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1.  Implantable Cardioverter Defibrillators. Prophylactic Use 
Executive Summary
Objective
The use of implantable cardiac defibrillators (ICDs) to prevent sudden cardiac death (SCD) in patients resuscitated from cardiac arrest or documented dangerous ventricular arrhythmias (secondary prevention of SCD) is an insured service. In 2003 (before the establishment of the Ontario Health Technology Advisory Committee), the Medical Advisory Secretariat conducted a health technology policy assessment on the prophylactic use (primary prevention of SCD) of ICDs for patients at high risk of SCD. The Medical Advisory Secretariat concluded that ICDs are effective for the primary prevention of SCD. Moreover, it found that a more clearly defined target population at risk for SCD that would be likely to benefit from ICDs is needed, given that the number needed to treat (NNT) from recent studies is 13 to 18, and given that the per-unit cost of ICDs is $32,000, which means that the projected cost to Ontario is $770 million (Cdn).
Accordingly, as part of an annual review and publication of more recent articles, the Medical Advisory Secretariat updated its health technology policy assessment of ICDs.
Clinical Need
Sudden cardiac death is caused by the sudden onset of fatal arrhythmias, or abnormal heart rhythms: ventricular tachycardia (VT), a rhythm abnormality in which the ventricles cause the heart to beat too fast, and ventricular fibrillation (VF), an abnormal, rapid and erratic heart rhythm. About 80% of fatal arrhythmias are associated with ischemic heart disease, which is caused by insufficient blood flow to the heart.
Management of VT and VF with antiarrhythmic drugs is not very effective; for this reason, nonpharmacological treatments have been explored. One such treatment is the ICD.
The Technology
An ICD is a battery-powered device that, once implanted, monitors heart rhythm and can deliver an electric shock to restore normal rhythm when potentially fatal arrhythmias are detected. The use of ICDs to prevent SCD in patients resuscitated from cardiac arrest or documented dangerous ventricular arrhythmias (secondary prevention) is an insured service in Ontario.
Primary prevention of SCD involves identification of and preventive therapy for patients who are at high risk for SCD. Most of the studies in the literature that have examined the prevention of fatal ventricular arrhythmias have focused on patients with ischemic heart disease, in particular, those with heart failure (HF), which has been shown to increase the risk of SCD. The risk of HF is determined by left ventricular ejection fraction (LVEF); most studies have focused on patients with an LVEF under 0.35 or 0.30. While most studies have found ICDs to reduce significantly the risk for SCD in patients with an LVEF less than 0.35, a more recent study (Sudden Cardiac Death in Heart Failure Trial [SCD-HeFT]) reported that patients with HF with nonischemic heart disease could also benefit from this technology. Based on the generalization of the SCD-HeFT study, the Centers for Medicare and Medicaid in the United States recently announced that it would allocate $10 billion (US) annually toward the primary prevention of SCD for patients with ischemic and nonischemic heart disease and an LVEF under 0.35.
Review Strategy
The aim of this literature review was to assess the effectiveness, safety, and cost effectiveness of ICDs for the primary prevention of SCD.
The standard search strategy used by the Medical Advisory Secretariat was used. This included a search of all international health technology assessments as well as a search of the medical literature from January 2003–May 2005.
A modification of the GRADE approach (1) was used to make judgments about the quality of evidence and strength of recommendations systematically and explicitly. GRADE provides a framework for structured reflection and can help to ensure that appropriate judgments are made. GRADE takes into account a study’s design, quality, consistency, and directness in judging the quality of evidence for each outcome. The balance between benefits and harms, quality of evidence, applicability, and the certainty of the baseline risks are considered in judgments about the strength of recommendations.
Summary of Findings
Overall, ICDs are effective for the primary prevention of SCD. Three studies – the Multicentre Automatic Defibrillator Implantation Trial I (MADIT I), the Multicentre Automatic Defibrillator Implantation Trial II (MADIT II), and SCD-HeFT – showed there was a statistically significant decrease in total mortality for patients who prophylactically received an ICD compared with those who received conventional therapy (Table 1).
Results of Key Studies on the Use of Implantable Cardioverter Defibrillators for the Primary Prevention of Sudden Cardiac Death – All-Cause Mortality
MADIT I: Multicentre Automatic Defibrillator Implantation Trial I; MADIT II: Multicentre Automatic Defibrillator Implantation Trial II; SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial.
EP indicates electrophysiology; ICD, implantable cardioverter defibrillator; NNT, number needed to treat; NSVT, nonsustained ventricular tachycardia. The NNT will appear higher if follow-up is short. For ICDs, the absolute benefit increases over time for at least a 5-year period; the NNT declines, often substantially, in studies with a longer follow-up. When the NNT are equalized for a similar period as the SCD-HeFT duration (5 years), the NNT for MADIT-I is 2.2; for MADIT-II, it is 6.3.
GRADE Quality of the Evidence
Using the GRADE Working Group criteria, the quality of these 3 trials was examined (Table 2).
Quality refers to the criteria such as the adequacy of allocation concealment, blinding and follow-up.
Consistency refers to the similarity of estimates of effect across studies. If there is important unexplained inconsistency in the results, our confidence in the estimate of effect for that outcome decreases. Differences in the direction of effect, the size of the differences in effect, and the significance of the differences guide the decision about whether important inconsistency exists.
Directness refers to the extent to which the people interventions and outcome measures are similar to those of interest. For example, there may be uncertainty about the directness of the evidence if the people of interest are older, sicker or have more comorbidity than those in the studies.
As stated by the GRADE Working Group, the following definitions were used to grade the quality of the evidence:
High: Further research is very unlikely to change our confidence n the estimate of effect.
Moderate: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low: Any estimate of effect is very uncertain.
Quality of Evidence – MADIT I, MADIT II, and SCD-HeFT*
MADIT I: Multicentre Automatic Defibrillator Implantation Trial I; MADIT II: Multicentre Automatic Defibrillator Implantation Trial II; SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial.
The 3 trials had 3 different sets of eligibility criteria for implantation of an ICD for primary prevention of SCD. Conclusions
Conclusions
Overall, there is evidence that ICDs are effective for the primary prevention of SCD. Three trials have found a statistically significant decrease in total mortality for patients who prophylactically received an ICD compared with those who received conventional therapy in their respective study populations.
As per the GRADE Working Group, recommendations consider 4 main factors:
The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates, and the relative value placed on the outcome;
The quality of the evidence (Table 2);
Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects, such as proximity to a hospital or availability of necessary expertise; and
Uncertainty about the baseline risk for the population of interest
The GRADE Working Group also recommends that incremental costs of health care alternatives should be considered explicitly with the expected health benefits and harms. Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 3 is the overall trade-off between benefits and harms and incorporates any risk or uncertainty.
For MADIT I, the overall GRADE and strength of the recommendation is “moderate” – the quality of the evidence is “moderate” (uncertainty due to methodological limitations in the study design), and risk/uncertainty in cost and budget impact was mitigated by the use of filters to help target the prevalent population at risk (Table 3).
For MADIT II, the overall GRADE and strength of the recommendation is “very weak” – the quality of the evidence is “weak” (uncertainty due to methodological limitations in the study design), but there is risk or uncertainty regarding the high prevalence, cost, and budget impact. It is not clear why screening for high-risk patients was dropped, given that in MADIT II the absolute reduction in mortality was small (5.6%) compared to MADIT I, which used electrophysiological screening (23%) (Table 3).
For SCD-HeFT, the overall GRADE and strength of the recommendation is “weak” – the study quality is “moderate,” but there is also risk/uncertainty due to a high NNT at 5 years (13 compared to the MADIT II NNT of 6 and MADIT I NNT of 2 at 5 years), high prevalent population (N = 23,700), and a high budget impact ($770 million). A filter (as demonstrated in MADIT 1) is required to help target the prevalent population at risk and mitigate the risk or uncertainty relating to the high NNT, prevalence, and budget impact (Table 3).
The results of the most recent ICD trial (SCD-HeFT) are not generalizable to the prevalent population in Ontario (Table 3). Given that the current funding rate of an ICD is $32,500 (Cdn), the estimated budget impact for Ontario would be as high as $770 million (Cdn). The uncertainty around the cost estimate of treating the prevalent population with LVEF < 0.30 in Ontario, the lack of human resources to implement such a strategy and the high number of patients required to prevent one SCD (NNT = 13) calls for an alternative strategy that allows the appropriate uptake and diffusion of ICDs for primary prevention for patients at maximum risk for SCD within the SCD-HeFT population.
The uptake and diffusion of ICDs for primary prevention of SCD should therefore be based on risk stratification through the use of appropriate screen(s) that would identify patients at highest risk who could derive the most benefit from this technology.
Overall GRADE and Strength of Recommendation for the Use of Implantable Cardioverter Defibrillators for the Primary Prevention of Sudden Cardiac Death
MADIT I: Multicentre Automatic Defibrillator Implantation Trial I; MADIT II: Multicentre Automatic Defibrillator Implantation Trial II; SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial.
NNT indicates number needed to treat. The NNT will appear higher if follow-up is short. For ICDs, the absolute benefit increases over time for at least a 5-year period; the NNT declines, often substantially, in studies with a longer follow-up. When the NNT are equalized for a similar period as the SCD-HeFT duration (5 years), the NNT for MADIT-I is 2.2; for MADIT-II, it is 6.3.
NSVT indicates nonsustained ventricular tachycardia; VT, ventricular tachycardia.
PMCID: PMC3382404  PMID: 23074465
2.  ECG Quantification of Myocardial Scar and Risk Stratification in MADIT-II 
Background
Low left ventricular ejection fraction (LVEF) increases risk for both sudden cardiac death (SCD) and for heart failure (HF) death; however, implantable cardioverter-defibrillators (ICDs) reduce the incidence of SCD, not HF death. Distinguishing individuals at risk for HF death (non-SCD) vs. SCD could improve ICD patient selection.
Objective
This study evaluated whether electrocardiogram (ECG) quantification of myocardial infarction (MI) could discriminate risk for SCD vs. non-SCD.
Methods
Selvester QRS scoring was performed on 995 MADIT-II trial subjects’ ECGs to quantify MI size. MIs were categorized as small (0–3 QRS points), medium (4–7) or large (≥8). Mortality, SCD and non-SCD rates in the conventional medical therapy (CMT) arm and mortality and ventricular tachycardia/fibrillation (VT/VF) rates in the ICD arm were analyzed by QRS score group. Both arms were analyzed to determine ICD efficacy by QRS score group.
Results
In the CMT arm, mortality, SCD and non-SCD rates were similar across QRS score groups (p=0.73. p=0.92 and p=0.77). The ICD arm showed similar rates of mortality (p=0.17) and VT/VF (p=0.24) across QRS score groups. ICD arm mortality was lower than CMT arm mortality across QRS score groups with greatest benefit in the large scar group.
Conclusion
Recently, QRS score was shown to be predictive of VT/VF in the SCD-HeFT population consisting of both ischemic and non-ischemic HF and having a maximum LVEF of 35% vs. 30% for MADIT-II. Our study found that QRS score did not add prognostic value in the MADIT-II population exhibiting relatively more severe cardiac dysfunction.
doi:10.1111/anec.12065
PMCID: PMC3779916  PMID: 24047486
Sudden death; heart failure; implantable cardioverter-defibrillator; electrocardiography; electrophysiology; tachyarrhythmias
3.  Comparison of the Relation Between Left Ventricular Anatomy and QRS Duration in Patients With Cardiomyopathy With Versus Without Left Bundle Branch Block 
The American journal of cardiology  2014;113(10):1717-1722.
QRS duration (QRSd) is used to diagnose left bundle branch block (LBBB) and is important for determining cardiac resynchronization therapy eligibility. The same QRSd thresholds established decades ago are used for all patients. However, significant inter-individual variability of normal QRSd exists and individualized QRSd thresholds may improve diagnosis and intervention strategies. Prior work reported left ventricular (LV) mass and papillary muscle location predicted QRSd in healthy subjects, but the relationship in diseased ventricles is unknown. We aimed to determine the association between LV anatomy and QRSd in cardiomyopathy patients. Patients referred for primary prevention implantable defibrillators (n=166) received cardiac magnetic resonance imaging and those with normal conduction (without bundle branch or fascicular block) and LBBB were studied. LV mass, length, internal diameter, end diastolic volume (LVEDV), septal and lateral wall thickness, and papillary muscle location were measured. In normal conduction patients, LV length (r=0.35, p<0.001), mass (r=0.32, p<0.001), diameter (r=0.20, p=0.03) and septal wall thickness (r=0.20, p=0.03) had positive correlations with QRSd. In LBBB patients, LV length (r=0.32, p=0.03), mass (r=0.39, p=0.01), diameter (r=0.34, p=0.02), and LVEDV (r=0.32, p=0.04) had positive correlations with QRSd. Contrary to prior studies in healthy subjects, papillary muscle angle (location) was not associated with QRSd in normal conduction or LBBB cardiomyopathy patients. In conclusion, increasing LV anatomical measurements are associated with increasing QRSd in cardiomyopathy patients. Future work should investigate the use of LV anatomical measurements in developing individualized QRSd thresholds for diagnosing conduction abnormalities such as LBBB and identifying candidates for cardiac resynchronization therapy.
doi:10.1016/j.amjcard.2014.02.026
PMCID: PMC4051227  PMID: 24698465
Left Ventricular Anatomy; QRS Duration; Cardiomyopathy; Left Bundle Branch Block
4.  Prolonged QRS Duration on the Resting ECG is Associated with Sudden Death Risk in Coronary Disease, Independent of Prolonged Ventricular Repolarization 
Background
Abnormalities of ventricular repolarization as well as depolarization have been associated with increased risk of ventricular arrhythmias.
Objective
We evaluated the relative contribution of these predictors to risk of sudden cardiac death (SCD) among patients with coronary artery disease (CAD).
Methods
In the ongoing Oregon Sudden Unexpected Death Study (Oregon SUDS), adult residents of Portland, OR metropolitan area (population ~1 million) who suffered SCD were identified prospectively (2002-2007). Of these, we analyzed the subgroup of SCDs that had a resting 12-lead ECG prior to SCD and also had associated CAD. Comparisons were conducted with a control group of subjects with known CAD, but no history of SCD from the same geographic region. Corrected QT interval (QTc), JT interval (JTc), QRS duration (QRSd) and other parameters were measured from ECG prior and unrelated to SCD. Analysis of LV function was limited to those subjects that had echocardiography performed prior to and remote from SCD.
Results
A total of 642 SCD cases (71±13 yrs, 62% male) were compared to 450 controls (66±12 yrs, 64% male). SCD cases had significantly longer QRSd (102±25 vs. 97±20 ms, p=0.0008) as well as JTc (348±44 vs. 339±34 ms, p=0.0006) vs. controls. In cases with prolonged QRSd, 38% had severe LV systolic dysfunction (LVSD) and 62% had normal, mild or moderately decreased LV systolic function. In a multivariable model, QRSd, JTc, age and severe LVSD were independent predictors. There was minimal overlap between prolonged QRSd and JTc in both case and control groups (3% and 4%, respectively).
Conclusions
Prolonged QRSd, JTc and severe LVSD had independent contributions to risk of SCD in coronary disease, in this community-based setting.
doi:10.1016/j.hrthm.2011.06.011
PMCID: PMC3183321  PMID: 21699869
Epidemiology; risk; stratification; predictor; population; sudden cardiac death; electrocardiogram; ventricular fibrillation; prevention
5.  Internet-Based Device-Assisted Remote Monitoring of Cardiovascular Implantable Electronic Devices 
Executive Summary
Objective
The objective of this Medical Advisory Secretariat (MAS) report was to conduct a systematic review of the available published evidence on the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted remote monitoring systems (RMSs) for therapeutic cardiac implantable electronic devices (CIEDs) such as pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. The MAS evidence-based review was performed to support public financing decisions.
Clinical Need: Condition and Target Population
Sudden cardiac death (SCD) is a major cause of fatalities in developed countries. In the United States almost half a million people die of SCD annually, resulting in more deaths than stroke, lung cancer, breast cancer, and AIDS combined. In Canada each year more than 40,000 people die from a cardiovascular related cause; approximately half of these deaths are attributable to SCD.
Most cases of SCD occur in the general population typically in those without a known history of heart disease. Most SCDs are caused by cardiac arrhythmia, an abnormal heart rhythm caused by malfunctions of the heart’s electrical system. Up to half of patients with significant heart failure (HF) also have advanced conduction abnormalities.
Cardiac arrhythmias are managed by a variety of drugs, ablative procedures, and therapeutic CIEDs. The range of CIEDs includes pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. Bradycardia is the main indication for PMs and individuals at high risk for SCD are often treated by ICDs.
Heart failure (HF) is also a significant health problem and is the most frequent cause of hospitalization in those over 65 years of age. Patients with moderate to severe HF may also have cardiac arrhythmias, although the cause may be related more to heart pump or haemodynamic failure. The presence of HF, however, increases the risk of SCD five-fold, regardless of aetiology. Patients with HF who remain highly symptomatic despite optimal drug therapy are sometimes also treated with CRT devices.
With an increasing prevalence of age-related conditions such as chronic HF and the expanding indications for ICD therapy, the rate of ICD placement has been dramatically increasing. The appropriate indications for ICD placement, as well as the rate of ICD placement, are increasingly an issue. In the United States, after the introduction of expanded coverage of ICDs, a national ICD registry was created in 2005 to track these devices. A recent survey based on this national ICD registry reported that 22.5% (25,145) of patients had received a non-evidence based ICD and that these patients experienced significantly higher in-hospital mortality and post-procedural complications.
In addition to the increased ICD device placement and the upfront device costs, there is the need for lifelong follow-up or surveillance, placing a significant burden on patients and device clinics. In 2007, over 1.6 million CIEDs were implanted in Europe and the United States, which translates to over 5.5 million patient encounters per year if the recommended follow-up practices are considered. A safe and effective RMS could potentially improve the efficiency of long-term follow-up of patients and their CIEDs.
Technology
In addition to being therapeutic devices, CIEDs have extensive diagnostic abilities. All CIEDs can be interrogated and reprogrammed during an in-clinic visit using an inductive programming wand. Remote monitoring would allow patients to transmit information recorded in their devices from the comfort of their own homes. Currently most ICD devices also have the potential to be remotely monitored. Remote monitoring (RM) can be used to check system integrity, to alert on arrhythmic episodes, and to potentially replace in-clinic follow-ups and manage disease remotely. They do not currently have the capability of being reprogrammed remotely, although this feature is being tested in pilot settings.
Every RMS is specifically designed by a manufacturer for their cardiac implant devices. For Internet-based device-assisted RMSs, this customization includes details such as web application, multiplatform sensors, custom algorithms, programming information, and types and methods of alerting patients and/or physicians. The addition of peripherals for monitoring weight and pressure or communicating with patients through the onsite communicators also varies by manufacturer. Internet-based device-assisted RMSs for CIEDs are intended to function as a surveillance system rather than an emergency system.
Health care providers therefore need to learn each application, and as more than one application may be used at one site, multiple applications may need to be reviewed for alarms. All RMSs deliver system integrity alerting; however, some systems seem to be better geared to fast arrhythmic alerting, whereas other systems appear to be more intended for remote follow-up or supplemental remote disease management. The different RMSs may therefore have different impacts on workflow organization because of their varying frequency of interrogation and methods of alerts. The integration of these proprietary RM web-based registry systems with hospital-based electronic health record systems has so far not been commonly implemented.
Currently there are 2 general types of RMSs: those that transmit device diagnostic information automatically and without patient assistance to secure Internet-based registry systems, and those that require patient assistance to transmit information. Both systems employ the use of preprogrammed alerts that are either transmitted automatically or at regular scheduled intervals to patients and/or physicians.
The current web applications, programming, and registry systems differ greatly between the manufacturers of transmitting cardiac devices. In Canada there are currently 4 manufacturers—Medtronic Inc., Biotronik, Boston Scientific Corp., and St Jude Medical Inc.—which have regulatory approval for remote transmitting CIEDs. Remote monitoring systems are proprietary to the manufacturer of the implant device. An RMS for one device will not work with another device, and the RMS may not work with all versions of the manufacturer’s devices.
All Internet-based device-assisted RMSs have common components. The implanted device is equipped with a micro-antenna that communicates with a small external device (at bedside or wearable) commonly known as the transmitter. Transmitters are able to interrogate programmed parameters and diagnostic data stored in the patients’ implant device. The information transfer to the communicator can occur at preset time intervals with the participation of the patient (waving a wand over the device) or it can be sent automatically (wirelessly) without their participation. The encrypted data are then uploaded to an Internet-based database on a secure central server. The data processing facilities at the central database, depending on the clinical urgency, can trigger an alert for the physician(s) that can be sent via email, fax, text message, or phone. The details are also posted on the secure website for viewing by the physician (or their delegate) at their convenience.
Research Questions
The research directions and specific research questions for this evidence review were as follows:
To identify the Internet-based device-assisted RMSs available for follow-up of patients with therapeutic CIEDs such as PMs, ICDs, and CRT devices.
To identify the potential risks, operational issues, or organizational issues related to Internet-based device-assisted RM for CIEDs.
To evaluate the safety, acceptability, and effectiveness of Internet-based device-assisted RMSs for CIEDs such as PMs, ICDs, and CRT devices.
To evaluate the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted RMSs for CIEDs compared to usual outpatient in-office monitoring strategies.
To evaluate the resource implications or budget impact of RMSs for CIEDs in Ontario, Canada.
Research Methods
Literature Search
The review included a systematic review of published scientific literature and consultations with experts and manufacturers of all 4 approved RMSs for CIEDs in Canada. Information on CIED cardiac implant clinics was also obtained from Provincial Programs, a division within the Ministry of Health and Long-Term Care with a mandate for cardiac implant specialty care. Various administrative databases and registries were used to outline the current clinical follow-up burden of CIEDs in Ontario. The provincial population-based ICD database developed and maintained by the Institute for Clinical Evaluative Sciences (ICES) was used to review the current follow-up practices with Ontario patients implanted with ICD devices.
Search Strategy
A literature search was performed on September 21, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from 1950 to September 2010. Search alerts were generated and reviewed for additional relevant literature until December 31, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Inclusion Criteria
published between 1950 and September 2010;
English language full-reports and human studies;
original reports including clinical evaluations of Internet-based device-assisted RMSs for CIEDs in clinical settings;
reports including standardized measurements on outcome events such as technical success, safety, effectiveness, cost, measures of health care utilization, morbidity, mortality, quality of life or patient satisfaction;
randomized controlled trials (RCTs), systematic reviews and meta-analyses, cohort and controlled clinical studies.
Exclusion Criteria
non-systematic reviews, letters, comments and editorials;
reports not involving standardized outcome events;
clinical reports not involving Internet-based device assisted RM systems for CIEDs in clinical settings;
reports involving studies testing or validating algorithms without RM;
studies with small samples (<10 subjects).
Outcomes of Interest
The outcomes of interest included: technical outcomes, emergency department visits, complications, major adverse events, symptoms, hospital admissions, clinic visits (scheduled and/or unscheduled), survival, morbidity (disease progression, stroke, etc.), patient satisfaction, and quality of life.
Summary of Findings
The MAS evidence review was performed to review available evidence on Internet-based device-assisted RMSs for CIEDs published until September 2010. The search identified 6 systematic reviews, 7 randomized controlled trials, and 19 reports for 16 cohort studies—3 of these being registry-based and 4 being multi-centered. The evidence is summarized in the 3 sections that follow.
1. Effectiveness of Remote Monitoring Systems of CIEDs for Cardiac Arrhythmia and Device Functioning
In total, 15 reports on 13 cohort studies involving investigations with 4 different RMSs for CIEDs in cardiology implant clinic groups were identified in the review. The 4 RMSs were: Care Link Network® (Medtronic Inc,, Minneapolis, MN, USA); Home Monitoring® (Biotronic, Berlin, Germany); House Call 11® (St Jude Medical Inc., St Pauls, MN, USA); and a manufacturer-independent RMS. Eight of these reports were with the Home Monitoring® RMS (12,949 patients), 3 were with the Care Link® RMS (167 patients), 1 was with the House Call 11® RMS (124 patients), and 1 was with a manufacturer-independent RMS (44 patients). All of the studies, except for 2 in the United States, (1 with Home Monitoring® and 1 with House Call 11®), were performed in European countries.
The RMSs in the studies were evaluated with different cardiac implant device populations: ICDs only (6 studies), ICD and CRT devices (3 studies), PM and ICD and CRT devices (4 studies), and PMs only (2 studies). The patient populations were predominately male (range, 52%–87%) in all studies, with mean ages ranging from 58 to 76 years. One study population was unique in that RMSs were evaluated for ICDs implanted solely for primary prevention in young patients (mean age, 44 years) with Brugada syndrome, which carries an inherited increased genetic risk for sudden heart attack in young adults.
Most of the cohort studies reported on the feasibility of RMSs in clinical settings with limited follow-up. In the short follow-up periods of the studies, the majority of the events were related to detection of medical events rather than system configuration or device abnormalities. The results of the studies are summarized below:
The interrogation of devices on the web platform, both for continuous and scheduled transmissions, was significantly quicker with remote follow-up, both for nurses and physicians.
In a case-control study focusing on a Brugada population–based registry with patients followed-up remotely, there were significantly fewer outpatient visits and greater detection of inappropriate shocks. One death occurred in the control group not followed remotely and post-mortem analysis indicated early signs of lead failure prior to the event.
Two studies examined the role of RMSs in following ICD leads under regulatory advisory in a European clinical setting and noted:
– Fewer inappropriate shocks were administered in the RM group.
– Urgent in-office interrogations and surgical revisions were performed within 12 days of remote alerts.
– No signs of lead fracture were detected at in-office follow-up; all were detected at remote follow-up.
Only 1 study reported evaluating quality of life in patients followed up remotely at 3 and 6 months; no values were reported.
Patient satisfaction was evaluated in 5 cohort studies, all in short term follow-up: 1 for the Home Monitoring® RMS, 3 for the Care Link® RMS, and 1 for the House Call 11® RMS.
– Patients reported receiving a sense of security from the transmitter, a good relationship with nurses and physicians, positive implications for their health, and satisfaction with RM and organization of services.
– Although patients reported that the system was easy to implement and required less than 10 minutes to transmit information, a variable proportion of patients (range, 9% 39%) reported that they needed the assistance of a caregiver for their transmission.
– The majority of patients would recommend RM to other ICD patients.
– Patients with hearing or other physical or mental conditions hindering the use of the system were excluded from studies, but the frequency of this was not reported.
Physician satisfaction was evaluated in 3 studies, all with the Care Link® RMS:
– Physicians reported an ease of use and high satisfaction with a generally short-term use of the RMS.
– Physicians reported being able to address the problems in unscheduled patient transmissions or physician initiated transmissions remotely, and were able to handle the majority of the troubleshooting calls remotely.
– Both nurses and physicians reported a high level of satisfaction with the web registry system.
2. Effectiveness of Remote Monitoring Systems in Heart Failure Patients for Cardiac Arrhythmia and Heart Failure Episodes
Remote follow-up of HF patients implanted with ICD or CRT devices, generally managed in specialized HF clinics, was evaluated in 3 cohort studies: 1 involved the Home Monitoring® RMS and 2 involved the Care Link® RMS. In these RMSs, in addition to the standard diagnostic features, the cardiac devices continuously assess other variables such as patient activity, mean heart rate, and heart rate variability. Intra-thoracic impedance, a proxy measure for lung fluid overload, was also measured in the Care Link® studies. The overall diagnostic performance of these measures cannot be evaluated, as the information was not reported for patients who did not experience intra-thoracic impedance threshold crossings or did not undergo interventions. The trial results involved descriptive information on transmissions and alerts in patients experiencing high morbidity and hospitalization in the short study periods.
3. Comparative Effectiveness of Remote Monitoring Systems for CIEDs
Seven RCTs were identified evaluating RMSs for CIEDs: 2 were for PMs (1276 patients) and 5 were for ICD/CRT devices (3733 patients). Studies performed in the clinical setting in the United States involved both the Care Link® RMS and the Home Monitoring® RMS, whereas all studies performed in European countries involved only the Home Monitoring® RMS.
3A. Randomized Controlled Trials of Remote Monitoring Systems for Pacemakers
Two trials, both multicenter RCTs, were conducted in different countries with different RMSs and study objectives. The PREFER trial was a large trial (897 patients) performed in the United States examining the ability of Care Link®, an Internet-based remote PM interrogation system, to detect clinically actionable events (CAEs) sooner than the current in-office follow-up supplemented with transtelephonic monitoring transmissions, a limited form of remote device interrogation. The trial results are summarized below:
In the 375-day mean follow-up, 382 patients were identified with at least 1 CAE—111 patients in the control arm and 271 in the remote arm.
The event rate detected per patient for every type of CAE, except for loss of atrial capture, was higher in the remote arm than the control arm.
The median time to first detection of CAEs (4.9 vs. 6.3 months) was significantly shorter in the RMS group compared to the control group (P < 0.0001).
Additionally, only 2% (3/190) of the CAEs in the control arm were detected during a transtelephonic monitoring transmission (the rest were detected at in-office follow-ups), whereas 66% (446/676) of the CAEs were detected during remote interrogation.
The second study, the OEDIPE trial, was a smaller trial (379 patients) performed in France evaluating the ability of the Home Monitoring® RMS to shorten PM post-operative hospitalization while preserving the safety of conventional management of longer hospital stays.
Implementation and operationalization of the RMS was reported to be successful in 91% (346/379) of the patients and represented 8144 transmissions.
In the RM group 6.5% of patients failed to send messages (10 due to improper use of the transmitter, 2 with unmanageable stress). Of the 172 patients transmitting, 108 patients sent a total of 167 warnings during the trial, with a greater proportion of warnings being attributed to medical rather than technical causes.
Forty percent had no warning message transmission and among these, 6 patients experienced a major adverse event and 1 patient experienced a non-major adverse event. Of the 6 patients having a major adverse event, 5 contacted their physician.
The mean medical reaction time was faster in the RM group (6.5 ± 7.6 days vs. 11.4 ± 11.6 days).
The mean duration of hospitalization was significantly shorter (P < 0.001) for the RM group than the control group (3.2 ± 3.2 days vs. 4.8 ± 3.7 days).
Quality of life estimates by the SF-36 questionnaire were similar for the 2 groups at 1-month follow-up.
3B. Randomized Controlled Trials Evaluating Remote Monitoring Systems for ICD or CRT Devices
The 5 studies evaluating the impact of RMSs with ICD/CRT devices were conducted in the United States and in European countries and involved 2 RMSs—Care Link® and Home Monitoring ®. The objectives of the trials varied and 3 of the trials were smaller pilot investigations.
The first of the smaller studies (151 patients) evaluated patient satisfaction, achievement of patient outcomes, and the cost-effectiveness of the Care Link® RMS compared to quarterly in-office device interrogations with 1-year follow-up.
Individual outcomes such as hospitalizations, emergency department visits, and unscheduled clinic visits were not significantly different between the study groups.
Except for a significantly higher detection of atrial fibrillation in the RM group, data on ICD detection and therapy were similar in the study groups.
Health-related quality of life evaluated by the EuroQoL at 6-month or 12-month follow-up was not different between study groups.
Patients were more satisfied with their ICD care in the clinic follow-up group than in the remote follow-up group at 6-month follow-up, but were equally satisfied at 12- month follow-up.
The second small pilot trial (20 patients) examined the impact of RM follow-up with the House Call 11® system on work schedules and cost savings in patients randomized to 2 study arms varying in the degree of remote follow-up.
The total time including device interrogation, transmission time, data analysis, and physician time required was significantly shorter for the RM follow-up group.
The in-clinic waiting time was eliminated for patients in the RM follow-up group.
The physician talk time was significantly reduced in the RM follow-up group (P < 0.05).
The time for the actual device interrogation did not differ in the study groups.
The third small trial (115 patients) examined the impact of RM with the Home Monitoring® system compared to scheduled trimonthly in-clinic visits on the number of unplanned visits, total costs, health-related quality of life (SF-36), and overall mortality.
There was a 63.2% reduction in in-office visits in the RM group.
Hospitalizations or overall mortality (values not stated) were not significantly different between the study groups.
Patient-induced visits were higher in the RM group than the in-clinic follow-up group.
The TRUST Trial
The TRUST trial was a large multicenter RCT conducted at 102 centers in the United States involving the Home Monitoring® RMS for ICD devices for 1450 patients. The primary objectives of the trial were to determine if remote follow-up could be safely substituted for in-office clinic follow-up (3 in-office visits replaced) and still enable earlier physician detection of clinically actionable events.
Adherence to the protocol follow-up schedule was significantly higher in the RM group than the in-office follow-up group (93.5% vs. 88.7%, P < 0.001).
Actionability of trimonthly scheduled checks was low (6.6%) in both study groups. Overall, actionable causes were reprogramming (76.2%), medication changes (24.8%), and lead/system revisions (4%), and these were not different between the 2 study groups.
The overall mean number of in-clinic and hospital visits was significantly lower in the RM group than the in-office follow-up group (2.1 per patient-year vs. 3.8 per patient-year, P < 0.001), representing a 45% visit reduction at 12 months.
The median time from onset of first arrhythmia to physician evaluation was significantly shorter (P < 0.001) in the RM group than in the in-office follow-up group for all arrhythmias (1 day vs. 35.5 days).
The median time to detect clinically asymptomatic arrhythmia events—atrial fibrillation (AF), ventricular fibrillation (VF), ventricular tachycardia (VT), and supra-ventricular tachycardia (SVT)—was also significantly shorter (P < 0.001) in the RM group compared to the in-office follow-up group (1 day vs. 41.5 days) and was significantly quicker for each of the clinical arrhythmia events—AF (5.5 days vs. 40 days), VT (1 day vs. 28 days), VF (1 day vs. 36 days), and SVT (2 days vs. 39 days).
System-related problems occurred infrequently in both groups—in 1.5% of patients (14/908) in the RM group and in 0.7% of patients (3/432) in the in-office follow-up group.
The overall adverse event rate over 12 months was not significantly different between the 2 groups and individual adverse events were also not significantly different between the RM group and the in-office follow-up group: death (3.4% vs. 4.9%), stroke (0.3% vs. 1.2%), and surgical intervention (6.6% vs. 4.9%), respectively.
The 12-month cumulative survival was 96.4% (95% confidence interval [CI], 95.5%–97.6%) in the RM group and 94.2% (95% confidence interval [CI], 91.8%–96.6%) in the in-office follow-up group, and was not significantly different between the 2 groups (P = 0.174).
The CONNECT Trial
The CONNECT trial, another major multicenter RCT, involved the Care Link® RMS for ICD/CRT devices in a15-month follow-up study of 1,997 patients at 133 sites in the United States. The primary objective of the trial was to determine whether automatically transmitted physician alerts decreased the time from the occurrence of clinically relevant events to medical decisions. The trial results are summarized below:
Of the 575 clinical alerts sent in the study, 246 did not trigger an automatic physician alert. Transmission failures were related to technical issues such as the alert not being programmed or not being reset, and/or a variety of patient factors such as not being at home and the monitor not being plugged in or set up.
The overall mean time from the clinically relevant event to the clinical decision was significantly shorter (P < 0.001) by 17.4 days in the remote follow-up group (4.6 days for 172 patients) than the in-office follow-up group (22 days for 145 patients).
– The median time to a clinical decision was shorter in the remote follow-up group than in the in-office follow-up group for an AT/AF burden greater than or equal to 12 hours (3 days vs. 24 days) and a fast VF rate greater than or equal to 120 beats per minute (4 days vs. 23 days).
Although infrequent, similar low numbers of events involving low battery and VF detection/therapy turned off were noted in both groups. More alerts, however, were noted for out-of-range lead impedance in the RM group (18 vs. 6 patients), and the time to detect these critical events was significantly shorter in the RM group (same day vs. 17 days).
Total in-office clinic visits were reduced by 38% from 6.27 visits per patient-year in the in-office follow-up group to 3.29 visits per patient-year in the remote follow-up group.
Health care utilization visits (N = 6,227) that included cardiovascular-related hospitalization, emergency department visits, and unscheduled clinic visits were not significantly higher in the remote follow-up group.
The overall mean length of hospitalization was significantly shorter (P = 0.002) for those in the remote follow-up group (3.3 days vs. 4.0 days) and was shorter both for patients with ICD (3.0 days vs. 3.6 days) and CRT (3.8 days vs. 4.7 days) implants.
The mortality rate between the study arms was not significantly different between the follow-up groups for the ICDs (P = 0.31) or the CRT devices with defribillator (P = 0.46).
Conclusions
There is limited clinical trial information on the effectiveness of RMSs for PMs. However, for RMSs for ICD devices, multiple cohort studies and 2 large multicenter RCTs demonstrated feasibility and significant reductions in in-office clinic follow-ups with RMSs in the first year post implantation. The detection rates of clinically significant events (and asymptomatic events) were higher, and the time to a clinical decision for these events was significantly shorter, in the remote follow-up groups than in the in-office follow-up groups. The earlier detection of clinical events in the remote follow-up groups, however, was not associated with lower morbidity or mortality rates in the 1-year follow-up. The substitution of almost all the first year in-office clinic follow-ups with RM was also not associated with an increased health care utilization such as emergency department visits or hospitalizations.
The follow-up in the trials was generally short-term, up to 1 year, and was a more limited assessment of potential longer term device/lead integrity complications or issues. None of the studies compared the different RMSs, particularly the different RMSs involving patient-scheduled transmissions or automatic transmissions. Patients’ acceptance of and satisfaction with RM were reported to be high, but the impact of RM on patients’ health-related quality of life, particularly the psychological aspects, was not evaluated thoroughly. Patients who are not technologically competent, having hearing or other physical/mental impairments, were identified as potentially disadvantaged with remote surveillance. Cohort studies consistently identified subgroups of patients who preferred in-office follow-up. The evaluation of costs and workflow impact to the health care system were evaluated in European or American clinical settings, and only in a limited way.
Internet-based device-assisted RMSs involve a new approach to monitoring patients, their disease progression, and their CIEDs. Remote monitoring also has the potential to improve the current postmarket surveillance systems of evolving CIEDs and their ongoing hardware and software modifications. At this point, however, there is insufficient information to evaluate the overall impact to the health care system, although the time saving and convenience to patients and physicians associated with a substitution of in-office follow-up by RM is more certain. The broader issues surrounding infrastructure, impacts on existing clinical care systems, and regulatory concerns need to be considered for the implementation of Internet-based RMSs in jurisdictions involving different clinical practices.
PMCID: PMC3377571  PMID: 23074419
6.  The Relevance of the Primary Prevention Criteria for Implantable Cardioverter Defibrillator Implantation in Korean Symptomatic Severe Heart Failure Patients 
Korean Circulation Journal  2012;42(3):173-183.
Background and Objectives
Implantable cardioverter defibrillator (ICD) therapy is recommended as the primary tool for prevention of sudden cardiac death (SCD) in symptomatic patients with severe left ventricular dysfunction. There is a paucity of information on whether this recommendation is appropriate for the Korean population with severe heart failure.
Subjects and Methods
The study group consisted of 275 consecutive patients (mean age 65 years, 71% male) who met the ICD implantation criteria for primary prevention (left ventricular ejection fraction ≤30% and New York Heart Association functional class II or III). We analyzed the clinical characteristics and outcomes of an ischemic cardiomyopathy (ICMP) group (n=131) and a non-ischemic cardiomyopathy (NICMP) group (n=144). The outcomes of these 2 groups were compared with the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) conventional and Defibrillators in the Non-ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) standard therapy groups, respectively.
Results
Eighty patients (29%) died during a follow-up period of 40±17 months. The NICMP group had better all-cause mortality rates than the ICMP group (19% vs. 40%, p<0.001), however both groups had a similar incidence of SCD (7% vs. 10%, p=0.272). The 2-year all-cause mortality and SCD for the ICMP group were similar to those of the MADIT-II conventional therapy group (20% vs. 20%, 7% vs. 10%, respectively, all p>0.05). All-cause mortality and the incidence of SCD in the NICMP group were comparable to those of the DEFINITE standard therapy group (13% vs. 17%, 6% vs. 6%, respectively, all p>0.05).
Conclusion
Korean patients with severe heart failure in both the ICMP and NICMP groups had all-caused mortality and risk of SCD comparable to patients in the MADIT-II and DEFINITE standard therapy groups. Therefore, the primary prevention criteria for ICD implantation would be appropriate in both Korean ICMP and NICMP patients.
doi:10.4070/kcj.2012.42.3.173
PMCID: PMC3318089  PMID: 22493612
Heart failure; Implantable defibrillators; Death, sudden, cardiac
7.  Rapid-Rate Nonsustained Ventricular Tachycardia Found on Implantable Cardioverter-Defibrillator Interrogation 
Objectives
The aim of this study was to examine rapid-rate nonsustained ventricular tachycardia (RR-NSVT) during routine implantable cardioverter-defibrillator (ICD) evaluation in patients with heart failure and its relationship to outcomes.
Background
The clinical implications of RR-NSVT identified during routine ICD interrogation are unclear. In this study, the occurrence of RR-NSVT and its association with ICD shocks and mortality in SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) were examined.
Methods
The 811 patients who received ICDs in SCD-HeFT constituted the study population. The occurrence of RR-NSVT and its association with ICD shocks and mortality in SCD-HeFT were examined.
Results
RR-NSVT was documented on ICD interrogation in 186 of 811 patients (22.9%). The mean duration of RR-NSVT was 26.4 ± 9.1 beats (7.5 ± 2.6 s), with a mean cycle length of 259 ± 32 ms. Polymorphic RR-NSVT accounted for 56% of episodes. Compared with patients without RR-NSVT, those with RR-NSVT were less likely to be taking beta-blockers, statins, or aspirin at enrollment. After adjusting for other known predictors of mortality in SCD-HeFT, RR-NSVT was independently associated with appropriate ICD shocks (hazard ratio: 4.25; 95% confidence interval: 2.94 to 6.14; p < 0.0001), with all-cause mortality (hazard ratio: 2.40; 95% confidence interval: 1.62 to 3.54; p < 0.0001), and with a composite of all-cause mortality and appropriate ICD shocks (hazard ratio: 3.03; 95% confidence interval: 2.21 to 4.15; p < 0.0001).
Conclusions
RR-NSVT identified on routine ICD interrogation should be considered an important clinical event. RR-NSVT during ICD interrogation is associated with appropriate ICD shocks and all-cause mortality. The clinical evaluation of patients with RR-NSVT should include intensification of medical therapy, particularly beta-blockers, or other appropriate clinical interventions. (Sudden Cardiac Death in Heart Failure Trial [SCD-HeFT]; NCT00000609)
doi:10.1016/j.jacc.2013.02.046
PMCID: PMC3760407  PMID: 23541974
arrhythmia; heart failure; implantable cardioverter-defibrillator; mortality; ventricular tachycardia
8.  Prolonged Tpeak to Tend Interval on the Resting Electrocardiogram Is Associated with Increased Risk of Sudden Cardiac Death 
Background
Early studies indicate that prolongation of the interval between the peak and end of the T wave (Tpeak to Tend, TpTe) on the 12-lead ECG, is a marker of ventricular arrhythmogenesis. However, community-based studies have not been conducted.
Methods and Results
TpTe and other ECG predictors were evaluated in the ongoing Oregon Sudden Unexpected Death Study based in the Portland, Oregon metropolitan area using a case-control design. Cases had sudden cardiac death (SCD), and were compared to living controls with coronary artery disease (CAD) from the same region. Analysis of TpTe and selected ECG intervals was limited to sinus rhythm 12-lead ECGs; for cases, these were obtained prior to and unrelated to SCD. Independent-samples t tests and multiple logistic regression were used. Mean TpTe was significantly greater in cases [89.4 (87.7 – 91.2) ms, p <0.0001; n=353, 66.6 (65.1 – 68.1) yr, 67% male] vs. controls [76.1 (74.8 – 77.4) ms; n=342, 64.7 (63.4 – 66.0) yr, 69% male)]. The other ECG intervals [Corrected QT interval (QTc), QRS duration (QRSD), and TpTe/QT ratio) were also significantly prolonged among cases vs. controls (p≤0.01). TpTe remained a significant predictor of SCD after adjusting for age, gender, QTc, QRSD and left ventricular function. Odds of SCD increased more with a one standard deviation increase in TpTe (12 ms) among subjects with prolonged QRSD [OR 3.49, 95% CI (2.06-5.91)] than with a one SD increase in TpTe among subjects with normal QRSD [OR1.96, 95% CI (1.65-2.32)]. TpTe remained significantly associated with SCD in subjects with normal QTc.
Conclusions
Prolongation of the TpTe interval measured in lead V5 was independently associated with SCD, with particular utility when the QTc was normal or not measurable due to prolonged QRSD.
doi:10.1161/CIRCEP.110.960658
PMCID: PMC3157547  PMID: 21593198
death; sudden; coronary disease; population; risk factors; stratification; electrocardiogram
9.  ECG Marker of Adverse Electrical Remodeling Post-Myocardial Infarction Predicts Outcomes in MADIT II Study 
PLoS ONE  2012;7(12):e51812.
Background
Post-myocardial infarction (MI) structural remodeling is characterized by left ventricular dilatation, fibrosis, and hypertrophy of the non-infarcted myocardium.
Objective
The goal of our study was to quantify post-MI electrical remodeling by measuring the sum absolute QRST integral (SAI QRST). We hypothesized that adverse electrical remodeling predicts outcomes in MADIT II study participants.
Methods
Baseline orthogonal ECGs of 750 MADIT II study participants (448 [59.7%] ICD arm) were analyzed. SAI QRST was measured as the arithmetic sum of absolute QRST integrals over all three orthogonal ECG leads. The primary endpoint was defined as sudden cardiac death (SCD) or sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) with appropriate ICD therapies. All-cause mortality served as a secondary endpoint.
Results
Adverse electrical remodeling in post-MI patients was characterized by wide QRS, increased magnitudes of spatial QRS and T vectors, J-point deviation, and QTc prolongation. In multivariable Cox regression analysis after adjustment for age, QRS duration, atrial fibrillation, New York Heart Association heart failure class and blood urea nitrogen, SAI QRST predicted SCD/VT/VF (HR 1.33 per 100 mV*ms (95%CI 1.11–1.59); P = 0.002), and all-cause death (HR 1.27 per 100 mV*ms (95%CI 1.03–1.55), P = 0.022) in both arms. No interaction with therapy arm and bundle branch block (BBB) status was found.
Conclusions
In MADIT II patients, increased SAI QRST is associated with increased risk of sustained VT/VF with appropriate ICD therapies and all-cause death in both ICD and in conventional medical therapy arms, and in patients with and without BBB. Further studies of SAI QRST are warranted.
doi:10.1371/journal.pone.0051812
PMCID: PMC3522579  PMID: 23251630
10.  Relation of QRS Shortening to Cardiac Output During Temporary Resynchronization Therapy after Cardiac Surgery 
Cardiac resynchronization therapy (CRT) can improve cardiac function in heart failure without increasing myocardial oxygen consumption. However, CRT optimization based on hemodynamics or echocardiography is difficult. QRS duration (QRSd) is a possible alternative optimization parameter. Accordingly, we assessed QRSd optimization of CRT during cardiac surgery. We hypothesized that QRSd shortening during changes in interventricular pacing delay (VVD) would increase cardiac output (CO). Seven patients undergoing coronary artery bypass, aortic or mitral valve surgery with LV ejection fraction ≤ 40% and QRSd ≥ 100 msec were studied. CRT was implemented at epicardial pacing sites in the left and right ventricle and right atrium during VVD variation after cardiopulmonary bypass. QRSd was correlated with CO from an electromagnetic aortic flow probe. Both positive and negative correlations were observed. Correlation coefficients ranged from 0.70 to −0.74 during VVD testing. Clear minima in QRSd were observed in four patients and were within 40 msec of maximum CO in two. We conclude that QRSd is not useful for routine optimization of VVD after cardiac surgery but may be useful in selected patients. Decreasing QRSd is associated with decreasing CO in some patients, suggesting that CRT can affect determinants of QRSd and ventricular function independently.
doi:10.1097/MAT.0b013e3181e88ac6
PMCID: PMC3086767  PMID: 20592584
biventricular pacing; heart failure; cardiac surgery; LV power failure; low output state
11.  Implantable Cardioverter Defibrillators for Primary Prevention of Sudden Cardiac Death in CKD: A Meta-analysis of Patient-Level Data from 3 Randomized Trials 
Background
The benefit of a primary prevention implantable cardioverter defibrillator (ICD) among patients with chronic kidney disease (CKD) is uncertain.
Study Design
Meta-analysis of patient-level data from randomized controlled trials.
Setting & Population
Patients with symptomatic heart failure and left ventricular ejection fraction of <35%.
Selection Criteria for Studies
From 7 available randomized control studies with patient level data, we selected studies with available data on important covariates. Studies without patient-level data on baseline eGFR were excluded.
Intervention
Primary prevention ICD versus usual care
Outcomes
Mortality, re-hospitalizations, and effect modification by estimated GFR (eGFR)
Results
We included data from the Multicenter Automatic Defibrillator Implantation Trial I (MADIT-I), MADIT-II, and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). 2,867 patients were included; 36.3% had at least stage 3 CKD (eGFR<60). The Kaplan-Meier estimate of the probability of death during follow-up was 43.3% among 1,334 patients receiving usual care and 35.8% among 1,533 ICD recipients. After adjustment for baseline differences, there was evidence that the survival benefit of ICDs in comparison to usual care depends on eGFR (posterior probability for null interaction p <0.001). The ICD was associated with survival benefit among patients with an eGFR ≥ 60 (adjusted HR (aHR)=0.49 [95% posterior credible interval (PCI) 0.24-0.95]) but not among patients with eGFR <60 (aHR = 0.80 [95% PCI 0.40-1.53]). eGFR did not modify the association between the ICD and re-hospitalizations.
Limitations
Few patients with eGFR <30 were available. Differences in trial-to-trial measurement techniques may lead to residual confounding.
Conclusions
Reductions in baseline eGFR decrease the survival benefit associated with the ICD. These findings should be confirmed by additional studies specifically targeting patients with varying levels of eGFR.
doi:10.1053/j.ajkd.2013.12.009
PMCID: PMC4383404  PMID: 24518128
12.  Genomics, heart failure and sudden cardiac death 
Heart failure reviews  2008;15(3):229-238.
Sudden cardiac death (SCD) is among the most common causes of death in developed countries throughout the world. Despite decreased overall cardiac mortality, SCD vrates appear to be increasing in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. This unfavorable trend is a consequence of our inability to identify those who will die suddenly from lethal ventricular arrhythmias and to develop effective therapies for all populations at risk. The known risk factors for SCD lack the predictive power needed to generate preventive strategies for the large number of fatal arrhythmic events that occur among lower-risk subsets of the population. Even among recognized high-risk subsets, prediction of SCD remains challenging. With the exception of the implantable cardioverter defibrillator (ICD) there are few effective strategies for the prevention and treatment of SCD. This article discusses the prospect of genomic science as an approach to the identification of patients at high-risk for SCD. While the final common pathway for SCD is malignant ventricular arrhythmias, there are many potential contributors, pathways, and mechanisms by which common genetic variants (polymorphisms) could affect initiation and propagation of life-threatening cardiac arrhythmias. Recent advances in genomic medicine now provide us with novel approaches to both identify candidate genes/pathways and relatively common polymorphisms which may predispose patients to increased risk for SCD. Improved understanding of the relationship between common polymorphisms and SCD will not only improve risk stratification such that ICDs can be targeted to those patients most likely to benefit from them but also provide new insight into the pathophysiology of SCD.
doi:10.1007/s10741-008-9095-9
PMCID: PMC2851840  PMID: 18437561
Sudden cardiac death; Genomics; Heart failure; Single nucleotide polymorphisms
13.  Association of QRS duration with left ventricular structure and function and risk of heart failure in middle-aged and older adults: the Multi-Ethnic Study of Atherosclerosis (MESA) 
European Journal of Heart Failure  2012;14(11):1285-1292.
Aims
Prolonged QRS duration (QRSd) on the electrocardiogram (ECG) has been associated with cardiac structural and functional abnormalities by echocardiography and an increased risk of heart failure (HF). Data are sparse on these relationships in middle-aged and elderly individuals free of baseline cardiovascular disease with respect to cardiac magnetic resonance imaging (MRI). We sought to determine whether QRSd is associated with incident HF and measures of cardiac structure and function by cardiac MRI.
Methods and results
We analysed baseline ECGs in the Multi-Ethnic Study of Atherosclerosis (MESA) to determine whether QRSd >100 ms was associated with incident HF. We adjusted for demographic and clinical risk factors, as well as MRI measures of left ventricular (LV) structure and function. Among 4591 eligible participants (51% women; 39% white; mean age 61 years), 75 developed incident HF over a mean follow-up of 7.1 years. QRSd >100 ms was significantly associated with MRI measures of cardiac structure and function, as well as incident HF, even after adjustment for demographic covariates [hazard ratio (HR) 2.10, 95% confidence interval (CI) 1.29–3.42; P = 0.003] and clinical risk factors (HR 1.86, 95% CI 1.14–3.03; P = 0.01). With further adjustment for individual LV structural measures, findings were attenuated to non-significance. Separate adjustment for LV functional measures yielded only mild attenuation.
Conclusion
In middle-aged and older adults without cardiovascular disease, a QRSd >100 ms was significantly associated with incident HF. After adjustment for LV structural measures, the association was attenuated to non-significance, suggesting that prolonged QRSd is potentially a useful marker of LV structure that may predispose to HF risk.
doi:10.1093/eurjhf/hfs112
PMCID: PMC3530347  PMID: 22791081
Electrocardiogram; Heart failure; Magnetic resonance imaging; QRS duration
14.  Measurement of QRS Duration for Biventricular Pacing Optimization 
Optimization of left ventricular pacing site (LVPS) or interventricular pacing delay (VVD) improves the efficacy of biventricular pacing (BiVP). Cardiac output (CO) based optimization, however, is invasive and slow. QRS duration (QRSd) is non-invasive and responds rapidly. Accordingly, we investigated the utility of QRSd for BiVP optimization in a model of acute right ventricular (RV) pressure overload. In 7 anesthetized open-chest pigs, BiVP was implemented with right atrial and RV pacing wires. A 6-electrode array was placed behind the LV. Heart block was established by alcohol ablation. The pulmonary artery was snared to double peak RV pressure. Fifty-four combinations of LVPS and VVD were tested in random order over 30 sec intervals. QRSd was assessed from ECG lead II, CO from aortic flow probe, and ventricular function from micromanometers. Comparisons were made with the Pearson’s correlation coefficient (r). QRSd narrowing was associated with improved RV function and transseptal synchrony, but correlation with CO was poor. Additionally, QRSd averaged over the last 20 cardiac cycles in each interval was compared to values averaged over successive cardiac cycles following each reprogramming. Seven cardiac cycles after reprogramming, the average r-value went above 0.90 and plateaued. QRSd-based optimization merits further study during BiVP in patients with congestive heart failure.
doi:10.1097/MAT.0b013e31817b5b29
PMCID: PMC2743922  PMID: 18645348
Heart Failure; Cardiac Surgery; Cardiac Function; Electrophysiology; Hemodynamics
15.  Angiotensin Receptor Type 1 Single Nucleotide Polymorphism A1166C is Associated with Malignant Arrhythmias and Altered Circulating miR-155 Levels in Patients with Chronic Heart Failure 
Journal of cardiac failure  2012;18(9):717-723.
Background
Sudden cardiac death (SCD) due to ventricular tachyarrhythmias accounts for approximately 450,000 annual deaths in the U.S.; many of these cases involve patients with chronic heart failure (HF). Prediction of which HF patients are most susceptible to SCD is difficult, and it is uncertain whether gene polymorphisms associated with HF outcomes are also linked to arrhythmic risk.
Methods
We evaluated 485 patients with chronic HF to see whether the Angiotensin Receptor Type 1 (AT1) A1166C or Angiotensin Converting Enzyme Insertion/Deletion (ACE I/D) polymorphisms were associated with a higher rate of ventricular arrhythmias requiring implantable cardioverter defibrillator (ICD) therapies over a 5-year period. We assessed the correlation between polymorphisms and antitachycardia pacing (ATP) and/or ICD shocks.
Results
Patients with AT1-1166 CC genotype had an increased rate of all events: ATP plus ICD shocks (p=0.02). There was no association between ACE I/D genotype and ICD therapies. Furthermore, circulating levels of microRNA-155 (miR-155), a microRNA known to posttranscriptionally regulate AT1R expression, were significantly decreased in the CC compared to the AC and AA genotypes and were associated with ICD events.
Conclusion
Our study suggests that the AT1R-1166 CC genotype is associated with increased ICD therapies in patients with chronic HF, and the level of circulating miR-155 may be a potential marker for arrhythmic risk. While these findings are novel, they will need replication and validation in larger cohorts of chronic HF patients.
doi:10.1016/j.cardfail.2012.06.531
PMCID: PMC3640363  PMID: 22939041
Genetic Polymorphisms; Angiotensin; Angiotensin Type 1 Receptor; Sudden Cardiac Death; Heart Failure; microRNA
16.  Wearable defibrillator use in heart failure (WIF): results of a prospective registry 
Background
Heart failure (HF) patients have a high risk of death, and implantable cardioverter defibrillators (ICDs) are effective in preventing sudden cardiac death (SCD). However, a certain percentage of patients may not be immediate candidates for ICDs, particularly those having a short duration of risk or an uncertain amount of risk. This includes the newly diagnosed patients, as well as those on the cardiac transplant list or NYHA class IV heart failure patients who do not already have an ICD. In these patients, a wearable cardioverter defibrillator (WCD) may be used until long term risk of SCD is defined. The purpose of this study was to determine the incidence of SCD in this population, and the efficacy of early defibrillation by a WCD.
Methods
Ten enrolling centers identified 89 eligible HF patients who were either listed for cardiac transplantation, diagnosed with dilated cardiomyopathy, or receiving inotropic medications. Data collected included medical history, device records, and outcomes (including 90 day mortality).
Results
Out of 89 patients, final data on 82 patients has been collected. Patients wore the device for 75±58 days. Mean age was 56.8±13.2, and 72% were male. Most patients (98.8%) were diagnosed with dilated cardiomyopathy with a low ejection fraction (<40%) and twelve were listed for cardiac transplantation. Four patients were on inotropes. There were no sudden cardiac arrests or deaths during the study. Interestingly, 41.5% of patients were much improved after WCD use, while 34.1% went on to receive an ICD.
Conclusions
In conclusion, the WCD monitored HF patients until further assessment of risk. The leading reasons for end of WCD use were improvement in left ventricular ejection fraction (LVEF) or ICD implantation if there was no significant improvement in LVEF.
doi:10.1186/1471-2261-12-123
PMCID: PMC3574049  PMID: 23234574
Heart failure; Wearable cardioverter defibrillator; Sudden cardiac death
17.  Clinical Utility of Microvolt T-wave Alternans Testing In Identifying Patients at High or Low Risk of Sudden Cardiac Death 
Background
Previous studies have demonstrated that microvolt T-wave alternans (MTWA) testing is a robust predictor of ventricular tachyarrhythmias and sudden cardiac death (SCD) in at-risk patients. However, recent studies have suggested that MTWA testing is not as good a predictor of “appropriate” implantable cardioverter-defibrillator (ICD) therapy as it is a predictor of SCD in patients without ICDs.
Objective
We sought to evaluate the utility of MTWA testing for SCD risk stratification in patients without ICDs.
Methods
Patient-level data were obtained from five prospective studies of MTWA testing in patients with no history of ventricular arrhythmia or SCD. In these studies, ICDs were implanted in only a minority of patients and patients with ICDs were excluded from the analysis. We conducted a pooled analysis and examined the 2-year risk for SCD based on MTWA test result.
Results
The pooled cohort included 2883 patients. MTWA testing was positive in 856 (30%), negative in 1627 (56%) and indeterminate in 400 (14%) patients. Among patients with LVEF ≤ 35%, annual SCD event rates were 4.0%, 0.9% and 4.6% among the MTWA positive, negative and indeterminate groups. The SCD rate was significantly lower among patients with a negative MTWA test compared to either the positive or the indeterminate groups (p<0.001 for both comparisons). In patients with LVEF > 35%, annual SCD event rates were 3.0%, 0.3% and 0.3% among the MTWA positive, negative and indeterminate groups. The SCD rate associated with a positive test was significantly higher than either the negative (p<0.001) or the indeterminate groups (p=0.003).
Conclusions
In patients without ICDs, MTWA testing is a powerful predictor of SCD. Among patients with LVEF ≤ 35%, a negative MTWA test is associated with a low risk for SCD. Conversely, among patients with LVEF > 35%, a positive MTWA test identifies patients at significantly heightened SCD risk. These findings may have important implications for refining primary prevention ICD treatment algorithms.
doi:10.1016/j.hrthm.2012.03.014
PMCID: PMC3411866  PMID: 22406384
T-wave alternans; arrhythmia; sudden death; risk stratification; electrophysiology; defibrillation
18.  Quality of Life with Defibrillator Therapy or Amiodarone in Heart Failure 
The New England journal of medicine  2008;359(10):999-1008.
Background
Implantable cardioverter defibrillator (ICD) therapy significantly prolongs life in patients at increased risk of sudden cardiac death from depressed left ventricular function. However, it is unclear whether this increased longevity is accompanied by deterioration in quality of life.
Methods
The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) compared ICD therapy or amiodarone versus state-of-the-art medical therapy alone in 2521 stable heart failure patients with depressed left ventricular function. Quality of life, a secondary end point of the trial, was prospectively measured at baseline, 3, 12, and 30 months and was 93% to 98% complete. The Duke Activity Status Index (which measures cardiac physical functioning) and the SF-36 Mental Health Inventory (which measures psychological well-being or distress) were prespecified principal quality-of-life outcomes. Multiple additional quality-of-life outcomes were also examined.
Results
Compared with medical therapy alone, psychological well-being in the ICD arm significantly improved at 3 months (p=0.01) and 12 months (p=0.004) but not at 30 months. No clinically or statistically significant differences in physical functioning by treatment were observed. Some other quality-of-life measures improved in the ICD arm at 3 and/or 12 months but none differed significantly at 30 months. ICD shocks within the month preceding a scheduled assessment were associated with decreased quality of life in multiple domains. Amiodarone had no significant effects on the principal quality-of-life outcomes.
Conclusions
In a large primary prevention population with moderately symptomatic heart failure, single lead ICD therapy was not associated with any detectable adverse quality-of-life effects over 30 months of follow-up.
doi:10.1056/NEJMoa0706719
PMCID: PMC2823628  PMID: 18768943
Sudden cardiac death; congestive heart failure; implantable cardioverter-defibrillator; quality of life
19.  Mortality benefits from implantable cardioverter-defibrillator therapy are not restricted to patients with remote myocardial infarction: an analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) 
Background
The implantable cardioverter-defibrillator (ICD) is an effective therapy for preventing sudden cardiac death (SCD) in patients with prior myocardial infarction (MI) and reduced left ventricular function; however, the optimal timing of ICD implantation after MI remains unknown.
Objective
The purpose of this study was to determine whether the benefit of single-lead conservatively programmed ICD therapy varies as a function of time from MI to ICD implantation.
Methods
We compared time to all-cause death and SCD between the ICD and placebo arms in the Sudden Cardiac Death in Heart Failure Trial. Rates of appropriate shocks in the ICD arm were also assessed as a function of time after MI.
Results
Among the 712 patients with a history of MI, 274 died (38.5%), and 68 of these deaths were SCD (24.8%). Appropriate shocks were more common with increasing time after MI (adjusted hazard ratio [HR] per year after MI 1.04 [1.00–1.08]). Despite these differences, there was no evidence of differential mortality benefit with ICD implantation as a function of time after MI: continuous variable adjusted HR 1.00 [0.98,1.03] and shortest versus longest tertile adjusted HR 0.95 [0.66–1.34]. Sensitivity analyses also failed to show differential mortality benefit by quartile or with the use of an 18-month cutoff: <18 versus ≥ 18 months adjusted HR 1.08 [0.77, 1.51].
Conclusion
There is no evidence that ICD benefit varied with time from MI to implantation/randomization in this primary prevention population. Single-lead ICD benefit is not restricted to patients with a remote MI (>18 months).
doi:10.1016/j.hrthm.2010.11.033
PMCID: PMC4165645  PMID: 21109025
Implantable cardioverter defibrillator; myocardial infarction; ischemic cardiomyopathy; heart failure; sudden cardiac death
20.  Maximizing Survival Benefit With Primary Prevention ICD Therapy in a Heart Failure Population 
Circulation  2009;120(10):835-842.
Introduction
Although implantable cardioverter defibrillator (ICD) therapy reduces mortality in moderately symptomatic heart failure patients with an ejection fraction ≤35%, many such patients do not require ICD shocks over long-term follow-up.
Methods
Using a modification of a previously validated risk prediction model based on routine clinical variables, we examined the relationship between baseline predicted mortality risk and the relative and absolute survival benefits of ICD treatment in the primary prevention Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).
Results
In the placebo arm, predicted 4-year mortality grouped into 5 equal-sized risk groups varied from 12% to 50% (c statistic=0.71), while the proportion of SCD in those same risk groups decreased from 52% to 24% of all deaths. ICD treatment decreased relative risk of SCD by 88% in the lowest risk group vs. 24% in the highest risk group (p =0.009 for the interaction), and relative risk of total mortality by 54% in the lowest risk group vs. no benefit (2%) in the highest risk group (p =0.014 for the interaction). Absolute 4-year mortality reductions were 6.6%, 8.8%, 10.6%, 14.0% and −4.9% across risk quintiles. In highest risk patients (predicted annual mortality >20%), no benefit of ICD treatment was seen. Projected over each patient’s predicted life span, ICD treatment added 6.3, 4.1, 3.0, 1.9, and 0.2 additional years of life in the lowest to highest risk groups, respectively.
Conclusions
A clinical risk-prediction model identified subsets of moderately symptomatic heart failure patients in SCD-HeFT in whom single lead ICD therapy was of no benefit and other subsets in which benefit was substantial.
doi:10.1161/CIRCULATIONAHA.108.816884
PMCID: PMC3774781  PMID: 19704100
Arrhythmias; clinical electrophysiology; drugs; Congestive Heart Failure; Ablation/ICD/surgery; Health policy and outcome research
21.  Sites of Latest Mechanical Activation as Assessed by SPECT Myocardial Perfusion Imaging in Ischemic and Dilated Cardiomyopathy Patients with LBBB 
Objective
Sites of latest mechanical activation (SOLA) have been recognized as optimal left-ventricular (LV) lead positions for cardiac resynchronization therapy (CRT). This study was aimed to investigate SOLA in ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) patients with left bundle branch block (LBBB).
Methods
Sixty-four consecutive LBBB patients (47 DCM, 17 ICM), who met the standard indications for CRT and underwent resting SPECT myocardial perfusion imaging (MPI), were selected. Phase analysis was used to assess LV dyssynchrony and SOLA. The Emory Cardiac Toolbox was used to measure perfusion defects. LV dyssynchrony and SOLA were compared between the DCM patients with wide (≥150 ms) and moderate (120–150 ms) QRS durations (QRSd). The relationship between SOLA and perfusion defects was analyzed in the ICM patients.
Results
The DCM patients with wide QRSd had significantly more LV dyssynchrony than those with moderate QRSd. Lateral SOLA were significantly more frequent in the DCM patients with wide QRSd than those with moderate QRSd (96% vs. 62%, p=0.010). In the ICM patients, SOLA were either in the scar segments (82%) or in the segments immediately adjacent to the scar segments (18%), regardless of QRSd.
Conclusion
Lateral SOLA were more frequent in the DCM patients with wide QRSd than those with moderate QRSd. Such relationship was not observed in the ICM patients, where SOLA were associated with scar location rather than QRSd. These findings support the use of SPECT MPI to aid the selection of potential CRT responders and guide LV lead placement.
doi:10.1007/s00259-014-2718-6
PMCID: PMC4096661  PMID: 24577952
Cardiac resynchronization therapy; SPECT myocardial perfusion imaging; phase analysis; LV dyssynchrony
22.  The Role of Microvolt T-Wave Alternans to Assess Arrhythmia Vulnerability Among Patients with Heart Failure and Systolic Dysfunction: Primary Results from the TWA SCD-HeFT Substudy 
Circulation  2008;118(20):2022-2028.
Background
Sudden cardiac death remains a leading cause of mortality despite advances in medical treatment for the prevention of ischemic heart disease and heart failure. Recent studies showed a benefit of ICD implantation, but appropriate shocks for ventricular tachyarrhythmias were only noted in a minority of patients during 4-5 years of follow-up. Accordingly, better risk stratification is needed to optimize patient selection. In this regard microvolt T-wave alternans (TWA) has emerged as a potentially useful measure of arrhythmia vulnerability, but it has not been evaluated previously in a prospective randomized trial of ICD therapy.
Methods and Results
This investigation was a prospective substudy of the SCD-HeFT trial including 490 patients at 37 clinical sites. TWA tests were classified by blinded readers as + (37%), - (22%), or indeterminate (41%) by standard criteria. The composite primary endpoint was the first occurrence of any of the following events: sudden cardiac death, sustained ventricular tachycardia/fibrillation or appropriate ICD discharge. During a median follow-up of 30 months, there were no significant differences in event rates between TWA + or − patients (Hazard ratio 1.24, p=0.56, [CI 0.60, 2.59]), or TWA − and non − (+ and indeterminate) subjects (Hazard ratio 1.28, p=0.46, CI [0.65, 2.53]). Similar results were obtained including or excluding patients randomized to amiodarone in the analyses.
Conclusions
TWA testing did not predict arrhythmic events or mortality in SCD-HeFT, although a small reduction of events (20-25%) among TWA − patients cannot be excluded given the sample size of this study. Accordingly, these results suggest that TWA is not useful to help make clinical decisions regarding ICD therapy among patients with heart failure and left ventricular systolic dysfunction.
doi:10.1161/CIRCULATIONAHA.107.748962
PMCID: PMC2777708  PMID: 18955671
Defibrillation; Electrocardiography; Heart Failure; T-wave alternans
23.  Impact of Implantable Cardioverter-Defibrillator, Amiodarone, and Placebo on the Mode of Death in Stable Patients With Heart Failure 
Circulation  2009;120(22):2170-2176.
Background
The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that implantable cardioverterdefibrillator (ICD) therapy reduces all-cause mortality in patients with New York Heart Association class II/III heart failure and a left ventricular ejection fraction ≤35% on optimal medical therapy. Whether ICD therapy reduced sudden death caused by ventricular tachyarrhythmias without affecting heart failure deaths in this population is unknown.
Methods and Results
SCD-HeFT randomized 2521 subjects to placebo, amiodarone, or shock-only, single-lead ICD therapy. Over a median follow-up of 45.5 months, a total of 666 deaths occurred, which were reviewed by an Events Committee and initially categorized as cardiac or noncardiac. Cardiac deaths were further adjudicated as resulting from sudden death presumed to be ventricular tachyarrhythmic, bradyarrhythmia, heart failure, or other cardiac causes. ICD therapy significantly reduced cardiac mortality compared with placebo (adjusted hazard ratio, 0.76; 95% confidence interval, 0.60 to 0.95) and tachyarrhythmia mortality (adjusted hazard ratio, 0.40; 95% confidence interval, 0.27 to 0.59) and had no impact on mortality resulting from heart failure or noncardiac causes. The cardiac and tachyarrhythmia mortality reductions were evident in subjects with New York Heart Association class II but not in subjects with class III heart failure. The reduction in tachyarrhythmia mortality with ICD therapy was similar in subjects with ischemic and nonischemic disease. Compared with placebo, amiodarone had no significant effect on any mode of death.
Conclusions
ICD therapy reduced cardiac mortality and sudden death presumed to be ventricular tachyarrhythmic in SCD-HeFT and had no effect on heart failure mortality. Amiodarone had no effect on all-cause mortality or its cause-specific components, except an increase in non-cardiac mortality in class III patients.
doi:10.1161/CIRCULATIONAHA.109.853689
PMCID: PMC2922511  PMID: 19917887
cardiomyopathy; death, sudden; heart failure; mortality; tachyarrhythmias
24.  Current Developments in Microvolt T-wave Alternans 
Microvolt T-wave alternans (MTWA), the beat-to-beat fluctuation in T wave amplitude and morphology, is closely linked to vulnerability to ventricular arrhythmias in various experimental and clinical conditions. Clinically, MTWA is most commonly measured using the spectral method, although non-spectral methods for its assessment from ambulatory electrocardiographical recordings also have been developed. Recent studies suggest that the quantitative assessment of TWA may also be clinically relevant. The standardisation of the criteria for abnormal MTWA test still needs to be completed. The expansion of indications for implantable cardioverter-defibrillator (ICD) therapy following the positive results of the MADIT-II and SCD-HeFT trials might have unacceptable economic and medical consequences, and therefore new tests are needed to better discriminate patients who will and will not benefit from ICD implantation. A recent meta-analysis of MTWA studies revealed an overall positive predictive value for arrhythmic events of 19.3%, negative predictive value of 97.2%, and 3.77% univariate relative risk of arrhythmic events. The negative predictive value of MTWA in MADIT-II type patients has been reported to be 97.5%. The predictive value of the test varied significantly in different patient population. Current data support the use of MTWA testing for evaluation of patients with low ejection fraction who are considered for ICD implantation. The independence of the prognostic value of MTWA from other clinical and electrophysiological variables needs further confirmation.
PMCID: PMC1586165  PMID: 17031416
microvolt T wave alternans; implantable cardioverter-defibrillator; ventricular arrhythmias; sudden cardiac death; risk stratification
25.  A prospective evaluation of cardiovascular magnetic resonance measures of dyssynchrony in the prediction of response to cardiac resynchronization therapy 
Background
Many patients with electrical dyssynchrony who undergo cardiac resynchronization therapy (CRT) do not obtain substantial benefit. Assessing mechanical dyssynchrony may improve patient selection. Results from studies using echocardiographic imaging to measure dyssynchrony have ultimately proved disappointing. We sought to evaluate cardiac motion in patients with heart failure and electrical dyssynchrony using cardiovascular magnetic resonance (CMR). We developed a framework for comparing measures of myocardial mechanics and evaluated how well they predicted response to CRT.
Methods
CMR was performed at 1.5 Tesla prior to CRT. Steady-state free precession (SSFP) cine images and complementary modulation of magnetization (CSPAMM) tagged cine images were acquired. Images were processed using a novel framework to extract regional ventricular volume-change, thickening and deformation fields (strain). A systolic dyssynchrony index (SDI) for all parameters within a 16-segment model of the ventricle was computed with high SDI denoting more dyssynchrony. Once identified, the optimal measure was applied to a second patient population to determine its utility as a predictor of CRT response compared to current accepted predictors (QRS duration, LBBB morphology and scar burden).
Results
Forty-four patients were recruited in the first phase (91% male, 63.3 ± 14.1 years; 80% NYHA class III) with mean QRSd 154 ± 24 ms. Twenty-one out of 44 (48%) patients showed reverse remodelling (RR) with a decrease in end systolic volume (ESV) ≥ 15% at 6 months. Volume-change SDI was the strongest predictor of RR (PR 5.67; 95% CI 1.95-16.5; P = 0.003). SDI derived from myocardial strain was least predictive. Volume-change SDI was applied as a predictor of RR to a second population of 50 patients (70% male, mean age 68.6 ± 12.2 years, 76% NYHA class III) with mean QRSd 146 ± 21 ms. When compared to QRSd, LBBB morphology and scar burden, volume-change SDI was the only statistically significant predictor of RR in this group.
Conclusion
A systolic dyssynchrony index derived from volume-change is a highly reproducible measurement that can be derived from routinely acquired SSFP cine images and predicts RR following CRT whilst an SDI of regional strain does not.
doi:10.1186/s12968-014-0058-0
PMCID: PMC4422256  PMID: 25084814
Cardiac resynchronization therapy; Cardiovascular magnetic resonance; Dyssynchrony; Heart failure; Strain; Regional volume-change SDI

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