital lesions and their prior surgical management challenges practitioners to generate optimal imaging, reporting, and interpretation of these complex anatomic structures. Standardization of echocardiographic studies can not only provide significant benefits in the surveillance of these patients, but also facilitate understanding of pathophysiologic mechanism and assist clinical management in the perioperative setting. Knowledge in obtaining and interpreting uniform imaging protocols is essential for the perioperative clinician. In this publication, the authors review current international consensus recommendations on echocardiographic imaging of adults with congenital heart disease and describe the fundamental components by specific lesion. The authors will emphasize key aspects pertinent to the clinical management when imaging these patients in the perioperative setting. The goal of this review is to familiarize the perioperative physician on how to structure and standardize echocardiographic image acquisition of congenital heart disease anatomy for optimal clinical management.