PRecision Event Monitoring for PatienTs with Heart Failure using HeartLogic (PREEMPT-HF) study design and enrolment.

AIMS: The HeartLogic multisensor index has been found to be a sensitive predictor of worsening heart failure (HF). However, there is limited data on this index's association and its constituent sensors with HF readmissions. METHODS AND RESULTS: The PREEMPT-HF study is a global, multicentre, prospective, observational, single-arm, post-market study. HF patients with an implantable defibrillator device or cardiac resynchronization therapy with defibrillator with HeartLogic capabilities were eligible if sensor data collection was turned on and the HeartLogic feature was not enabled. Thus, the HeartLogic Index/alert and heart sounds sensor trends were unavailable via the LATITUDE remote monitoring system to clinicians (blinded). Evaluation of subject medical records at 6 months and a final in-clinic visit at 12 months was required for collection of all-cause hospitalizations and HF outpatient visits. The purpose of this study is exploratory, no formal hypothesis tests are planned, and no adjustment for multiple testing will be performed. A total of 2183 patients were enrolled at 103 sites between June 2018 and June 2020. A significant proportion of the patients were implanted with implantable defibrillator devices (39%) versus cardiac resynchronization therapy with defibrillator (61%); were female (27%); over 65 (61%); New York Heart Association class I (13%), II (53%), and III (33%); ejection fraction < 25% (21%); ischaemic (50%); and with a history of renal dysfunction (23%). CONCLUSIONS: The PREEMPT study will provide clinical data and blinded sensor trends for the characterization of sensor changes with HF readmission, tachyarrhythmias, and event subgroups. These data may help to refine the clinical use of HeartLogic and to improve patient outcomes.

Multiple cArdiac seNsors for mAnaGEment of Heart Failure (MANAGE-HF) - Phase I Evaluation of the Integration and Safety of the HeartLogic Multisensor Algorithm in Patients With Heart Failure.

BACKGROUND: Patients with heart failure (HF) and reduced ejection fraction suffer from a relapsing and remitting disease course, where early treatment changes may improve outcomes. We assessed the clinical integration and safety of the HeartLogic multisensor index and alerts in HF care. METHODS: The Multiple cArdiac seNsors for mAnaGEment of Heart Failure (MANAGE-HF) study enrolled 200 patients with HF and reduced ejection fraction (<35%), New York Heart Association functional class II-III symptoms, implanted with a cardiac resynchronization therapy-defibrillator or and implantable cardioverter defibrillator, who had either a hospitalization for HF within 12 months or unscheduled visit for HF exacerbation within 90 days or an elevated natriuretic peptide concentration (brain natriuretic peptide [BNP] of ≥150 pg/mL or N-terminal pro-BNP [NT-proBNP] of ≥600 pg/mL). This phase included the development of an alert management guide and evaluated changes in medical treatment, natriuretic peptide levels, and safety. RESULTS: The mean age of participants was 67 years, 68% were men, 81% were White, and 61% had a HF hospitalization in prior 12 months. During follow-up, there were 585 alert cases with an average of 1.76 alert cases per patient-year. HF medications were augmented during 74% of the alert cases. HF treatment augmentation within 2 weeks from an initial alert was associated with more rapid recovery of the HeartLogic Index. Five serious adverse events (0.015 per patient-year) occurred in relation to alert-prompted medication change. NTproBNP levels decreased from median of 1316 pg/mL at baseline to 743 pg/mL at 12 months (P < .001). CONCLUSIONS: HeartLogic alert management was safely implemented in HF care and may optimize HF management. This phase supports further evaluation in larger studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03237858).

Multiparameter diagnostic sensor measurements in heart failure patients presenting with SARS-CoV-2 infection.

AIMS: Implantable device-based sensor measurements including heart sounds, markers of ventilation, and thoracic impedance have been shown to predict heart failure (HF) hospitalizations. We sought to assess how these parameters changed prior to COVID-19 (Cov-19) and how these compared with those presenting with decompensated HF or pneumonia. METHODS AND RESULTS: This retrospective analysis explores patterns of changes in daily measurements by implantable sensors in 10 patients with Cov-19 and compares these findings with those observed prior to HF (n = 88) and pneumonia (n = 12) hospitalizations from the MultiSENSE, PREEMPT-HF, and MANAGE-HF trials. The earliest sensor changes prior to Cov-19 were observed in respiratory rate (6 days) and temperature (5 days). There was a three-fold to four-fold greater increase in respiratory rate, rapid shallow breathing index, and night heart rate compared with those presenting with HF or pneumonia. Furthermore, activity levels fell more in those presenting with Cov-19, a change that was often sustained for some time. In contrast, there were no significant changes in 1st or 3rd heart sound (S1 and S3 ) amplitude in those presenting with Cov-19 or pneumonia compared with the known changes that occur in HF decompensation. CONCLUSIONS: Multi-sensor device diagnostics may provide early detection of Cov-19, distinguishable from worsening HF by an extreme and fast rise in respiratory rate along with no changes in S3.

Small decreases in biventricular pacing percentages are associated with multiple metrics of worsening heart failure as measured from a cardiac resynchronization therapy defibrillator.

BACKGROUND: Lower BiVentricular (BiV) pacing percentages have been associated with significantly worse survival in patients with chronic heart failure (HF). However, the pathophysiology behind this observation has not been further delineated. This analysis evaluated whether small incremental decreases in BiV pacing percentages were associated with worse measures, related to HF physiology using individual sensor trends and the HeartLogic composite index. METHODS: Sensor data was obtained from 900 ambulatory HF patients with implanted CRT devices. The percent of cardiac cycles with BiV pacing was assessed for periods (median = 7.3 days) between data downloads (median = 55 periods/patient). RESULTS: The third heart sound (S3), respiration rate, RSBI, and night-time heart rate were significantly elevated with sub-optimal pacing (<98%), while the first heart sound (S1), thoracic impedance, and activity were significantly lower. All sensor changes were in the direction associated with worsening HF. While IN the HeartLogic alert state (threshold above an Index of 16) the odds of optimal BiV pacing (≥98%) were less than when OUT of the HeartLogic alert state for a given subject (OR: 0.655; 95% CI: 0.626-0.686; p < 0.0001). The percent BiV pacing was reduced and the HeartLogic Index was increased in the periods surrounding HFhospitalizations. CONCLUSION: Lower BiV pacing percent is associated with multiple sensor changes indicative of worsening HF, and patients in HeartLogic alert are more likely to have suboptimal BiV pacing. Collectively, these data provide strong evidence that even small decreases in BiV percent pacing can lead to worsening HF.

Case Reports of Implantable Cardiac Device Physiologic Sensor Changes in Subjects with Coronavirus Disease-2019 Infection.

The severe acute respiratory syndrome novel coronavirus-2 pandemic has established a new set of challenges to health care delivery. Remotely monitored physiologic sensors on implantable cardiac devices can provide insight into the differential diagnosis of dyspnea in the heart failure population. We report on a unique pattern of sensor deviations that seem to occur specifically with severe acute respiratory syndrome novel coronavirus-2 infection.

Development of a biomarker panel to predict cardiac resynchronization therapy response: Results from the SMART-AV trial.

BACKGROUND: Predicting a favorable cardiac resynchronization therapy (CRT) response holds great clinical importance. OBJECTIVE: The purpose of this study was to examine proteins from broad biological pathways and develop a prediction tool for response to CRT. METHODS: Plasma was collected from patients before CRT (SMART-AV [SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy] trial). A CRT response was prespecified as a ≥15-mL reduction in left ventricular end-systolic volume at 6 months, which resulted in a binary CRT response (responders 52%, nonresponders 48%; n = 758). RESULTS: Candidate proteins (n = 74) were evaluated from the inflammatory, signaling, and structural domains, which yielded 12 candidate biomarkers, but only a subset of these demonstrated predictive value for CRT response: soluble suppressor of tumorgenicity-2, soluble tumor necrosis factor receptor-II, matrix metalloproteinase-2, and C-reactive protein. These biomarkers were used in a composite categorical scoring algorithm (Biomarker CRT Score), which identified patients with a high/low probability of a response to CRT (P <.001) when adjusted for a number of clinical covariates. For example, a Biomarker CRT Score of 0 yielded 5 times higher odds of a response to CRT compared to a Biomarker CRT Score of 4 (P <.001). The Biomarker CRT Score demonstrated additive predictive value when considered against a composite of clinical variables. CONCLUSION: These unique findings demonstrate that developing a biomarker panel for predicting individual response to CRT is feasible and holds potential for point-of-care testing and integration into evaluation algorithms for patients presenting for CRT.

A Multisensor Algorithm Predicts Heart Failure Events in Patients With Implanted Devices: Results From the MultiSENSE Study.

OBJECTIVES: The aim of this study was to develop and validate a device-based diagnostic algorithm to predict heart failure (HF) events. BACKGROUND: HF involves costly hospitalizations with adverse impact on patient outcomes. The authors hypothesized that an algorithm combining a diverse set of implanted device-based sensors chosen to target HF pathophysiology could detect worsening HF. METHODS: The MultiSENSE (Multisensor Chronic Evaluation in Ambulatory Heart Failure Patients) study enrolled patients with investigational chronic ambulatory data collection via implanted cardiac resynchronization therapy defibrillators. HF events (HFEs), defined as HF admissions or unscheduled visits with intravenous treatment, were independently adjudicated. The development cohort of patients was used to construct a composite index and alert algorithm (HeartLogic) combining heart sounds, respiration, thoracic impedance, heart rate, and activity; the test cohort was sequestered for independent validation. The 2 coprimary endpoints were sensitivity to detect HFE >40% and unexplained alert rate <2 alerts per patient-year. RESULTS: Overall, 900 patients (development cohort, n = 500; test cohort, n = 400) were followed for up to 1 year. Coprimary endpoints were evaluated using 320 patient-years of follow-up data and 50 HFEs in the test cohort (72% men; mean age 66.8 ± 10.3 years; New York Heart Association functional class at enrollment: 69% in class II, 25% in class III; mean left ventricular ejection fraction 30.0 ± 11.4%). Both endpoints were significantly exceeded, with sensitivity of 70% (95% confidence interval [CI]: 55.4% to 82.1%) and an unexplained alert rate of 1.47 per patient-year (95% CI: 1.32 to 1.65). The median lead time before HFE was 34.0 days (interquartile range: 19.0 to 66.3 days). CONCLUSIONS: The HeartLogic multisensor index and alert algorithm provides a sensitive and timely predictor of impending HF decompensation. (Evaluation of Multisensor Data in Heart Failure Patients With Implanted Devices [MultiSENSE]; NCT01128166).

Soluble ST2 and Risk of Arrhythmias, Heart Failure, or Death in Patients with Mildly Symptomatic Heart Failure: Results from MADIT-CRT.

Soluble ST2 is an established biomarker of heart failure (HF) progression. Data about its prognostic implications in patients with mildly symptomatic HF eligible to receive cardiac resynchronization therapy defibrillators (CRT-D) are limited. In a cohort of 684 patients enrolled in Multicenter Automated Defibrillator Implantation Trial (MADIT)-CRT, levels of soluble ST2 (sST2) were serially assessed at baseline and 1 year (n = 410). In multivariable-adjusted models, elevated baseline sST2 was associated with an increased risk of death, death or HF, and death or ventricular arrhythmia (VA) even when adjusting for baseline brain natriuretic protein (BNP) levels. In addition, patients with lower baseline sST2 levels had greater risk reduction with CRT-D (p = 0.006). Serial assessment revealed increased risk of VA and death or VA (HR per 10 % increase in sST2 1.11 (1.04-1.20), p = 0.004). Among patients with mildly symptomatic HF and eligibility for CRT-D, baseline and serial assessments sST2 may provide important information for risk stratification.

Vagal Nerve Stimulation Evoked Heart Rate Changes and Protection from Cardiac Remodeling.

This study investigated whether vagal nerve stimulation (VNS) leads to improvements in ischemic heart failure via heart rate modulation. At 7 ± 1 days post left anterior descending artery (LAD) ligation, 63 rats with myocardial infarctions (MI) were implanted with ECG transmitters and VNS devices (MI + VNS, N = 44) or just ECG transmitters (MI, N = 17). VNS stimulation was active from 14 ± 1 days to 8 ± 1 weeks post MI. The average left ventricular (LV) end diastolic volumes at 8 ± 1 weeks were MI = 672.40 µl and MI + VNS = 519.35 µl, p = 0.03. The average heart weights, normalized to body weight (± std) at 14 ± 1 weeks were MI = 3.2 ± 0.6 g*kg(-1) and MI + VNS = 2.9 ± 0.3 g*kg(-1), p = 0.03. The degree of cardiac remodeling was correlated with the magnitude of acute VNS-evoked heart rate (HR) changes. Further research is required to determine if the acute heart rate response to VNS activation is useful as a heart failure biomarker or as a tool for VNS therapy characterization.

Review and Updates in Regenerative and Personalized Medicine, Preclinical Animal Models, and Clinical Care in Cardiovascular Medicine.

The goal of this paper is to provide an updated review for scientists and clinicians on the major areas in cardiovascular medicine published in the Journal. Leading topics in regenerative and personalized medicine are presented along with a critical overview of the field. New standards in large preclinical animal models of pulmonary hypertension and left bundle branch block are highlighted. Finally, clinical care in the areas of atherosclerosis, the aortic valve, platelet biology, and myocarditis is discussed as well as autonomic modulation therapies.

Plasma galectin-3 and heart failure outcomes in MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy).

BACKGROUND: Elevated circulating levels of the protein galectin-3, a mediator of fibrogenesis, have previously been associated with adverse outcomes in heart failure (HF) patients and appear to modify response to certain pharmacologic therapies. This study investigated the relationship between galectin-3 level and clinical outcomes in HF patients randomized to implantable cardioverter defibrillator (ICD-only) or cardiac resynchronization therapy (CRT-D). METHODS AND RESULTS: Plasma galectin-3 concentrations were measured in 654 New York Heart Association functional class I/II patients participating in the MADIT-CRT trial. A heterogeneity of response was detected between pre-implantation galectin-3 and randomization group (CRT-D or ICD-only) on the primary MADIT-CRT trial end point of nonfatal HF event or death (P = .045). Among patients with baseline galectin-3 levels in the top quartile of the distribution, CRT-D was associated with a 65% reduction in risk of the primary end point (hazard ratio [HR] 0.35, 95% confidence interval [CI] 0.19-0.67), whereas among patients with lower baseline galectin-3 values CRT-D was associated with a 25% decrease in risk (HR 0.75, 95% CI. 0.51-1.11). Baseline galectin-3 level also was observed to be an independent predictor of the primary end point (multivariable adjusted HR per log unit increase: 1.55; 95% CI 1.01-2.38; P = .043). CONCLUSIONS: Elevated galectin-3 was found to be an independent predictor of adverse HF outcome in patients with mildly symptomatic HF. A significant interaction of device randomization group with pre-implantation galectin-3 level was detected, with HF patients with the highest baseline galectin-3 levels deriving a disproportionately larger benefit from CRT-D.

Pacing to reduce refractory angina in patients with severe coronary artery disease: a crossover pilot trial.

Biventricular pacing (BiV) has been shown to reduce wall stress and workload in regions near the pacing sites. This trial investigated if BiV near the ischemic region would reduce chest pain in patients with refractory angina due to severe coronary artery disease (CAD). Eleven patients were implanted with BiV devices with leads positioned at or adjacent to their ischemic regions as detected by single-photon emission computed tomography (SPECT) and randomized to either pacing turned ON or OFF for 3 months, and then crossed over for 3 months. With pacing turned ON, a Dynamic atrioventricular (AV) delay was set for approximately 90% and 70% of the intrinsic AV delay at the resting heart rate and at the onset of symptoms, respectively. One patient was excluded from the analysis due to a large amount of RV pacing during the OFF periods (24-64%) and due to an inability to properly deliver therapy because of an excessive number of ventricular premature complexes. Overall, with the device ON vs. OFF, the number of angina episodes (0.8 ± 0.4 vs. 1.2 ± 0.7 per week, P = 0.03) and amount of nitroglycerin used (0.2 ± 0.1 vs. 1.0 ± 0.7 per week, P = 0.11) was lower with BiV pacing. Furthermore, the treadmill exercise time to symptoms trended higher (427 ± 65 vs. 408 ± 64 s, P = 0.19), and the sum of fluorodeoxyglucose-positron emission tomography (FDG-PET) scores trended lower (7.9 ± 3.5 vs. 12.0 ± 4.0, P = 0.11) with the device ON vs. OFF. Nevertheless, there were no significant differences in SPECT myocardial perfusion scores, left ventricle ejection fraction, wall motion score index, and quality of life scores with device programmed ON vs. OFF (all P > 0.05). In conclusion, this pilot study demonstrated that BiV-P at or near the ischemic region was feasible and associated with significant reductions in angina in patients with severe CAD. Adequately powered prospective studies are needed to confirm these findings.

Effect of peri-infarct pacing early after myocardial infarction: results of the prevention of myocardial enlargement and dilatation post myocardial infarction study.

BACKGROUND: Left ventricular (LV) remodeling has been attributed to the segmental loss of viable myocardium due to myocardial infarction (MI), which results in redistribution of cardiac workload, with increased regional wall stress in and around the infarct zone. Because ventricular pacing has been shown to reduce regional wall stress and workload in regions near the pacing site, this trial was designed to test whether chronic pacing near the infarct attenuates LV remodeling. METHODS AND RESULTS: Eighty patients with an anterior MI, peak creatine kinase >2000 mU/mL, ejection fraction ≤35%, wall motion abnormality (WMA) in >5 of 16 segments, and QRS <120 ms, were randomized to either control (implantable cardioverter-defibrillator [ICD]) or biventricular pacing with peri-infarct LV lead placement (cardiac resynchronization therapy [CRT]-D) arms between 2 and 14 days after the MI. The primary end point-change in LV end-diastolic volume (LVEDV) from baseline to 12 months-was not significantly different between the 2 groups (CRT, 10.6±27.7 mL; ICD, 11.2±31.2 mL; 2-sample t test P>0.05). In a hypothesis-generating secondary analysis, there was a sustained reduction in the WMA score at 12 months in paced patients (CRT, -0.16±0.28; ICD, -0.01±0.24, 2-sample t test P=0.03). No differences were found in the therapy-related event rate, hospitalizations, or mortality (all P>0.05). CONCLUSIONS: Chronic pacing in the infarct region did not alter the primary end point of LV remodeling over 1 year.

Function-blocking antibodies to human vascular adhesion protein-1: a potential anti-inflammatory therapy.

Human vascular adhesion protein-1 (VAP-1) is a homodimeric 170-kDa sialoglycoprotein that is expressed on the surface of endothelial cells and functions as a semicarbazide-sensitive amine oxidase and as an adhesion molecule. Blockade of VAP-1 has been shown to reduce leukocyte adhesion and transmigration in in vivo and in vitro models, suggesting that VAP-1 is a potential target for anti-inflammatory therapy. In this study we have constructed mouse-human chimeric antibodies by genetic engineering in order to circumvent the potential problems involved in using murine antibodies in man. Our chimeric anti-VAP-1 antibodies, which were designed to lack Fc-dependent effector functions, bound specifically to cell surface-expressed recombinant human VAP-1 and recognized VAP-1 in different cell types in tonsil. Furthermore, the chimeric antibodies prevented leukocyte adhesion and transmigration in vitro and in vivo. Hence, these chimeric antibodies have the potential to be used as a new anti-inflammatory therapy.

Absence of the endothelial oxidase AOC3 leads to abnormal leukocyte traffic in vivo.

Leukocyte migration from the blood to tissues is a prerequisite for normal immune responses. We produced mice deficient in an endothelial cell-surface oxidase (amine oxidase, copper containing-3 [AOC3], also known as vascular adhesion protein-1 [VAP-1]) and found that this enzyme is needed for leukocyte extravasation in vivo. Real-time imaging shows that AOC3 mediates slow rolling, firm adhesion, and transmigration of leukocytes in vessels at inflammatory sites and lymphoid tissues. Absence of AOC3 results in reduced lymphocyte homing into lymphoid organs and in attenuated inflammatory response in peritonitis. These data alter the paradigm of leukocyte extravasation cascade by providing the first physiological proof for the concept that endothelial cell surface enzymes regulate the development of inflammatory reactions in vivo and suggest that this enzyme should be useful as an anti-inflammatory target.

Origins of serum semicarbazide-sensitive amine oxidase.

Semicarbazide-sensitive amine oxidases (SSAO) are enzymes that are capable of deaminating primary amines to produce aldehyde, ammonia, and hydrogen peroxide. This activity has been associated with vascular adhesion protein-1 (VAP-1) and is found in the serum, endothelium, adipose, and smooth muscle of mammals. Circulating SSAO activity is increased in congestive heart failure, diabetes, and inflammatory liver diseases. To investigate the origin of circulating SSAO activity, two transgenic mouse models were created with full-length human VAP-1 (hVAP-1) expressed on either endothelial (mTIEhVAP-1) or adipose tissues (aP2hVAP-1), with tie-1 and adipocyte P2 promoters, respectively. Under normal conditions a circulating form of hVAP-1 was found at high levels in the serum of mice with endothelium-specific expression and at low levels in the serum of mice with adipose specific expression. The level of circulating hVAP-1 in the transgenic mice varied with gender, transgene zygosity, diabetes, and fasting. Serum SSAO activity was absent from VAP-1 knockout mice and endothelial cell-specific expression of human VAP-1 restored SSAO activity to the serum of VAP-1 knockout mice. Together, these experiments show that in the mouse VAP-1 is the only source of serum SSAO, that under physiological conditions vascular endothelial cells can be a major source of circulating VAP-1 protein and SSAO, and that serum VAP-1 can originate from both endothelial cells and adipocytes during experimental diabetes. An increased endothelial cell capacity for lymphocyte binding and altered expression of redox-sensitive proteins was also associated with the mTIEhVAP-1 transgene.

Semicarbazide sensitive amine oxidase overexpression has dual consequences: insulin mimicry and diabetes-like complications.

Semicarbazide-sensitive amine oxidases (SSAO) are copper-containing enzymes that oxidatively deaminate primary amines to produce hydrogen peroxide, ammonium, and specific aldehydes. Vascular adhesion protein-1 (VAP-1) is a cell surface and soluble molecule that possesses SSAO activity. VAP-1 protein, SSAO activity, and SSAO reaction products are elevated in the serum of patients with diabetes, congestive heart failure, and specific inflammatory liver diseases. By expressing human VAP-1/SSAO on mouse endothelial cells and subsequently in the serum, and by chronically treating the transgenic mice for 15 months with a high-fat diet and a physiological substrate for SSAO, methylamine, the in vivo roles of SSAO were assessed. The VAP-1 transgene increased the mouse body mass index and subcutaneous abdominal fat pad weights in a manner independent of food consumption. The transgene together with increased SSAO substrate availability enhanced glucose uptake in an SSAO-dependent manner. The increased SSAO activity also led to diabetes-like complications, including advanced glycation end product formation, elevated blood pressure, altered atherosclerosis progression, and nephropathy. These findings suggest that, although manipulation of VAP-1/SSAO has potential to serve as a therapeutic treatment in insulin-resistant conditions, care must be taken to fully understand its impact on obesity and vascular damage.