Advocate Heart Institute

This article updates the Heart Failure Association of the European Society of Cardiology (ESC) 2007 classification of advanced heart failure and describes new diagnostic and treatment options for these patients. Recognizing the patient with advanced heart failure is critical to facilitate timely referral to advanced heart failure centres. Unplanned visits for heart failure decompensation, malignant arrhythmias, co-morbidities, and the 2016 ESC guidelines criteria for the diagnosis of heart failure with preserved ejection fraction are included in this updated definition. Standard treatment is, by definition, insufficient in these patients. Inotropic therapy may be used as a bridge strategy, but it is only a palliative measure when used on its own, because of the lack of outcomes data. Major progress has occurred with short-term mechanical circulatory support devices for immediate management of cardiogenic shock and long-term mechanical circulatory support for either a bridge to transplantation or as destination therapy. Heart transplantation remains the treatment of choice for patients without contraindications. Some patients will not be candidates for advanced heart failure therapies. For these patients, who are often elderly with multiple co-morbidities, management of advanced heart failure to reduce symptoms and improve quality of life should be emphasized. Robust evidence from prospective studies is lacking for most therapies for advanced heart failure. There is an urgent need to develop evidence-based treatment algorithms to prolong life when possible and in accordance with patient preferences, increase life quality, and reduce the burden of hospitalization in this vulnerable patient population.

Background: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone–system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF. Methods: We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8399) and PARAGON-HF (LVEF eligibility≥45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: ≤22.5% (n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF. Results: Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone–system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78–0.90]), cardiovascular death (HR 0.84 [95% CI, 0.76–0.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77–0.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81–0.96]). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction P =0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions. Conclusions: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone–system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly, advanced by a growing body of scientific data and investigations that both examine proposed criteria sets and establish new evidence to guide refinements. On 26-27 February 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington (USA), to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural, or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly over the last decade; pushed by a growing body of scientific data that both tests proposed criteria sets and establishes new evidence to guide refinements. On 26-27 February 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington, to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

Among the most exciting developments in the field of heart failure in recent times has been the rediscovery of the natriuretic peptide system and its pleuripotent effects on cardiac structure and function. This is particularly true of its natriuretic and hemodynamic effects. There has been an explosion of the knowledge base seeking to understand the wide range of homeostatic, regulatory, and counter-regulatory functions in which the natriuretic peptide system participates. Additional interest has been stimulated by advances in technology such as point-of-care and core laboratory BNP assays and the use of the recombinant B-type natriuretic peptide nesiritide as a treatment option. Despite this recent interest, the available literature lacks a comprehensive expert review of the current science and roles of natriuretic peptides for diagnostic, prognostic, screening, treatment monitoring, and therapeutic purposes. More importantly, a summary updating and guiding the clinician on most of these advances was lacking. An expert Consensus Panel with basic, methodological, and clinical expertise was convened to summarize current knowledge in these areas and the findings and consensus statements are contained herein.

Background: Ambulatory hemodynamic monitoring with an implantable pulmonary artery (PA) sensor is approved for patients with New York Heart Association Class III heart failure (HF) and a prior HF hospitalization (HFH) within 12 months. The objective of this study was to assess the efficacy and safety of PA pressure-guided therapy in routine clinical practice with special focus on subgroups defined by sex, race, and ejection fraction. Methods: This multi-center, prospective, open-label, observational, single-arm trial of 1200 patients across 104 centers within the United States with New York Heart Association class III HF and a prior HFH within 12 months evaluated patients undergoing PA pressure sensor implantation between September 1, 2014, and October 11, 2017. The primary efficacy outcome was the difference between rates of adjudicated HFH 1 year after compared with the 1 year before sensor implantation. Safety end points were freedom from device- or system-related complications at 2 years and freedom from pressure sensor failure at 2 years. Results: Mean age for the population was 69 years, 37.7% were women, 17.2% were non-White, and 46.8% had preserved ejection fraction. During the year after sensor implantation, the mean rate of daily pressure transmission was 76±24% and PA pressures declined significantly. The rate of HFH was significantly lower at 1 year compared with the year before implantation (0.54 versus 1.25 events/patient-years, hazard ratio 0.43 [95% CI, 0.39–0.47], P <0.0001). The rate of all-cause hospitalization was also lower following sensor implantation (1.67 versus 2.28 events/patient-years, hazard ratio 0.73 [95% CI, 0.68–0.78], P <0.0001). Results were consistent across subgroups defined by ejection fraction, sex, race, cause of cardiomyopathy, presence/absence of implantable cardiac defibrillator or cardiac resynchronization therapy and ejection fraction. Freedom from device- or system-related complications was 99.6%, and freedom from pressure sensor failure was 99.9% at 1 year. Conclusions: In routine clinical practice as in clinical trials, PA pressure-guided therapy for HF was associated with lower PA pressures, lower rates of HFH and all-cause hospitalization, and low rates of adverse events across a broad range of patients with symptomatic HF and prior HFH. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02279888.

BACKGROUND: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. METHODS AND RESULTS: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), β-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464-1610), and structural heart disease. CONCLUSIONS: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

More than 1 million heart failure hospitalizations occur annually, and congestion is the predominant cause. Rehospitalizations for recurrent congestion portend poor outcomes independently of age and renal function. Persistent congestion trumps serum creatinine increases in predicting adverse heart failure outcomes. No decongestive pharmacological therapy has reduced these harmful consequences. Simplified ultrafiltration devices permit fluid removal in lower-acuity hospital settings, but with conflicting results regarding safety and efficacy. Ultrafiltration performed at fixed rates after onset of therapy-induced increased serum creatinine was not superior to standard care and resulted in more complications. In contrast, compared with diuretic agents, some data suggest that adjustment of ultrafiltration rates to patients' vital signs and renal function may be associated with more effective decongestion and fewer heart failure events. Essential aspects of ultrafiltration remain poorly defined. Further research is urgently needed, given the burden of congestion and data suggesting sustained benefits of early and adjustable ultrafiltration.

Background— Fetal long QT syndrome (LQTS) is associated with complex arrhythmias including torsades de pointes and 2° atrioventricular block. Sinus bradycardia has also been associated with fetal LQTS, but little is known of this rhythm manifestation. Our purpose was to characterize the fetal heart rate (FHR)/gestational age (GA) profile of fetal LQTS. Methods and Results— We ascertained fetal LQTS subjects by family history (Group 1) or fetal arrhythmia referral (Group 2). We compared FHR in LQTS subjects versus normal fetuses. To identify FHR predictors of LQTS, we calculated a bradycardia index as % of LQTS FHR recordings either ≤110 beats per minute (obstetric standard) or ≤3 rd percentile for GA. Among 42 LQTS subjects, 26 were in Group 1 and 16 in Group 2. There were 536 normal fetuses. The bradycardia index was only 15% for FHR ≤110 beats per minute, but 66% for FHR ≤3rd percentile for GA. Ten fetuses with complex arrhythmias also had severe and sustained sinus bradycardia throughout gestation. Identifying a fetal proband in Group 2 resulted in LQTS diagnosis in 9 unsuspected members of 6 families. Conclusions— FHR varies by GA in both normal and LQTS fetuses. Postnatal evaluation of neonates with FHR ≤3 rd percentile for GA may improve ascertainment of LQTS in fetuses, neonates, and undiagnosed family members.

Background: Left ventricular assist device (LVAD) therapy improves the hemodynamics of advanced heart failure patients. However, it is unknown whether hemodynamic optimization improves clinical outcomes. The aim of this study was to investigate whether hemodynamic optimization reduces hospital readmission rate in LVAD patients. Methods and Results: LVAD patients undergoing an invasive hemodynamic ramp test were prospectively enrolled and followed for 1 year. LVAD speed was optimized using a ramp test, targeting the following goals: central venous pressure <12 mm Hg, pulmonary capillary wedge pressure <18 mm Hg, and cardiac index >2.2 L/(min·m 2 ). The frequency and cause of hospital readmissions were compared between patients who achieved (optimized group) or did not achieve (nonoptimized group) these goals. Eighty-eight outpatients (median 61 years old, 53 male) underwent ramp testing 236 days after LVAD implantation, and 54 (61%) had optimized hemodynamics after LVAD speed adjustment. One-year survival after the ramp study was comparable in both groups (89% versus 88%). The total hospital readmission rate was lower in the optimized group compared with the nonoptimized group (1.15 versus 2.86 events/y, P <0.001). This result was predominantly because of a reduction in the heart failure readmission rate in the optimized group (0.08 versus 0.71 events/y, P =0.016). Conclusions: LVAD patients, in whom hemodynamics were optimized, had a significantly lower rate of hospital readmissions, primarily because of fewer heart failure admissions. These findings highlight the importance of achieving hemodynamic optimization in LVAD patients.

AIMS: The presence of central sleep apnoea (CSA) is associated with poor prognosis in patients with heart failure (HF). The aim of this analysis was to evaluate if using phrenic nerve stimulation to treat CSA in patients with CSA and HF was associated with changes in HF-specific metrics. METHODS AND RESULTS: All patients randomized in the remedē System Pivotal Trial and identified at baseline with HF were included (n = 96). Effectiveness data from treatment and former control groups were pooled based on months since therapy activation. Changes from baseline to 6 and 12 months in sleep metrics, Epworth Sleepiness Scale, patient global assessment health-related quality of life, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and echocardiographic parameters are reported. HF hospitalization, cardiovascular death, and the composite of HF hospitalization or cardiovascular death within 6 months are reported by the original randomized group assignment for safety assessment. Sleep metrics and quality of life improved from baseline to 6 and 12 months. At 12 months, MLHFQ scores changed by -6.8 ± 20.0 (P = 0.005). The 6-month rate of HF hospitalization was 4.7% in treatment patients (standard error = 3.3) and 17.0% in control patients (standard error = 5.5) (P = 0.065). Reported adverse events were as expected for a transvenous implantable system. CONCLUSIONS: Phrenic nerve stimulation reduces CSA severity in patients with HF. In parallel, this CSA treatment was associated with benefits on HF quality of life.

Drug-induced cardiotoxicity is a life-threatening side effect of doxorubicin (DOX) treatment that impacts patient prognosis and survival. In the majority of cases, the acute clinical form often remains asymptomatic, with few patients presenting rather nonspecific electrocardiographic abnormalities. While chronic toxicity has been more widely studied, the alterations appearing in acute cardiotoxicity are much less investigated. Thus, our in vivo study aimed to evaluate the process of DOX-induced acute myocardial toxicity by investigating oxidative stress and autophagy markers as mechanisms of myocardial toxicity in correlation with echocardiography and electrocardiography findings. Our results show that both autophagy and oxidative homeostasis were disrupted as soon as 7 days after DOX treatment, alterations that occurred even before the significant increase of NT-proBNP, a clinical marker for cardiac suffering. Moreover, we found a large number of alterations in the electrocardiography and echocardiography of treated rats. These findings suggest that DOX-induced myocardial toxicity started early after treatment initiation, possibly marking the initial phase of the unfolding process of cardiac damage. Further studies are required to completely decipher the mechanisms of DOX-induced cardiotoxicity.

Importance: In a randomized clinical trial, heart failure (HF) hospitalizations were lower in patients managed with guidance from an implantable pulmonary artery pressure sensor compared with usual care. It remains unclear if ambulatory monitoring could also improve long-term clinical outcomes in real-world practice. Objective: To determine the association between ambulatory hemodynamic monitoring and rates of HF hospitalization at 12 months in clinical practice. Design, Setting, and Participants: This matched cohort study of Medicare beneficiaries used claims data collected between June 1, 2014, and March 31, 2016. Medicare patients who received implants of a pulmonary artery pressure sensor were identified from the 100% Medicare claims database. Each patient who received an implant was matched to a control patient by demographic features, history of HF hospitalization, and number of all-cause hospitalizations. Propensity scoring based on comorbidities (arrhythmia, hypertension, diabetes, pulmonary disease, and renal disease) was used for additional matching. Data analysis was completed from July 2017 through January 2019. Exposures: Implantable pulmonary artery pressure monitoring system. Main Outcomes and Measures: The rates of HF hospitalization were compared using the Andersen-Gill method. Days lost owing to events were compared using a nonparametric bootstrap method. Results: The study cohort consisted of 1087 patients who received an implantable pulmonary artery pressure sensors and 1087 matched control patients. The treatment and control cohorts were well matched by age (mean [SD], 72.7 [10.2] years vs 72.9 [10.1] years) and sex (381 of 1087 female patients [35.1%] in each group), medical history, comorbidities, and timing of preimplant HF hospitalization. At 12 months postimplant, 616 HF hospitalizations occurred in the treatment cohort compared with 784 HF hospitalizations in the control cohort. The rate of HF hospitalization was lower in the treatment cohort at 12 months postimplant (hazard ratio [HR], 0.76 [95% CI, 0.65-0.89]; P < .001). The percentage of days lost to HF hospitalizations or death were lower in the treatment group (HR, 0.73 [95% CI, 0.64-0.84]; P < .001) and the percentage of days lost owing to all-cause hospitalization or death were also lower (HR, 0.77 [95% CI, 0.68-0.88]; P < .001). Conclusions and Relevance: Patients with HF who were implanted with a pulmonary artery pressure sensor had lower rates of HF hospitalization than matched controls and spent more time alive out of hospital. Ambulatory hemodynamic monitoring may improve outcomes in patients with chronic HF.

In view of the increasing complexity of both cardiovascular implantable electronic devices (CIEDs) and patients in the current era, practice guidelines, by necessity, have become increasingly specific. This document is an expert consensus statement that has been developed to update and further delineate indications and management of CIEDs in pediatric patients, defined as ≤21 years of age, and is intended to focus primarily on the indications for CIEDs in the setting of specific disease categories. The document also highlights variations between previously published adult and pediatric CIED recommendations and provides rationale for underlying important differences. The document addresses some of the deterrents to CIED access in low- and middle-income countries and strategies to circumvent them. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by class of recommendation and level of evidence. Several questions addressed in this document either do not lend themselves to clinical trials or are rare disease entities, and in these instances recommendations are based on consensus expert opinion. Furthermore, specific recommendations, even when supported by substantial data, do not replace the need for clinical judgment and patient-specific decision-making. The recommendations were opened for public comment to Pediatric and Congenital Electrophysiology Society (PACES) members and underwent external review by the scientific and clinical document committee of the Heart Rhythm Society (HRS), the science advisory and coordinating committee of the American Heart Association (AHA), the American College of Cardiology (ACC), and the Association for European Paediatric and Congenital Cardiology (AEPC). The document received endorsement by all the collaborators and the Asia Pacific Heart Rhythm Society (APHRS), the Indian Heart Rhythm Society (IHRS), and the Latin American Heart Rhythm Society (LAHRS). This document is expected to provide support for clinicians and patients to allow for appropriate CIED use, appropriate CIED management, and appropriate CIED follow-up in pediatric patients.

STUDY OBJECTIVE: To evaluate long-term efficacy and safety of phrenic nerve stimulation (PNS) in patients with moderate-to-severe central sleep apnea (CSA) through 3 years of therapy. METHODS: Patients in the remedē System Pivotal Trial were observed every 3 months after implant until US Food and Drug Administration approval. At the time of approval and study closure, all patients completed 24 months of follow-up; 33 patients had not reached the 36-month visit. Sleep metrics (polysomnography) and echocardiographic parameters are reported at baseline, 12, 18, and 24 months, in addition to available 36-month sleep results from polygraphy. Safety was assessed through 36 months; however, analysis focused through 24 months and available 36-month results are provided. RESULTS: Patients were assessed at 24 (n = 109) and 36 (n = 60) months. Baseline characteristics included mean age 64 years, 91% male, and mean apnea-hypopnea index 47 events per hour. Sleep metrics (apnea-hypopnea index (AHI), central apnea index, arousal index, oxygen desaturation index, rapid eye movement sleep) remained improved through 24 and 36 months with continuous use of PNS therapy. At least 60% of patients in the treatment group achieved at least 50% reduction in AHI through 24 months. Serious adverse events (SAEs) related to the remedē System implant procedure, device, or therapy through 24 months were reported by 10% of patients, no unanticipated adverse device effects or deaths, and all events resolved. No additional related SAEs were reported between 24 and 36 months. CONCLUSION: These data suggest beneficial effects of long-term PNS in patients with CSA appear to sustain through 36 months with no new safety concerns. TRIAL REGISTRATION: NCT01816776.

Heart transplantation is advocated in selected patients with advanced heart failure in the absence of contraindications. Principal challenges in heart transplantation centre around an insufficient and underutilized donor organ pool, the need to individualize titration of immunosuppressive therapy, and to minimize late complications such as cardiac allograft vasculopathy, malignancy, and renal dysfunction. Advances have served to increase the organ donor pool by advocating the use of donors with underlying hepatitis C virus infection and by expanding the donor source to use hearts donated after circulatory death. New techniques to preserve the donor heart over prolonged ischaemic times, and enabling longer transport times in a safe manner, have been introduced. Mechanical circulatory support as a bridge to transplantation has allowed patients with advanced heart failure to avoid progressive deterioration in hepato-renal function while awaiting an optimal donor organ match. The management of the heart transplantation recipient remains a challenge despite advances in immunosuppression, which provide early gains in rejection avoidance but are associated with infections and late-outcome challenges. In this article, we review contemporary advances and challenges in this field to focus on donor recovery strategies, left ventricular assist devices, and immunosuppressive monitoring therapies with the potential to enhance outcomes. We also describe opportunities for future discovery to include a renewed focus on long-term survival, which continues to be an area that is under-studied and poorly characterized, non-human sources of organs for transplantation including xenotransplantation as well as chimeric transplantation, and technology competitive to human heart transplantation, such as tissue engineering.

There are multiple conditions that can make children prone to having a sudden cardiac arrest (SCA) or sudden cardiac death (SCD). Efforts have been made by multiple organizations to screen children for cardiac conditions, but the emphasis has been on screening before athletic competition. This article is an update of the previous American Academy of Pediatrics policy statement of 2012 that addresses prevention of SCA and SCD. This update includes a comprehensive review of conditions that should prompt more attention and cardiology evaluation. The role of the primary care provider is of paramount importance in the evaluation of children, particularly as they enter middle school or junior high. There is discussion about whether screening should find any cardiac condition or just those that are associated with SCA and SCD. This update reviews the 4 main screening questions that are recommended, not just for athletes, but for all children. There is also discussion about how to handle post-SCA and SCD situations as well as discussion about genetic testing. It is the goal of this policy statement update to provide the primary care provider more assistance in how to screen for life-threatening conditions, regardless of athletic status.

In that study, incremental reductions in the PA pressures in the monitored arm were associated with both reduction in the frequency of HFH and improvements in health-related quality of life among patients with both preserved (HFpEF) and reduced ejection fraction (HFrEF).3,4 Additionally, hemodynamic-guided HF management in the subset of HFrEF patients treated with guideline-directed medical therapy (GDMT) was associated with a strong trend toward improved survival compared to traditional clinical management.4,7 Consistent benefit is demonstrated in several retrospective studies from the CHAMPION Trial.10-13 as well as extensive analysis of “real-world� experience.6,14 and in Medicare claims data managed in a commercial setting.5,15 Whether the benefits of PA pressure guided therapy can be extended to a broader pool of patients with milder (NYHA class II) or more severe (NYHA class IV) HF or to those without recent hospitalization for HF but with elevation in natriuretic peptide levels remains unclear. Remotely uploaded PA pressure information from the control group will be blocked from investigator review. [...]other than medication changes resulting from information from RHC procedures, control group subjects will not have pressure-based medication changes over time and should be managed instead according to routine practice as informed by published clinical guidelines. Thresholds for NT-proBNP/BNP corrected for BMI using a 4% reduction per BMI unit over 25 kg/m2 Subjects ≥18 y of age able and willing to provide informed consent Chest circumference of &lt;65 in if BMI is ≥35 kg/m2 Willing and able to upload PA pressure information and comply with the follow-up requirements Exclusion criteria Intolerance to all neurohormonal antagonists (ie, intolerance to ACE-I, ARB, ARNi, hydralazine/isosorbide dinitrate, and β-blockers) ACC/AHA stage D refractory HF (including having received or currently receiving pharmacologic circulatory support with inotropes) Received or are likely to receive an advanced therapy (eg, mechanical circulatory support or cardiac transplant) in the next 12 m NYHA class IV HF patients with: continuous or chronic use of scheduled intermittent inotropic therapy for HF and an INTERMACS level of ≤4, or persistence of fluid overload with maximum (or dose equivalent) diuretic intervention eGFR &lt; 25 mL/min/1.73 m2 and nonresponsive to diuretic therapy, or receiving chronic dialysis Inability to tolerate or receive dual antiplatelet therapy or anticoagulation therapy for 1 m postimplantation Significant congenital heart disease that has not been repaired and would prevent implantation of the CardioMEMS PA Sensor Implanted with mechanical right heart valve(s) Unrepaired severe valvular disease Pregnant or planning to become pregnant in the next 12 m An active, ongoing infection, defined as being febrile, an elevated white blood cell count, on intravenous antibiotics, and/or positive cultures (blood, sputum or urine). History of current or recurrent (≥2 episodes within 5 y prior to consent) pulmonary emboli and/or deep vein thromboses Major cardiovascular event (eg, unstable angina, myocardial infarction, percutaneous coronary intervention, open heart surgery, or stroke) within 90 d prior to consent Implanted with CRT-P or CRT-D for less than 90 d prior to consent Enrollment into another trial with an active treatment arm Anticipated life expectancy of &lt;12 m Any condition that, in the opinion of the Investigator, would not allow for utilization of the CardioMEMS HF System to manage the subject using information gained from hemodynamic measurements to adjust medications, including the presence of unexpectedly severe pulmonary hypertension (eg, transpulmonary gradient &gt;15) at implant RHC, a history of noncompliance, or any condition that would preclude CardioMEMS PA Sensor implantation Table I Inclusion and exclusion criteria PA pressure goals PA diastolic: 8-20 mm Hg PA mean: 10-25 mm Hg PA systolic: 15-35 mm Hg Optimization phase

BACKGROUND: The remedē System Pivotal Trial was a prospective, multi-center, randomized trial demonstrating transvenous phrenic nerve stimulation (TPNS) therapy is safe and effectively treats central sleep apnea (CSA) and improves sleep architecture and daytime sleepiness. Subsequently, the remedē System was approved by FDA in 2017. As a condition of approval, the Post Approval Study (PAS) collected clinical evidence regarding long-term safety and effectiveness in adults with moderate to severe CSA through five years post implant. METHODS: Patients remaining in the Pivotal Trial at the time of FDA approval were invited to enroll in the PAS and consented to undergo sleep studies (scored by a central laboratory), complete the Epworth Sleepiness Scale (ESS) questionnaire to assess daytime sleepiness, and safety assessment. All subjects (treatment and former control group) receiving active therapy were pooled; data from both trials were combined for analysis. RESULTS: Fifty-three of the original 151 Pivotal Trial patients consented to participate in the PAS and 52 completed the 5-year visit. Following TPNS therapy, the apnea-hypopnea index (AHI), central-apnea index (CAI), arousal index, oxygen desaturation index, and sleep architecture showed sustained improvements. Comparing 5 years to baseline, AHI and CAI decreased significantly (AHI baseline median 46 events/hour vs 17 at 5 years; CAI baseline median 23 events/hour vs 1 at 5 years), though residual hypopneas were present. In parallel, the arousal index, oxygen desaturation index and sleep architecture improved. The ESS improved by a statistically significant median reduction of 3 points at 5 years. Serious adverse events related to implant procedure, device or delivered therapy were reported by 14% of patients which include 16 (9%) patients who underwent a pulse generator reposition or lead revision (primarily in the first year). None of the events caused long-term harm. No unanticipated adverse device effects or related deaths occurred through 5 years. CONCLUSION: Long-term TPNS safely improves CSA, sleep architecture and daytime sleepiness through 5 years post implant. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01816776.

Heart failure (HF) is a disorder characterized by hemodynamic abnormalities including a reduction in the heart's ability to deliver oxygenated blood to the body. HF is also associated with important neurohormonal abnormalities, including activation of the renin-angiotensin-aldosterone and sympathetic nervous systems and their resulting effects on the heart and vascular endothelium. Our understanding of the neurohormonal role in the progression of HF has greatly improved in the past 10 years,1 and many of the therapies that significantly improve the symptoms and prognosis of patients with HF now target the underlying neurohormonal abnormalities. As shown in Figure 1, neurohormonal activation can lead to progression of hemodynamic abnormalities resulting in reduced cardiac output (CO); increased filling pressures; and ultimately worsening symptoms of fatigue, dyspnea, and decreased exercise tolerance. Although the neurohormonal mechanisms may cause progression of the disease process, nearly all medications used in HF treatment have demonstrable effects on hemodynamics. Current acute HF treatment is aimed directly at stabilizing and improving a patient's short-term hemodynamic condition; chronic HF treatments can alter short-term and improve long-term hemodynamics. Neurohormonal activation and resultant hemodynamic and symptom changes. RAS=renin-angiotensin-aldosterone system Specific hemodynamic measurements such as CO and systemic vascular resistance are generally obtained for only the most critically ill HF patients, in large part due to the risk, discomfort, and cost of invasive procedures such as pulmonary artery catheterization.2 Nonetheless, understanding and measuring the factors that affect CO are central to the assessment, prognosis, and treatment of patients with HF. The four determinants of CO are the rate of the pump (heart rate), the volume of blood available to pump (preload), the pumping strength (contractility), and the force the heart must overcome to pump (afterload, generally approximated by systemic vascular resistance). Symptoms—physical findings like vital signs—and laboratory findings such as blood tests and chest radiographs are imprecise measures of hemodynamic function. Unfortunately, they are the only data many clinicians have at their disposal when making important decisions in the care of patients with HF. The direct cost of treating HF is estimated to be $56 billion per year in the United States3 and the number of HF patients in this country may reach 10 million by 2010.4 A significant portion of the cost of HF care is the high cost of hospitalizations for patients with acute decompensation. Through careful surveillance of patients with chronic HF using improved methods for measuring hemodynamic and neurohormonal status, primary care physicians and cardiologists may be able to intervene in a timely manner and prevent acute episodes leading to hospitalization, major morbidity, or death. Warner-Stevenson5 has developed and popularized the concept of categorizing HF patients by hemodynamic subset based on perfusion with CO (warm vs. cold) and congestion with pulmonary artery wedge pressure (wet vs. dry). The four quadrants, representing the four hemodynamic classes, are shown in Figure 2. Studies have suggested that these profiles provide a useful framework to risk stratify patients with HF, predict outcomes, and identify therapeutic options. However, this framework is based on invasive pulmonary artery catheterization, with its requisite risk and cost, or on physical examination and patient history, which have been shown to lack sensitivity and specificity, even in the hands of experienced clinicians.6 HF management using hemodynamic subsets could be substantially improved by the existence of more objective data with which to classify patients and evaluate the effectiveness of subsequent pharmacologic and implantable interventions. Clinical profiles in heart failure. PND=paroxysmal nocturnal dyspnea; JV=jugular vein; ACE=angiotensin-converting enzyme. Adapted from J Am Coll Cardiol. 2003;41(10):1797–1804.5 Impedance cardiography (ICG) is a noninvasive method of determining hemodynamic status. In the past, studies questioned the reliability of ICG technology,7, 8 leading some to conclude that the technology did not have value in clinical decision making. However, refinements in signal processing and CO algorithms have greatly improved the reliability of ICG technology. The latest generation of ICG devices (BioZ ICG Monitor, CardioDynamics, San Diego, CA; and BioZ ICG Module, GE Medical Systems Information Technologies, Milwaukee, WI) are both highly reproducible and accurate in a number of clinical settings, including HF.9-11 A recent search of the literature failed to show a single citation since US Food and Drug Administration 510(k) clearances of these particular devices that suggests they are not valid for clinical applications. ICG is a form of plethysmography that utilizes changes in thoracic electrical impedance to estimate changes in blood volume in the aorta and changes in fluid volume in the thorax. As shown in Figures 3 and 4, the ICG procedure involves the placement of four dual sensors on a patient's neck and chest. A low-amplitude, high-frequency alternating current is delivered from the four outer sensors and the four inner sensors detect instantaneous changes in voltage. As suggested by Ohm's law, when a constant current is applied to the thorax, the changes in voltage are directly proportional to the changes in measured impedance. The overall thoracic impedance, called base impedance (Z0) is the sum of the impedances of the components of the thorax, including fat, cardiac and skeletal muscle, lung and vascular tissue, bone, and air. Changes from Z0 occur due to changes in lung volumes with respiration and changes in the volume and velocity of blood in the great vessels during systole and diastole. The rapidly changing component of chest impedance (ΔZ) is filtered to remove the respiratory variation, leaving the impedance changes due to ventricular ejection. Figure 5 details the elements contributing to Z0 and ΔZ, and Figure 6 illustrates how the first derivative of the impedance waveform (ΔZ/Δt) is used with an electrocardiogram to determine the beginning of electrical systole, aortic valve opening, maximal deflection of the ΔZ/Δt waveform, and the closing of the aortic valve. From these fiducial points, a variety of measured and calculated parameters (Table I) are continuously displayed on the ICG device screen for monitoring purposes, or in a printed report for review (Figure 7). Front view of impedance cardiography method Lateral view of impedance cardiography method Contributing elements to thoracic impedance. Z0=baseline impedance; ΔZ=change in impedanceAdapted from Osypka MJ, Bernstein DP. Electrophysiologic principles and theory of stroke volume determination by thoracic electrical bioimpedance. AACN Clin Issues. 1999;10(3):385–399. Fiducial points derived from electrocardiogram (ECG) and impedance waveforms. ΔZ=change in impedance; ΔZ/Δt=first derivative of the impedance waveform; PEP=preejection period; LVET=left ventricular ejection time Impedance cardiography hemodynamic status report (BioZ ICG Monitor, CardioDynamics, San Diego, CA) The hemodynamic parameters derived from ICG can aid in the diagnostic and prognostic evaluation of patients with HF. Using ICG, a clinician is able to evaluate direct or indirect measures of each of the four major determinants of CO (preload, afterload, contractility, and heart rate). Figure 8 is a conceptual diagram of CO and its determinants, ICG parameters associated with the determinants, and the effects of pharmacologic agent classes on each determinant. Due to greater acceptance of ICG in clinical and research settings, clinicians are now able to use ICG-derived hemodynamic data to help decide when to initiate and titrate these types of medications. A summary of applications of ICG in HF is presented in Table II, demonstrating its broad clinical applicability. Pharmacologic agent effect on cardiac output determinants and impedance cardiography parameters. CO=cardiac output; CI=cardiac index; HR=heart rate; SV=stroke volume; SI=stroke index; ΔTFC=change in thoracic fluid content; SVR=systemic vascular resistance; SVRI=systemic vascular resistance index; VI=velocity index; PEP=preejection period; ACI=acceleration index; LVET=left ventricular ejection time; STR=systolic time ratio In this supplement to Congestive Heart Failure, we seek to further define the role of ICG through a series of original contributions. The study by Yung et al. (p. 7) validates the accuracy of ICG in patients with pulmonary hypertension by comparing ICG to both direct Fick method and thermodilution CO. In doing so, the authors demonstrate the potential hazard of using thermodilution as the only reference standard for CO measurement. Parrott et al. (p. 11) compare changes in ejection fraction by echocardiography to changes in ICG parameters in established HF patients. Their findings demonstrate the ability of ICG to simply and cost-effectively identify changes in ventricular function. While pulmonary artery catheterization in patients with HF has been criticized and is largely unproven by clinical trial, an estimated 2 million such catheters are sold worldwide each year.12 Springfield et al. (p. 14) illustrate the role of ICG in the differential diagnosis of patients with dyspnea. Although B-type natriuretic peptide testing has gained wide attention recently as an aid to diagnose HF in the emergency department,13 ICG may also have a diagnostic role and provides additional value because of its ability to identify appropriate therapeutic options and monitor the response to therapy in real time. Silver et al. (page 17) report on the ability of ICG to replace pulmonary artery catheterization, which has tremendous cost implications for hospitals caring for such patients. Vijayaraghavan et al. (page 22) demonstrate the prognostic role of ICG in patients with chronic HF, and show strong association of ICG changes to changes in functional status and quality-of-life measures. Summers et al. (page 28) provide a series of case reports that illustrate ICG's practical role in the initiation and titration of neurohormonal agents and their patient-specific hemodynamic effects. This compilation of studies adds to the growing body of data supporting the role of ICG in the management of patients with HF. Within a year, the results of two multicenter trials studying key roles for ICG should be available: Prospective Evaluation and identification of Decompensation by Impedance Cardiography Test (PREDICT), conducted in patients with chronic HF; and the BioImpedance cardioGraphy (BIG) substudy of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE).14 PREDICT specifically addresses the ability of ICG-derived hemodynamic data to identify patients at risk for death, hospitalization, or emergency department visit. The BIG substudy will evaluate the diagnostic and prognostic role of ICG in both arms of a randomized, controlled trial in pulmonary artery catheter—hemodynamic-guided management of patients admitted with an acute episode of HF. There is now a compelling body of literature that demonstrates the validity of ICG using the most current technology. More and more studies have shown the value of ICG in clinical settings in addition to HF, including dyspnea,15 hypertension,16 and atrioventricular sequential pacemakers.17 The studies presented in this issue of Congestive Heart Failure further define the role of this valuable, noninvasive technology in clinical medicine. It is likely that these and other studies of ICG in HF will be used to refine our understanding and ability to assess patients and predict prognosis, expanding on the concept of the four quadrants presented in Figure 2. The impact of adding ICG hemodynamic data to the four quadrants is depicted in Figure 9. Knowledge of stroke index, cardiac index, systemic vascular resistance index, and changes in fluid with thoracic fluid content would likely provide more quantitative, objective, and sensitive measurements of hemodynamic factors, and has significant implications for the management of patients with HF. Model for clinical profiles in heart failure utilizing impedance cardiography hemodynamic measurements Incorporating this model of assessment into a proposed therapeutic algorithm is shown in Figure 10. Ideally, a baseline measurement of ICG in addition to other standard clinical variables would be collected and utilized in combination to more precisely assess a patient's perfusion, congestion, and vasoactive status. This assessment would lead to a categorization of the patient's absolute or relative change in hemodynamic profile, facilitating assessment of short-term risk for adverse HF-related events. The change in hemodynamic status and assessment of higher risk may lead to increased clinical surveillance or a decision to intervene to prevent a negative patient outcome. In addition, ICG parameters may aid in the assessment of a stable, low-risk hemodynamic profile toward the initiation and up-titration of neurohormonal agents that are often under-prescribed but are known to improve event-free survival. Therapeutic algorithm for incorporating impedance cardiography (ICG) parameters into clinical assessment of heart failure. SI=stroke index; CI=cardiac index; TFC=thoracic fluid content; SVRI=systemic vascular resistance index; ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin-receptor blocker Note: This supplement to Congestive Heart Failure contains articles dealing with ICG. Readers are reminded that positive statements about the clinical utility of ICG, and the BioZ ICG Monitor in particular, are solely the opinions of the authors and do not represent an official endorsement by Congestive Heart Failure, its Editors or Editorial Board, or the Heart Failure Society of America.