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1.  Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients 
European Heart Journal  2010;31(18):2253-2261.
Aims
Dialysis patients experience an excess mortality, predominantly of sudden cardiac death (SCD). Accumulating evidence suggests a role of vitamin D for myocardial and overall health. This study investigated the impact of vitamin D status on cardiovascular outcomes and fatal infections in haemodialysis patients.
Methods and results
25-hydroxyvitamin D [25(OH)D] was measured in 1108 diabetic haemodialysis patients who participated in the German Diabetes and Dialysis Study and were followed up for a median of 4 years. By Cox regression analyses, we determined hazard ratios (HR) for pre-specified, adjudicated endpoints according to baseline 25(OH)D levels: SCD (n = 146), myocardial infarction (MI, n = 174), stroke (n = 89), cardiovascular events (CVE, n = 414), death due to heart failure (n = 37), fatal infection (n = 111), and all-cause mortality (n = 545). Patients had a mean age of 66 ± 8 years (54% male) and median 25(OH)D of 39 nmol/L (interquartile range: 28–55). Patients with severe vitamin D deficiency [25(OH)D of≤ 25 nmol/L] had a 3-fold higher risk of SCD compared with those with sufficient 25(OH)D levels >75 nmol/L [HR: 2.99, 95% confidence interval (CI): 1.39–6.40]. Furthermore, CVE and all-cause mortality were strongly increased (HR: 1.78, 95% CI: 1.18–2.69, and HR: 1.74, 95% CI: 1.22–2.47, respectively), all persisting in multivariate models. There were borderline non-significant associations with stroke and fatal infection while MI and deaths due to heart failure were not meaningfully affected.
Conclusion
Severe vitamin D deficiency was strongly associated with SCD, CVE, and mortality, and there were borderline associations with stroke and fatal infection. Whether vitamin D supplementation decreases adverse outcomes requires further evaluation.
doi:10.1093/eurheartj/ehq246
PMCID: PMC2938469  PMID: 20688781
Vitamin D; Sudden cardiac death; Mortality; Dialysis; Kidney; Cardiovascular
2.  Homoarginine and Mortality in Pre-Dialysis Chronic Kidney Disease (CKD) Patients 
PLoS ONE  2013;8(9):e72694.
Background and Aims
Homoarginine, a precursor of nitric oxide, is an inverse predictor of death in dialysis patients and in subjects with cardiovascular disease and normal kidney function but its relationship with clinical outcomes in chronic kidney disease (CKD) patients not yet on dialysis is unknown.
Design, setting, participants and measurements
We enrolled 168 consecutive predialysis CKD patients (Age: 70±11 yrs; 26% Diabetics; eGFR 34±18 ml/min/1.73 m2) referred to a tertiary care centre and measured laboratory data on kidney function and cardiovascular risk factors. We modeled progression to dialysis or death as a function of homoarginine, using Cox’s regression, accounting for clinical characteristics, baseline levels of kidney function, and markers of inflammation.
Results
On crude and adjusted analyses homoarginine was directly associated with the eGFR and patients with more compromised renal function exhibited lower homoarginine levels. Furthermore homoarginine was also independently related to L-arginine, serum albumin and body mass index, and inversely related to proteinuria, C-reactive protein and age. During the study (follow up median time 4 years, inter-quartile range 1.7 to 7.0 years) 56 patients started dialysis and 103 died and homoarginine was a strong inverse predictor of the incidence rate of both outcomes (P = 0.002 and P = 0.017).
Conclusions
Homoarginine declines with advancing renal disease and is inversely related to progression to dialysis and mortality. The nature of the link between homoarginine and clinical outcomes is amenable to testing in clinical trials.
doi:10.1371/journal.pone.0072694
PMCID: PMC3762798  PMID: 24023762
3.  Homoarginine and Progression of Chronic Kidney Disease: Results from the Mild to Moderate Kidney Disease Study 
PLoS ONE  2013;8(5):e63560.
Background
Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD).
Methods
We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54–5.19) using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease.
Results
Study participants were at baseline on average 47±13 years old and 65% were male. Mean±standard deviation of homoarginine concentrations were 2.5±1.1 µmol/L and concentrations were incrementally lower at lower levels of GFR with mean concentrations of 2.90±1.02 µmol/L (GFR>90 ml/min), 2.64±1.06 µmol/L (GFR 60–90 ml/min), 2.52±1.24 µmol/L (GFR 30–60 ml/min) and 2.05±0.78 µmol/L (GFR<30 ml/min), respectively (p = 0.002). The age- and sex-adjusted risk to reach the renal endpoint was significantly higher by 62% with each decrease by one standard deviation (1.1 µmol/L) of homoarginine (HR 1.62, 95% CI 1.16–2.27, p = 0.005). This association was independent of proteinuria (HR 1.56, 95% CI 1.11–2.20, p = 0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95% CI 0.98–1.98, p = 0.06).
Conclusions
Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations.
doi:10.1371/journal.pone.0063560
PMCID: PMC3655120  PMID: 23691067
4.  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
5.  Sudden Death after Myocardial Infarction 
Context
Sudden cardiac death (SCD) after myocardial infarction (MI) has not recently been assessed in the community. Post-MI risk stratification for SCD commonly relies on baseline characteristics and little is known about the relationship between recurrent ischemia or heart failure (HF) and SCD.
Objective
To evaluate the risk of SCD after MI and the impact of recurrent ischemia and HF on SCD.
Design, setting, and participants
2,997 Olmsted County residents experiencing an MI between 1979 and 2005.
Main outcome measures
SCD defined as out-of-hospital death due to coronary disease. Observed survival free of SCD compared to that expected in Olmsted County.
Results
During a median follow-up of 4.7 years (25th–75th percentile 1.6–7.1, date of last follow-up 02-29-2008), 1,160 deaths occurred, 282 (24%) SCD. The 30-day cumulative incidence of SCD was 1.2% (95% confidence interval [CI] 0.8–1.6%). Thereafter, the rate of SCD was constant at 1.2%/year yielding a 5-year cumulative incidence of 6.9% (95% CI 5.9% to 7.9%). The 30-day incidence of SCD was 4-fold higher than expected (standardized mortality ratio=4.2, 95% CI 2.9 to 5.8). In the year thereafter, the risk of SCD was lower than expected (standardized mortality ratio=0.66, 95% CI 0.50 to 0.85). The risk of SCD declined over time (hazard ratio=0.62, 95% CI 0.44 to 0.88 for MIs in 1997–2005 compared to 1979–1987; p =0.03). Recurrent events, ischemia (n=842) or HF (n=365), occurred in 2,080 patients. After adjustment for baseline characteristics, recurrent ischemia was not associated with SCD (hazard ratio=1.26, 95% CI 0.96 to 1.65; p=0.09), while HF markedly increased the risk of SCD (hazard ratio= 4.20, 95% CI 3.10 to 5.69; p<0.001)
Conclusions
The risk of SCD is highest during the first month after MI and declined over time. SCD is independently associated with HF but not with recurrent ischemia.
doi:10.1001/jama.2008.553
PMCID: PMC2731625  PMID: 18984889
6.  Change in N-terminal-pro-B-type-natriuretic-peptide and the risk of sudden death, stroke, myocardial infarction, and all-cause mortality in diabetic dialysis patients 
European Heart Journal  2008;29(17):2092-2099.
Aims
N-terminal-pro-B-type-natriuretic-peptide (NT-pro-BNP) concentrations are altered in renal failure. This study examined the effect of baseline and change from baseline NT-pro-BNP on cardiovascular outcome and mortality in haemodialysis patients.
Methods and results
On the basis of the German Diabetes and Dialysis Study, which evaluated atorvastatin in 1255 type 2 diabetes mellitus (T2DM) haemodialysis patients (median follow-up 4 years), the impact of NT-pro-BNP on pre-specified, adjudicated endpoints was investigated: sudden death (SD; n = 160), stroke (n = 99), myocardial infarction (MI; n = 200), cardiovascular events (CVEs: cardiac death, MI, stroke; n = 465), all-cause mortality (n = 612). Patients with baseline NT-pro-BNP ≥9252 pg/mL (fourth quartile) exhibited a more than four-fold risk of stroke [hazard ratio (HR) 4.1; 95% confidence interval (CI) 2.0–8.4] and a more than two-fold risk of SD (HR 2.0; 95% CI 1.2–3.3), CVE (HR 2.0; 95% CI 1.5–2.7), and mortality (HR 2.1; 95% CI 1.6–2.7) compared with patients with baseline NT-pro-BNP ≤ 1433 pg/mL (first quartile). Change in NT-pro-BNP was strongly associated with SD, CVE, and mortality. Doubling of NT-pro-BNP increased the risk of death by 46% (95% CI 1.1–2.0). Neither baseline nor change in NT-pro-BNP was significantly associated with MI.
Conclusion
Increasing NT-pro-BNP is a risk factor for SD, CVE, and mortality in haemodialysis patients with T2DM. Whether NT-pro-BNP-guided treatment improves outcome needs to be evaluated prospectively.
doi:10.1093/eurheartj/ehn278
PMCID: PMC2519248  PMID: 18617483
NT-pro-BNP; Serial measurement; Cardiovascular events; Mortality; Haemodialysis; Diabetes mellitus
7.  Risk Factor and Prediction Modeling for Sudden Cardiac Death in Women with Coronary Artery Disease 
Archives of internal medicine  2011;171(19):1703-1709.
Background
The risk of sudden cardiac death and the assessment of risk factors in prediction models have not been assessed in women with coronary artery disease (CAD). We sought to evaluate sudden cardiac death (SCD) incidence, risk factors and their predictive accuracy among a population of women with CAD.
Methods
The Hormone and Estrogen Replacement Study (HERS) evaluated the effects of hormone replacement therapy on cardiovascular events among 2,763 postmenopausal women with CAD. SCD was defined as death from cardiac origin that occurred within 1 hour of symptom onset. The associations between candidate predictor variables and SCD were evaluated in a Cox proportional hazards model. The C-index was used to compare the predictive value of the clinical risk factors with left ventricular ejection fraction alone and in combination. The net reclassification improvement (NRI) was also computed.
Results
Over a mean follow-up of 6.8 years, SCD comprised 136 of the 254 cardiac deaths. The annual SCD event rate was 0.79% (95% CI, 0.67–0.94%). The following variables were independently associated with SCD in the multivariate model: myocardial infarction, heart failure, estimated glomerular filtration rate (eGFR) <40ml/min/1.73m2, atrial fibrillation, physical inactivity and diabetes. The incidences of SCD among women with 0 (n=683), 1 (n=1224), 2 (n=610), and 3 plus (n=246) risk factors at baseline were 0.3, 0.5, 1.2 and 2.9% per year, respectively. The combination of clinical risk factors and LVEF (C-index 0.681) were better predictors of SCD than LVEF alone (C-index 0.600) and resulted in a NRI of 0.20 (p<0.001).
Conclusions
SCD comprised the majority of cardiac deaths among postmenopausal women with CAD. Independent predictors of SCD including myocardial infarction, heart failure, eGFR <40ml/min/1.73m2, atrial fibrillation, physical inactivity and diabetes improved SCD prediction when used in addition to LVEF.
doi:10.1001/archinternmed.2011.328
PMCID: PMC3547327  PMID: 21788534
8.  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
9.  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
10.  Cardiomyocyte Injury Assessed by a Highly Sensitive Troponin Assay and Sudden Cardiac Death in the Community: The Cardiovascular Health Study 
Objectives
To study the association between markers of cardiomyocyte injury in ambulatory subjects and sudden cardiac death (SCD).
Background
The pathophysiology of SCD is complex but is believed to be associated with an abnormal cardiac substrate in most cases. The association between biomarkers of cardiomyocyte injury in ambulatory subjects and SCD has not been investigated.
Methods
Levels of cardiac Troponin T, a biomarker of cardiomyocyte injury, were measured by a highly sensitive assay (hsTnT) in 4431 ambulatory participants in the Cardiovascular Health Study, a longitudinal community-based prospective cohort study. Serial measures were obtained in 3089 subjects. All deaths, including SCD, were adjudicated by a central events committee.
Results
Over a median follow-up of 13.1 years, 246 participants had SCD. Baseline levels of hsTnT were significantly associated with SCD [Hazard ratio (HR) for +1Log(hsTnT) 2.04, 95% confidence interval (CI) 1.78–2.34]. This association persisted in covariate-adjusted Cox analyses accounting for baseline risk factors (HR 1.30, 95%CI 1.05–1.62), as well as for incident heart failure and myocardial infarction (HR 1.26, 95%CI 1.01–1.57). The population was also categorized into 3 groups based on baseline hsTnT levels and SCD risk [Fully-adjusted HRs 1.89 vs. 1.55 vs. 1 (reference group) for hsTnT≥12.10 vs. 5.01–12.09 vs. ≤5.00 pg/mL, respectively; Ptrend=0.005]. On serial measurements, change in hsTnT levels was also associated with SCD risk (Fully-adjusted HR for +1pg/ml per year increase from baseline 1.03, 95%CI 1.01–1.06).
Conclusions
The findings suggest an association between cardiomyocyte injury in ambulatory subjects and SCD risk beyond that of traditional risk factors.
doi:10.1016/j.jacc.2013.07.049
PMCID: PMC4157919  PMID: 23973690
death; sudden; myocytes; general population
11.  Impact of age and sex on sudden cardiovascular death following myocardial infarction 
Heart  2002;88(6):573-578.
Objective: To evaluate and compare the risk of sudden cardiovascular death (SCD) and non-SCD after myocardial infarction (MI) associated with age and sex.
Design: Cohort study of patients admitted with an enzyme verified acute MI and discharged alive. Patients were followed up for up to four years.
Patients: 5983 consecutive hospital survivors of acute MI were enrolled in the TRACE (trandolapril cardiac evaluation) registry from 1990–92. Four age groups were prespecified: < 56, 56–65, 66–75, and ≥ 76 years.
Main outcome measures: SCD was defined as cardiovascular death within one hour of onset of symptoms.
Results: There were 536 SCD and 725 non-SCD. SCD mortality was 4.8% in the youngest and 15.7% in the oldest age groups. Non-SCD mortality was 3.5% and 25%, respectively. The ratio of SCD to non-SCD mortality varied from 1.44 in the youngest (< 56 years) to 0.55 in the oldest patients (≥ 76 years). Age significantly increased both SCD and non-SCD risk (p < 0.0001), but the increase in non-SCD risk was 40% higher (p < 0.0001). Male sex was associated with increased risk of SCD independently of age (risk ratio 1.34, p < 0.005). However, the absolute three year probability of SCD among women older than 66 years exceeded 10%.
Conclusions: Compared with non-SCD the risk of SCD is relatively highest in the younger age groups, but the absolute risk of SCD is much higher among the upper age groups than the younger. The risk of SCD was slightly lower in women but not enough to warrant a different treatment strategy.
PMCID: PMC1767447  PMID: 12433881
sudden death; women; aging; myocardial infarction
12.  Trends in sudden cardiac death and its risk factors in Japan from 1981 to 2005: the Circulatory Risk in Communities Study (CIRCS) 
BMJ Open  2012;2(2):e000573.
Objective
There is little evidence whether sudden cardiac death (SCD) is increasing in Asia, although the incidence of coronary heart disease among urban middle-aged Japanese men has increased recently. We examined trends in the incidence of SCD and its risk factors in the Circulatory Risk in Communities Study.
Design and setting
This was a population-based longitudinal study. Surveillance of men and women for SCD incidence and risk factors was conducted from 1981 to 2005.
Subjects
The surveyed population was all men and women aged 30–84 years who lived in three rural communities and one urban community in Japan.
Main outcome measures
Trends in SCD incidence and its risk factors.
Results
Age-adjusted and sex-adjusted incidence of SCD decreased from 1981–1985 to 1991–1995, and plateaued thereafter. The annual incidence per 100 000 person-years was 76.0 in 1981–1985, 57.9 in 1986–1990, 39.3 in 1991–1995, 31.6 in 1996–2000 and 36.8 in 2001–2005. The prevalence of hypertension decreased from 1981–1985 to 1991–1995, and plateaued thereafter for men and women. The age-adjusted prevalence of current smoking for men decreased while that of diabetes mellitus increased for both sexes from 1981–1985 to 2001–2005.
Conclusions
The incidence of SCD decreased from 1981 to 1995 but was unchanged from 1996 to 2005. Continuous surveillance is necessary to clarify future trends in SCD in Japan because of an increasing incidence of diabetes mellitus.
Article summary
Article focus
The incidence of coronary heart disease among urban middle-aged Japanese men increased from the 1990s to the 2000s, therefore the incidence of sudden cardiac death (SCD) may have increased in recent decades.
This is the first study to examine recent trends in SCD in Japan.
Key messages
The age-adjusted and sex-adjusted incidence of SCD among men and women aged 30–84 years in four Japanese communities decreased from 1981–1985 to 1991–1995 and plateaued after 1996.
Continuous surveillance is necessary to clarify future trends in SCD in Japan because of an increasing incidence of diabetes mellitus.
Strengths and limitations of this study
Trends in SCD were analysed using population-based data from a large number of participants in a long-term observational study and annual cardiovascular risk factor surveys ascertained the trends in predisposing risk factors of SCD.
The incidence of SCD was only examined for people aged 30–84 years; other age ranges were not included.
Clinical features and neuroimaging reports were used to exclude death due to stroke; some cases may have been misclassified, especially out-of-hospital deaths.
doi:10.1136/bmjopen-2011-000573
PMCID: PMC3312077  PMID: 22446988
13.  Atrial Fibrillation and the Risk of Sudden Cardiac Death: The Atherosclerosis Risk in Communities (ARIC) Study and Cardiovascular Health Study (CHS) 
JAMA internal medicine  2013;173(1):29-35.
Background
It is unknown whether atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. This association was examined in 2 population-based cohorts.
Methods
In the Atherosclerosis Risk in Communities (ARIC) Study, we analyzed data from 15439 participants (baseline 45–64 years, 55% women, and 27% black) from baseline (1987–1989) through December 31, 2001. In the Cardiovascular Health Study (CHS), we analyzed data from 5479 participants (baseline ≥65 years, 58% women, and 15% black) from baseline (first cohort, 1989–1990; second cohort, 1992–1993) through December 31, 2006. The main outcome was physician-adjudicated SCD, defined as death from a sudden, pulseless condition presumed due to a ventricular tachyarrhythmia. The secondary outcome was non-SCD (NSCD): coronary heart disease death not meeting SCD criteria. We used Cox proportional hazards models to assess the association between AF and SCD/NSCD, adjusting for baseline demographic and cardiovascular risk factors.
Results
In ARIC, 894 AF, 269 SCD, and 233 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 2.89/1000 person-years (with AF) and 1.30/1000 person-years (without AF). The multivariable hazard ratios (HRs) (95% CI) of AF for SCD and NSCD were 3.26 (2.17–4.91) and 2.43 (1.60–3.71), respectively. In CHS, 1458 AF, 292 SCD, and 581 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 12.00/1000 person-years (with AF) and 3.82/1000 person-years (without AF). The multivariable HRs (95% CI) of AF for SCD and NSCD were 2.14 (1.60–2.87) and 3.10 (2.58–3.72), respectively. The meta-analyzed HRs (95% CI) of AF for SCD and NSCD were 2.47 (1.95–3.13) and 2.98 (2.52–3.53), respectively.
Conclusions
Incident AF is associated with an increased risk of SCD and NSCD in the general population. Additional research to identify predictors of SCD in AF patients is warranted.
doi:10.1001/2013.jamainternmed.744
PMCID: PMC3578214  PMID: 23404043
14.  Strategies for the prevention and treatment of sudden cardiac death 
Cardiovascular diseases account for 40% of all deaths in the West. Sudden cardiac death (SCD) is a major health problem affecting over 300,000 patients annually in the United States alone. Presence of coronary artery disease (CAD), usually in the setting of diminished left ventricular ejection fraction, is still the single major risk factor for SCD. Additionally, acute myocardial ischemia, structural cardiac defects, anomalous coronary arteries, cardiomyopathies, genetic mutations, and ventricular arrhythmias are all attributed to SCD, demonstrating the perplexity of this condition. With the recent advancements in cardiovascular medicine, the incidence of SCD is expected to increase steeply as the prevalence of CAD and heart failure is uprising in general population. Considering SCD, the major challenge confronting contemporary cardiology, multiple strategies for prevention against SCD have been developed. β-blockers have been shown to reduce the risk of SCD, whereas implantable cardioverter–defibrillator devices are found to be effective at terminating the malignant arrhythmias. In recent years, multiple clinical trials were carried out to identify patients who may benefit from preventive intervention, including medical therapy and automatic cardioverter–defibrillator implantations. This review article provides insight into the advanced strategies for the prevention and treatment of SCD based on the data available in medical literature to date.
doi:10.2147/OAEM.S6869
PMCID: PMC3219585  PMID: 22102788
risk stratification; sudden cardiac death; prevention; treatment
15.  Smoking, Smoking Cessation and Risk of Sudden Cardiac Death in Women 
Background
Few prospective studies have examined quantitative cigarette consumption and smoking cessation on sudden cardiac death (SCD) risk among individuals without pre-existing coronary heart disease (CHD) with long-term follow-up.
Methods and Results
We prospectively examined the association between cigarette smoking and smoking cessation on the risk of SCD among 101,018 women participating in the Nurses’ Health Study without CHD, stroke and cancer at baseline 1980. During 30 years of follow-up, we identified 351 SCD events. Compared to never smokers, current smokers had a 2.46-fold (95% CI, 1.81–3.33) increased risk of SCD after controlling for coronary risk factors. In multivariable analyses, quantity of cigarettes smoked daily (P for trend, <.0001) and smoking duration (P for trend, <.0001) were linearly associated with SCD risk among current smokers. Small to moderate amounts of cigarette consumption (1–14 per day) were associated with a significant 1.86-fold (95% CI, 1.17–2.96) increase in SCD risk and every 5 years of continued smoking was associated with an 8% increase in SCD risk (HR 1.08; 95% CI, 1.05–1.12, p<.0001). The SCD risk linearly decreased over time after quitting and was equivalent to that of a never smoker after 20 years of cessation (p for trend <0.0001).
Conclusions
In this large prospective cohort of women without CHD at baseline, a strong dose response relationship between cigarette smoking and SCD risk was observed, and smoking cessation significantly reduced and eventually eliminated excess SCD risk. This suggests efforts to prevent SCD among women should include aggressive strategies for smoking cessation.
doi:10.1161/CIRCEP.112.975219
PMCID: PMC4025959  PMID: 23233741
16.  Obstructive Sleep Apnea and the Risk of Sudden Cardiac Death: A Longitudinal Study of 10,701 Adults 
Journal of the American College of Cardiology  2013;62(7):10.1016/j.jacc.2013.04.080.
Objective
To identify the risk of sudden cardiac death (SCD) associated with obstructive sleep apnea (OSA).
Background
Risk stratification for SCD, a major cause of mortality, is difficult. OSA is linked to cardiovascular disease and arrhythmias, and has been shown to increase the risk of nocturnal SCD. It is unknown if OSA independently increases the risk of SCD.
Methods
We included 10,701 consecutive adults undergoing their first diagnostic polysomnogram between 7/1987 and 7/2003. During follow-up up to 15 years, we assessed incident resuscitated or fatal SCD in relationship to the presence of OSA, physiological data including the apnea-hypopnea index (AHI) and nocturnal oxygen saturation (O2sat) parameters, and relevant comorbidities.
Results
During an average follow-up of 5.3 years, 142 patients had resuscitated or fatal SCD (annual rate 0.27%). In multivariate analysis, independent risk factors for SCD were age, hypertension, coronary artery disease, cardiomyopathy or heart failure, ventricular ectopy or nonsustained ventricular tachycardia, and lowest nocturnal O2sat (per -10%, HR 1.14, P=0.029). SCD was best predicted by age >60 years (HR 5.53), AHI >20 (HR 1.60), mean nocturnal O2sat <93% (HR 2.93), and lowest nocturnal O2sat <78% (HR 2.60, all P<0.0001).
Conclusions
In a population of 10,701 adults referred for polysomnography, OSA predicted incident SCD, and the magnitude of risk was predicted by multiple parameters characterizing OSA severity. Nocturnal hypoxemia, an important pathophysiological feature of OSA, strongly predicted SCD independently of well-established risk factors. These findings implicate OSA, a prevalent condition, as a novel risk factor for SCD.
doi:10.1016/j.jacc.2013.04.080
PMCID: PMC3851022  PMID: 23770166
Arrhythmia; Heart disease; Risk factor; Sleep apnea; Sudden cardiac death
17.  Sudden Cardiac Death in Patients with Human Immunodeficiency Virus Infection 
Objectives
We sought to determine the incidence and clinical characteristics of sudden cardiac death (SCD) in patients with HIV.
Background
As the HIV-infected population ages, cardiovascular disease prevalence and mortality are increasing; however, the incidence and features of SCD have not yet been described.
Methods
Records of 2860 consecutive patients in a public HIV clinic in San Francisco, CA between April 2000 and August 2009 were examined. Identification of deaths, causes of death, and clinical characteristics were obtained by search of the National Death Index and/or clinic records. SCDs were determined using published retrospective criteria: (1) ICD10 code for all cardiac causes of death and (2) circumstances of death meeting WHO criteria.
Results
Of 230 deaths over 3.7 median years’ follow-up, 30 (13%) met SCD criteria, 131 (57%) were due to AIDS, 25 (11%) other (natural) diseases, and 44 (19%) overdose/suicides/unknown. SCDs accounted for 86% (30/35) of all cardiac deaths. The mean SCD rate was 2.6 per 1,000 person-years (95%CI 1.8-3.8), 4.5-fold higher than expected. SCDs occurred in older patients than AIDS deaths (mean 49.0 vs. 44.9 years, p=0.02). Compared to AIDS and natural deaths combined, SCDs had higher prevalence of prior MI (17% vs. 1%, p<0.0005), cardiomyopathy (23% vs. 3%, p<0.0005), heart failure (30% vs. 9%, p=0.004), and arrhythmias (20% vs. 3%, p=0.003).
Conclusions
SCDs account for most cardiac and many non-AIDS natural deaths in HIV-infected patients. Further investigation is needed to ascertain underlying mechanisms, which may include inflammation, antiretroviral therapy interruption, and concomitant medications.
doi:10.1016/j.jacc.2012.02.024
PMCID: PMC3356565  PMID: 22595409
AIDS; death, sudden; arrhythmia
18.  Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients 
European Heart Journal  2012;34(8):578-587.
Background
Sudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients.
Methods and results
We analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95% CI: 1.06–2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95% CI: 1.32–6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95% CI: 1.01–2.62).
Conclusions
The joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials.
doi:10.1093/eurheartj/ehs361
PMCID: PMC3578266  PMID: 23211232
Aldosterone; Cortisol; Sudden cardiac death; Cardiovascular events; Mortality; Kidney disease
19.  Association of Holter-Based Measures Including T-wave Alternans with Risk of Sudden Cardiac Death in the Community-Dwelling Elderly: The Cardiovascular Health Study 
Journal of electrocardiology  2010;43(3):251-259.
Background
Sudden cardiac death (SCD) can be the first manifestation of cardiovascular disease. Development of screening methods for higher / lower risk is critical.
Methods
The Cardiovascular Healthy Study (CHS) is a population-based study of risk factors for coronary heart disease and stroke those ≥65 years. N=49 (of 1649) with usable Holters and in normal sinus rhythm, suffered SCD during follow up and were matched with 2 controls, alive at the time of death of the case and not suffering SCD on follow up. Univariate and multivariate conditional logistic regression determined the association of Holter-based information and SCD.
Results
In univariate models, the upper half of VPC counts, abnormal heart rate turbulence, decreased normalized low frequency power, increased T-wave alternans (TWA) and decreased DFA1 (short-term fractal scaling exponent) were associated with SCD, but time domain HRV was not. In multivariate models, the upper half of VPC counts (OR=6.6) and having TWA ≥37µV on Ch2 (OR=4.8) were independently associated with SCD. Also, the upper half of VPC counts (OR=6.9) and having DFA1 <1.05 (OR=5.0) were independently associated with SCD. When additive effects were explored: having both higher VPCs and higher TWA was associated with an OR of 8.2 for SCD compared to 2.6 for having either. Also, having both higher VPCs and lower DFA1 was associated with an OR of 9.6 for SCD compared to 3.1 for having either.
Conclusions
Results support a potential role for 24-hour Holter recordings to identify older adults at increased or lower risk of SCD.
doi:10.1016/j.jelectrocard.2009.12.009
PMCID: PMC2856790  PMID: 20096853
Sudden death; risk stratification; ambulatory ECG monitoring; heart rate variability; heart rate turbulence; T-wave alternans; arrhythmias; population-dwelling elderly
20.  Opposite Associations of Plasma Homoarginine and Ornithine with Arginine in Healthy Children and Adolescents 
Homoarginine, a non-proteinogenic amino acid, is formed when lysine replaces ornithine in reactions catalyzed by hepatic urea cycle enzymes or lysine substitutes for glycine as a substrate of renal arginine:glycine amidinotransferase. Decreased circulating homoarginine and elevated ornithine, a downstream product of arginase, predict adverse cardiovascular outcome. Our aim was to investigate correlates of plasma homoarginine and ornithine and their relations with carotid vascular structure in 40 healthy children and adolescents aged 3–18 years without coexistent diseases or subclinical carotid atherosclerosis. Homoarginine, ornithine, arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) were measured by liquid chromatography-tandem mass spectrometry with stable isotope-labeled internal standards. Intima-media thickness (IMT) and extra-medial thickness (EMT) of common carotid arteries were estimated by B-mode ultrasound. Homoarginine correlated with arginine (r = 0.43, p = 0.005), age (r = 0.42, p = 0.007) and, weakly, with an increased arginine-to-ornithine ratio, a putative measure of lower arginase activity (r = 0.31, p = 0.048). Ornithine correlated inversely with arginine (r = −0.64, p < 0.001). IMT, EMT or their sum were unrelated to any of the biochemical parameters (p > 0.12). Thus, opposite associations of plasma homoarginine and ornithine with arginine may partially result from possible involvement of arginase, an enzyme controlling homoarginine degradation and ornithine synthesis from arginine. Age-dependency of homoarginine levels can reflect developmental changes in homoarginine metabolism. However, neither homoarginine nor ornithine appears to be associated with carotid vascular structure in healthy children and adolescents.
doi:10.3390/ijms141121819
PMCID: PMC3856037  PMID: 24192823
homoarginine; ornithine; arginine; children; carotid vascular structure
21.  Association of prolonged QRS duration with ventricular tachyarrhythmias and sudden cardiac death in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) 
OBJECTIVES
We evaluated the prognostic significance of prolonged QRS duration (QRSd) relative to arrhythmic outcomes in medically- and implantable cardioverter-defibrillator (ICD)-treated patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II.
BACKGROUND
There is conflicting literature on the relationship between prolonged QRSd and arrhythmic events, including sudden cardiac death (SCD), in heart failure patients with or without ICDs.
METHODS
Using a Cox-proportional hazards model adjusting for ejection fraction (EF), heart failure class, and blood urea nitrogen, we estimated the association of prolonged QRSd ≥ 140 milliseconds with SCD in the medically-treated arm, and SCD or first ICD therapy for rapid ventricular tachycardia/fibrillation (VT/VF, cycle length ≤ 260 ms) in the ICD-treated arm.
RESULTS
In the medically-treated arm, prolonged QRSd was a significant independent predictor of SCD (HR 2.12 [95% CI 1.20–3.76], p = 0.01). However, in the ICD-treated arm, prolonged QRSd did not predict SCD or rapid VT/VF (HR 0.77 [95% CI 0.47–1.24], p = 0.28). The difference in the prognostic effect of prolonged QRSd in these two groups was significant (p<0.01). These results were not affected by varying the cycle length defining rapid VT/VF or the duration defining QRSd prolongation.
CONCLUSIONS
In patients with prior myocardial infarction and EF ≤ 30%, prolonged QRSd does not predict SCD/VT/VF in ICD-treated patients, but does predict SCD in medically-treated patients. This underscores the non-equivalence of VT/VF and SCD, and the need for caution in inferring risk of SCD when using non-randomized databases that include only patients with ICDs.
doi:10.1016/j.hrthm.2008.02.013
PMCID: PMC2692879  PMID: 18534364
Death; sudden; defibrillation; tachyarrhythmias; risk factors; QRS duration
22.  N-terminal pro-B-type Natriuretic Peptide is Associated with Sudden Cardiac Death Risk: the Cardiovascular Health Study 
Background
Sudden cardiac death (SCD), the cause of 250,000-450,000 deaths per year, is a major public health problem. The majority of those affected do not have a prior cardiovascular diagnosis. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure and mortality, as well as sudden death in women.
Objective
To examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population.
Methods
The risk of SCD associated with baseline NT-proBNP was examined in 5447 participants. Covariate-adjusted Cox model regressions were used to estimate the hazard ratios of developing SCD as a function of baseline NT-proBNP
Results
Over a median follow-up of 12.5 years (maximum of 16), there were 289 cases of SCD. Higher NT-proBNP levels were strongly associated with SCD, with an unadjusted hazard ratio of 4.2 (95% CI: 2.9, 6.1, p<0.001) in the highest quintile compared to the lowest. NT-proBNP remained associated with SCD even after adjustment for numerous clinical characteristics and risk-factors (age, sex, race, and other associated conditions), with an adjusted hazard ratio for the 5th versus the 1st quintile of 2.5 (95% CI: 1.6, 3.8, p<0.001).
Conclusion
NT-proBNP provides information regarding the risk of sudden cardiac death in a community based population of older adults, beyond other traditional risk factors. This biomarker may ultimately prove useful in targeting the population at risk with aggressive medical management of comorbid conditions.
doi:10.1016/j.hrthm.2010.10.038
PMCID: PMC3826546  PMID: 21044699
Sudden cardiac death; B-type natriuretic peptide; BNP; NT-proBNP
23.  Genetic variation in NOS1AP is associated with sudden cardiac death: evidence from the Rotterdam Study 
Human Molecular Genetics  2009;18(21):4213-4218.
Common variation within the nitric oxide-1 synthase activator protein (NOS1AP) locus is strongly related to QT interval, a sudden cardiac death (SCD) risk factor. A recent report describes common variation in NOS1AP associated with SCD in a US population of European ancestry. The objective of the current study was to obtain additional evidence by investigating the association between NOS1AP variants and SCD in the prospective population-based Rotterdam Study. The study population consisted of 5974 European ancestry subjects, aged 55 years and older, genotyped on Illumina arrays. SCD was defined according to European Society of Cardiology guidelines. Smoking, body mass index, diabetes mellitus, hypertension, heart failure and myocardial infarction were used as covariates in Cox proportional hazard models. Results were combined with reported evidence using inverse-variance weighted meta-analysis. Two hundred and eight (109 witnessed) cases of SCD occurred during a mean follow-up of 10.4 years. Within the Rotterdam Study alone, no significant associations were observed. Upon pooling of results with existing data, we observed strengthening of existing evidence for rs16847549 (US data HR = 1.31, P = 0.0024; Rotterdam Study HR = 1.18, P = 0.16; joint HR = 1.26, P = 0.0011). When the case definition in the Rotterdam Study was restricted to witnessed SCD, association of rs16847549 with SCD became stronger (joint P = 0.00019) and additionally the association between rs12567209 and SCD gained significance (US data HR = 0.57, P = 0.0035; Rotterdam Study HR = 0.69, P = 0.23; joint HR = 0.60, P = 0.0018). In conclusion, this study provided additional evidence for association between genetic variation within NOS1AP and SCD. The mechanism by which this effect is exerted remains to be elucidated.
doi:10.1093/hmg/ddp356
PMCID: PMC2758139  PMID: 19643915
24.  Reduced Glomerular Filtration Rate and Its Association with Clinical Outcome in Older Patients at Risk of Vascular Events: Secondary Analysis 
PLoS Medicine  2009;6(1):e1000016.
Background
Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).
Methods and Findings
Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease equation and was categorized in the ranges ([20–40], [40–50], [50–60]) ≥ 60 ml/min/1.73 m2. Baseline risk factors were analysed by category of eGFR, with and without adjustment for other risk factors. The associations between baseline eGFR and morbidity and mortality outcomes, accrued after an average of 3.2 y, were investigated using Cox proportional hazard models adjusting for traditional risk factors. We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status. Age, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index, fasting glucose, female sex, histories of hypertension and vascular disease were associated with eGFR (p = 0.001 or less) after adjustment for other risk factors. Low eGFR was independently associated with risk of all cause mortality, vascular mortality, and other noncancer mortality and with fatal and nonfatal coronary and heart failure events (hazard ratios adjusted for CRP and other risk factors (95% confidence intervals [CIs]) for eGFR < 40 ml/min/1.73m2 relative to eGFR ≥ 60 ml/min/1.73m2 respectively 2.04 (1.48–2.80), 2.37 (1.53–3.67), 3.52 (1.78–6.96), 1.64 (1.18–2.27), 3.31 (2.03–5.41). There were no nominally statistically significant interactions (p < 0.05) between randomized treatment allocation and eGFR for clinical outcomes, with the exception of the outcome of coronary heart disease death or nonfatal myocardial infarction (p = 0.021), with the interaction suggesting increased benefit of statin treatment in subjects with impaired GFRs.
Conclusions
We have established that, in an elderly population over the age of 70 y, impaired GFR is associated with female sex, with presence of vascular disease, and with levels of other risk factors that would be associated with increased risk of vascular disease. Further, impaired GFR is independently associated with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal coronary and heart failure outcomes. Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that there is no reason to exclude elderly patients with impaired renal function from treatment with a statin.
Using data from the PROSPER trial, Ian Ford and colleagues investigate whether reduced glomerular filtration rate is associated with cardiovascular and mortality risk among elderly people.
Editors' Summary
Background.
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of death in developed countries. In the USA, for example, the single leading cause of death is coronary heart disease, a CVD in which narrowing of the heart's blood vessels slows or stops the blood supply to the heart and eventually causes a heart attack. Other types of CVD include stroke (in which narrowing of the blood vessels interrupts the brain's blood supply) and heart failure (a condition in which the heart can no longer pump enough blood to the rest of the body). Many factors increase the risk of developing CVD, including high blood pressure (hypertension), high blood cholesterol, having diabetes, smoking, and being overweight. Tools such as the “Framingham risk calculator” assess an individual's overall CVD risk by taking these and other risk factors into account. CVD risk can be minimized by taking drugs to reduce blood pressure or cholesterol levels (for example, pravastatin) and by making lifestyle changes.
Why Was This Study Done?
Another potential risk factor for CVD is impaired kidney (renal) function. In healthy people, the kidneys filter waste products and excess fluid out of the blood. A reduced “estimated glomerular filtration rate” (eGFR), which indicates impaired renal function, is associated with increased CVD in young and middle-aged people and increased all-cause and cardiovascular death in people who have vascular disease. But is reduced eGFR also associated with CVD and death in older people? If it is, it would be worth encouraging elderly people with reduced eGFR to avoid other CVD risk factors. In this study, the researchers determine the predictive value of eGFR for all-cause and vascular mortality (deaths caused by CVD) and for incident vascular events (a first heart attack, stroke, or heart failure) using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). This clinical trial examined pravastatin's effects on CVD development among 70–82 year olds with pre-existing vascular disease or an increased risk of CVD because of smoking, hypertension, or diabetes.
What Did the Researchers Do and Find?
The trial participants were divided into four groups based on their eGFR at the start of the study. The researchers then investigated the association between baseline CVD risk factors and baseline eGFR and between baseline eGFR and vascular events and deaths that occurred during the 3-year study. Several established CVD risk factors were associated with a reduced eGFR after allowing for other risk factors. In addition, people with a low eGFR (between 20 and 40 units) were twice as likely to die from any cause as people with an eGFR above 60 units (the normal eGFR for a young person is 100 units; eGFR decreases with age) and more than three times as likely to have nonfatal coronary heart disease or heart failure. A low eGFR also increased the risk of vascular mortality, other noncancer deaths, and fatal coronary heart disease and heart failure. Finally, pravastatin treatment reduced coronary heart disease deaths and nonfatal heart attacks most effectively among participants with the greatest degree of eGFR impairment.
What Do These Findings Mean?
These findings suggest that, in elderly people, impaired renal function is associated with levels of established CVD risk factors that increase the risk of vascular disease. They also suggest that impaired kidney function increases the risk of all-cause mortality, fatal vascular events, and fatal and nonfatal coronary heat disease and heart failure. Because the study participants were carefully chosen for inclusion in PROSPER, these findings may not be generalizable to all elderly people with vascular disease or vascular disease risk factors. Nevertheless, increased efforts should probably be made to encourage elderly people with reduced eGFR and other vascular risk factors to make lifestyle changes to reduce their overall CVD risk. Finally, although the effect of statins in elderly patients with renal dysfunction needs to be examined further, these findings suggest that this group of patients should benefit at least as much from statins as elderly patients with healthy kidneys.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000016.
The MedlinePlus Encyclopedia has pages on coronary heart disease, stroke, and heart failure (in English and Spanish)
MedlinePlus provides links to many other sources of information on heart disease, vascular disease, and stroke (in English and Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on how the kidneys work and what can go wrong with them, including a list of links to further information about kidney disease
The American Heart Association provides information on all aspects of cardiovascular disease for patients, caregivers, and professionals (in several languages)
More information about PROSPER is available on the Web site of the Vascular Biochemistry Department of the University of Glasgow
doi:10.1371/journal.pmed.1000016
PMCID: PMC2628400  PMID: 19166266
25.  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

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