Wearables, telemedicine, and artificial intelligence in arrhythmias and heart failure: Proceedings of the European Society of Cardiology Cardiovascular Round Table.

Digital technology is now an integral part of medicine. Tools for detecting, screening, diagnosis, and monitoring health-related parameters have improved patient care and enabled individuals to identify issues leading to better management of their own health. Wearable technologies have integrated sensors and can measure physical activity, heart rate and rhythm, and glucose and electrolytes. For individuals at risk, wearables or other devices may be useful for early detection of atrial fibrillation or sub-clinical states of cardiovascular disease, disease management of cardiovascular diseases such as hypertension and heart failure, and lifestyle modification. Health data are available from a multitude of sources, namely clinical, laboratory and imaging data, genetic profiles, wearables, implantable devices, patient-generated measurements, and social and environmental data. Artificial intelligence is needed to efficiently extract value from this constantly increasing volume and variety of data and to help in its interpretation. Indeed, it is not the acquisition of digital information, but rather the smart handling and analysis that is challenging. There are multiple stakeholder groups involved in the development and effective implementation of digital tools. While the needs of these groups may vary, they also have many commonalities, including the following: a desire for data privacy and security; the need for understandable, trustworthy, and transparent systems; standardized processes for regulatory and reimbursement assessments; and better ways of rapidly assessing value.

Design and performance of a multisensor heart failure monitoring algorithm: results from the multisensor monitoring in congestive heart failure (MUSIC) study.

BACKGROUND: Remote monitoring of heart failure (HF) patients may help in the early detection of acute decompensation before the onset of symptoms, providing the opportunity for early intervention to reduce HF-related hospitalizations, improve outcomes, and lower costs. METHODS AND RESULTS: MUSIC is a multicenter nonrandomized study designed to develop and validate an algorithm for prediction of impending acute HF decompensation with the use of physiologic signals obtained from an external device adhered to the chest. A total of 543 HF patients (206 development, 337 validation) with ejection fraction ≤40% and a recent HF admission were enrolled. Patients were remotely monitored for 90 days using a multisensor device. Accounting for device failure and patient withdrawal, 314 patients (114 development, 200 validation) were included in the analysis. Development patient data were used to develop a multiparameter HF detection algorithm. Algorithm performance in the development cohort had 65% sensitivity, 90% specificity, and a false positive rate of 0.7 per patient-year for detection of HF events. In the validation cohort, algorithm performance met the prespecified end points with 63% sensitivity, 92% specificity, and a false positive rate of 0.9 per patient-year. The overall rate of significant adverse skin response was 0.4%. CONCLUSION: Using an external multisensor monitoring system, an HF decompensation prediction algorithm was developed that met the prespecified performance end point. Further studies are required to determine whether the use of this system will improve patient outcomes.

Design of the Multi-Sensor Monitoring in Congestive Heart Failure (MUSIC) study: prospective trial to assess the utility of continuous wireless physiologic monitoring in heart failure.

BACKGROUND: Remote monitoring of heart failure (HF) patients may help in the early detection of acute HF decompensation before the onset of symptoms. Appropriate early intervention in these patients may reduce HF-related hospitalizations and costs. METHODS: The MUSIC (Multi-Sensor Monitoring in Congestive Heart Failure) study comprises 2 multicenter nonrandomized phases (MUSIC-Development and MUSIC-Validation) designed to develop and validate an algorithm for the prediction of acute HF decompensation using multiple physiologic signals obtained from an external, adherent, multisensor system capable of intermittent transmission of physiologic signals. Data obtained from MUSIC-Development will be used to develop the algorithm to predict HF decompensation. The algorithm will be validated in MUSIC-Validation with the objectives of ≥ 60% sensitivity for correctly predicting an acute HF event, a false-positive patient status signal rate of ≤ 1.0 per patient-year, and a safety endpoint of ≤ 5% of patients experiencing significant adverse skin conditions related to the prolonged wearing of the adherent device. A total of 542 patients in New York Heart Association functional class III-IV HF, with ejection fraction ≤ 40% and a recent HF admission, are enrolled in MUSIC-Development (n = 180) and MUSIC-Validation (n = 362). All patients are remotely monitored for 90 days using the Corventis multisensor system that transmits bioimpedance, electrocardiogram, and accelerometer data. RESULTS: The MUSIC study has completed patient enrollment and follow-up in both phases. Once algorithm development is complete from the MUSIC-Development phase, the sequestered data set from the MUSIC-Validation phase will be used for algorithm validation.

Spontaneous calcium release in tissue from the failing canine heart.

Abnormalities in calcium handling have been implicated as a significant source of electrical instability in heart failure (HF). While these abnormalities have been investigated extensively in isolated myocytes, how they manifest at the tissue level and trigger arrhythmias is not clear. We hypothesize that in HF, triggered activity (TA) is due to spontaneous calcium release from the sarcoplasmic reticulum that occurs in an aggregate of myocardial cells (an SRC) and that peak SCR amplitude is what determines whether TA will occur. Calcium and voltage optical mapping was performed in ventricular wedge preparations from canines with and without tachycardia-induced HF. In HF, steady-state calcium transients have reduced amplitude [135 vs. 170 ratiometric units (RU), P < 0.05] and increased duration (252 vs. 229 s, P < 0.05) compared with those of normal. Under control conditions and during beta-adrenergic stimulation, TA was more frequent in HF (53% and 93%, respectively) compared with normal (0% and 55%, respectively, P < 0.025). The mechanism of arrhythmias was SCRs, leading to delayed afterdepolarization-mediated triggered beats. Interestingly, the rate of SCR rise was greater for events that triggered a beat (0.41 RU/ms) compared with those that did not (0.18 RU/ms, P < 0.001). In contrast, there was no difference in SCR amplitude between the two groups. In conclusion, TA in HF tissue is associated with abnormal calcium regulation and mediated by the spontaneous release of calcium from the sarcoplasmic reticulum in aggregates of myocardial cells (i.e., an SCR), but importantly, it is the rate of SCR rise rather than amplitude that was associated with TA.

Cellular mechanism of calcium-mediated triggered activity in the heart.

Calcium overload due to enhanced calcium entry is a mechanism for spontaneous calcium release (SCR) from the sarcoplasmic reticulum, delayed-afterdepolarizations (DAD), and triggered activity. However, the exact mechanistic relationship between elevated intracellular calcium levels and triggered activity originating from a specific location remains unclear. We hypothesize that under conditions of enhanced calcium entry, elevation of intracellular calcium will result in multiple calcium release events of which only one is more likely to initiate a triggered beat. We used optical mapping of action potentials and ratiometric calcium transients in an electromechanically-uncoupled canine wedge model of enhanced calcium entry, using I(Ks) blockade with beta-adrenergic stimulation. Under conditions of enhanced calcium entry, the rate of calcium uptake was faster compared with control conditions; however, during rapid pacing, cytoplasmic calcium elevation at the endocardium was significantly increased (15+/-4%) compared with control (10+/-3, P<0.04). Rapid pacing induced multiple simultaneous SCR events with largest amplitude and earliest onset near the endocardium compared with the epicardium. Furthermore, SCR events with largest amplitude and earliest onset served as a focus for DAD-mediated triggered activity. Interestingly, polymorphic VT occurred in some experiments when multiple SCR events occurred. In conclusion, multiple, simultaneous SCR events occur over a broad region of relatively slower calcium uptake and elevated diastolic calcium levels. However, SCR events closer to the endocardium have the largest amplitude and earliest onset and are, thereby, more likely to initiate DAD-mediated triggered activity. Finally, multiple SCR events may be a mechanism of polymorphic VT under calcium overload conditions.

Role of calcium cycling versus restitution in the mechanism of repolarization alternans.

T-wave alternans, a powerful marker of arrhythmic events, results from alternation in action potential duration (APD). The underlying cellular mechanism of APD alternans is unknown but has been attributed to either intracellular calcium (Ca2+) cycling or membrane ionic currents, manifested by a steep slope of cellular APD restitution. To address these mechanisms, high-resolution optical mapping techniques were used to measure action potentials and Ca2+ transients simultaneously from hundreds of epicardial sites in the guinea pig model of pacing-induced T-wave alternans (n=7). The pacing rates (ie, alternans threshold) at which T-wave (369+/-11 bpm), APD (369+/-21 bpm), and Ca2+ (371+/-29 bpm) alternans first appeared were comparable. Importantly, the site of origin of APD alternans and Ca2+ alternans consistently occurred together near the base of the left ventricle, not where APD restitution was steepest. In addition, APD and Ca2+ alternans were remarkably similar both spatially and temporally during discordant alternans. In conclusion, the mechanism underlying T-wave alternans in the intact heart is more closely associated with intracellular Ca2+ cycling rather than APD restitution.

Sex differences in ß-adrenergic responsiveness of action potentials and intracellular calcium handling in isolated rabbit hearts.

Cardioprotection in females, as observed in the setting of heart failure, has been attributed to sex differences in intracellular calcium handling and its modulation by ß-adrenergic signaling. However, further studies examining sex differences in ß-adrenergic responsiveness have yielded inconsistent results and have mostly been limited to studies of contractility, ion channel function, or calcium handling alone. Given the close interaction of the action potential (AP) and intracellular calcium transient (CaT) through the process of excitation-contraction coupling, the need for studies exploring the relationship between agonist-induced AP and calcium handling changes in female and male hearts is evident. Thus, the aim of this study was to use optical mapping to examine sex differences in ventricular APs and CaTs measured simultaneously from Langendorff-perfused hearts isolated from naïve adult rabbits during ß-adrenergic stimulation. The non-selective ß-agonist isoproterenol (Iso) decreased AP duration (APD90), CaT duration (CaD80), and the decay constant of the CaT (τ) in a dose-dependent manner (1-316.2 nM), with a plateau at doses ≥31.6 nM. The Iso-induced changes in APD90 and τ (but not CaD80) were significantly smaller in female than male hearts. These sex differences were more significant at faster (5.5 Hz) than resting rates (3 Hz). Treatment with Iso led to the development of spontaneous calcium release (SCR) with a dose threshold of 31.6 nM. While SCR occurrence was similar in female (49%) and male (53%) hearts, the associated ectopic beats had a lower frequency of occurrence (16% versus 40%) and higher threshold (100 nM versus 31.6 nM) in female than male hearts (p<0.05). In conclusion, female hearts had a decreased capacity to respond to ß-adrenergic stimulation, particularly under conditions of increased demand (i.e. faster pacing rates and "maximal" levels of Iso effects), however this reduced ß-adrenergic responsiveness of female hearts was associated with reduced arrhythmic activity.

Monitoring changes in fluid status with a wireless multisensor monitor: results from the Fluid Removal During Adherent Renal Monitoring (FARM) study.

Body fluid assessment is important for managing chronic kidney disease (CKD) and heart failure (HF). However, accurate detection of fluid retention remains elusive. The Fluid Removal During Adherent Renal Monitoring (FARM) study is a prospective, nonrandomized trial examining the performance of a wireless, noninvasive, multisensor fluid monitoring system, applied to the chest, to determine its performance and reliability during hemodialysis. Patients undergoing regular hemodialysis (n=25) were monitored continuously for 2 consecutive dialysis sessions and the interdialysis period. Physiologic variables, including tissue impedance, were recorded. The volume of fluid removed and weight change during dialysis were measured. An average of 3.4±1.2 L of fluid was removed during dialysis, which was associated with an increase in bioimpedance of 11.3±7.2 Ω. Change in bioimpedance was highly correlated with the amount of fluid removed but less so with weight loss. Normalized bioimpedance change (21.0%±12.1% increase from baseline, P<001) was larger than the normalized weight change (3.6%±1.1%, P<.01), suggesting a higher sensitivity and dynamic range than weight change for detecting fluid removal. The fluid monitoring system accurately tracked fluid and weight loss in patients during hemodialysis, supporting its use as a tool for the management of patient fluid status in disease states.

Remote at-home detection and monitoring of functional chronotropic incompetence in heart failure patients.

Chronotropic incompetence (CI) is common in heart failure (HF) patients and is associated with worsening outcome. Detecting and tracking functional CI during activities of daily living could provide insight into its contribution to HF symptoms and facilitate effective HF patient management. HF patients (n = 180, NYHA Class III/IV, ejection fraction (EF) ≤40%) were enrolled in a multi-center prospective monitoring study and had an external multi-sensor system applied to the chest and replaced weekly during a 90-day study. Medical information was collected at baseline and study close. Heart rate, respiration, activity, and body fluid data from the system were transmitted at regular intervals and used for offline analysis. Patients were primarily male (70%), with 61 ± 13 years mean age, 25 ± 5 kg/m(2) BMI, and 28 ± 7% EF. By correlating age-adjusted activity level and heart rate adaptation with a proprietary algorithm, functional CI was detected in 45% and ruled out in 29% of patients under conditions of daily living. In the remaining patients (26%), functional CI assessment was indeterminate due to insufficient age-adjusted activity level. Functional CI and No-CI groups were not significantly different in terms of baseline demographics, characteristics or HF outcome over the study period. ß-blocker use was 16% in the CI group and 82% in the no-CI group (p < 0.001), and therefore, could not explain the manifestation of functional CI. This proof-of-concept study suggests that a chronotropic response that may be functionally debilitating during activities of daily living in HF patients can be detected and tracked in a point-of-care telemonitoring approach using a non-invasive, adherent device.

Estimation of patient compliance in application of adherent mobile cardiac telemetry device.

In an in home usage outpatient setting, patient compliance is a key factor in determining the adoption and efficacy of treatment for any illness and is paramount for patient dependent medical technologies such as mobile patient monitoring systems. As a leader in the development of these technologies, Corventis has deployed its NUVANT™ Mobile Cardiac Telemetry System to thousands of patients around the world. The NUVANT system includes an externally worn adherent sensing device, the PiiX, whose proper application is critical to the on-patient longevity and thus performance of the NUVANT system. Patient compliance in this context is a universal challenge for such patient-applied adherent devices. Understanding and tracking a problem is key to solving it and the integrated suite of vital sign sensors in the Corventis PiiX offers a unique opportunity for extracting patient application compliance information from the incoming health data. Analysis of data from 5000 randomly selected patients has shown that improper application of the PiiX is a factor in 2.3% of patients. However, no reduction in adherent device longevity or performance was observed. Such information is a valuable feedback metric for product design, instructions for use, packaging of medical technologies, level of customer support and replacement costs.

Cardiac resynchronization therapy may benefit patients with left ventricular ejection fraction >35%: a PROSPECT trial substudy.

AIMS: Cardiac resynchronization therapy (CRT) is currently limited to those with left ventricular ejection fraction (LVEF) < or =35%. To evaluate whether patients with LVEF >35% might benefit from CRT, we performed a retrospective analysis of the predictors of response to CRT (PROSPECT) database. METHODS AND RESULTS: PROSPECT was a prospective, multicentre study that enrolled CRT patients based on enrolling centre-evaluated LVEF <35%, but all echocardiograms were subsequently analysed by a core laboratory. Patients with core laboratory-measured LVEF >35% (OVER35) were compared with those whose LVEF was <35% (UNDER35). Clinical composite score (CCS) and change in LV end systolic volume (LVESV) were analysed from baseline to 6-month follow-up. Of 361 patients, 86 (24%) had LVEF >35%. At entry, OVER35 had smaller LV volumes, shorter QRS duration, shorter 6-min walk distance, and were more likely to have ischaemic aetiology than UNDER35. Outcomes were comparable between the groups, with 62.8% of OVER35 improved in CCS (70.2% in UNDER35) and 50.8% of OVER35 improved in LVESV (57.8% in UNDER35). CONCLUSION: Patients with LVEF >35%, New York heart association functional Class III-IV status, and QRS >130 ms appear to derive clinical and structural benefit from CRT. As CRT may offer a valuable option for these patients, this hypothesis should be formally tested in a prospective, randomized multicentre trial.

Ryanodine receptor dysfunction and triggered activity in the heart.

Arrhythmogenesis has been increasingly linked to cardiac ryanodine receptor (RyR) dysfunction. However, the mechanistic relationship between abnormal RyR function and arrhythmogenesis in the heart is not clear. We hypothesize that, under abnormal RyR conditions, triggered activity will be caused by spontaneous calcium release (SCR) events that depend on transmural heterogeneities of calcium handling. We performed high-resolution optical mapping of intracellular calcium and transmembrane potential in the canine left ventricular wedge preparation (n = 28). Rapid pacing was used to initiate triggered activity under normal and abnormal RyR conditions induced by FKBP12.6 dissociation and beta-adrenergic stimulation (20-150 microM rapamycin, 0.2 microM isoproterenol). Under abnormal RyR conditions, almost all preparations experienced SCRs and triggered activity, in contrast to control, rapamycin, or isoproterenol conditions alone. Furthermore, under abnormal RyR conditions, complex arrhythmias (monomorphic and polymorphic tachycardia) were commonly observed. After washout of rapamycin and isoproterenol, no triggered activity was observed. Surprisingly, triggered activity and SCRs occurred preferentially near the epicardium but not the endocardium (P < 0.01). Interestingly, the occurrence of triggered activity and SCR events could not be explained by cytoplasmic calcium levels, but rather by fast calcium reuptake kinetics. These data suggest that, under abnormal RyR conditions, triggered activity is caused by multiple SCR events that depend on the faster calcium reuptake kinetics near the epicardium. Furthermore, multiple regions of SCR may be a mechanism for multifocal arrhythmias associated with RyR dysfunction.

Delayed after depolarization-mediated triggered activity associated with slow calcium sequestration near the endocardium.

INTRODUCTION: Previously, we have shown that cells near the endocardium are more prone to elevated diastolic intracellular calcium levels than cells near the epicardium. The arrhythmogenic consequence of such regional differences in calcium handling is not clear. METHODS AND RESULTS: Using optical mapping techniques, calcium transients and action potentials were recorded simultaneously from ventricular sites across the transmural wall of the arterially perfused canine left ventricular wedge preparation during control conditions, and under conditions of increased calcium entry (I(K) blockade and beta-adrenergic stimulation). Under conditions of enhanced calcium entry, the decay of the calcium transient and diastolic calcium levels during rapid pacing were slower (38%, P < 0.01) and higher (215%, P < 0.02), respectively, near (within approximately 3 mm) the endocardium compared to the epicardium (n = 9). Immediately after termination of rapid pacing under conditions of increased calcium entry, ectopic activity and simultaneous delayed after depolarizations and spontaneous calcium release events were observed. Over all experiments, ectopic activity occurred more frequently closer to the endocardium compared to the epicardium. CONCLUSIONS: Under conditions of enhanced calcium entry, myocytes closer to the endocardium exhibit a higher level of diastolic calcium and greater ectopic activity compared to the epicardium. We show for the first time simultaneous delayed after depolarization and spontaneous calcium release events from myocytes in a normally coupled multicellular preparation. These data combined suggest that myocytes near the endocardium are more susceptible to calcium-mediated triggered activity.

Intracellular calcium handling heterogeneities in intact guinea pig hearts.

Regional heterogeneities of ventricular repolarizing currents and their role in arrhythmogenesis have received much attention; however, relatively little is known regarding heterogeneities of intracellular calcium handling. Because repolarization properties and contractile function are heterogeneous from base to apex of the intact heart, we hypothesize that calcium handling is also heterogeneous from base to apex. To test this hypothesis, we developed a novel ratiometric optical mapping system capable of measuring calcium fluorescence of indo-1 at two separate wavelengths from 256 sites simultaneously. With the use of intact Langendorff-perfused guinea pig hearts, ratiometric calcium transients were recorded under normal conditions and during administration of known inotropic agents. Ratiometric calcium transients were insensitive to changes in excitation light intensity and fluorescence over time. Under control conditions, calcium transient amplitude near the apex was significantly larger (60%, P < 0.01) compared with the base. In contrast, calcium transient duration was significantly longer (7.5%, P < 0.03) near the base compared with the apex. During isoproterenol (0.05 microM) and verapamil (2.5 microM) administration, ratiometric calcium transients accurately reflected changes in contractile function, and, the direction of base-to-apex heterogeneities remained unchanged compared with control. Ratiometric optical mapping techniques can be used to accurately quantify heterogeneities of calcium handling in the intact heart. Significant heterogeneities of calcium release and sequestration exist from base to apex of the intact heart. These heterogeneities are consistent with base-to-apex heterogeneities of contraction observed in the intact heart and may play a role in arrhythmogenesis under abnormal conditions.