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.
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.
Vitamin D; Sudden cardiac death; Mortality; Dialysis; Kidney; Cardiovascular
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.
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).
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.
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.
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.
NT-pro-BNP; Serial measurement; Cardiovascular events; Mortality; Haemodialysis; Diabetes mellitus
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).
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.
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).
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.
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).
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.
Aldosterone; Cortisol; Sudden cardiac death; Cardiovascular events; Mortality; Kidney disease
Cardiovascular deaths account for about 40% of all deaths of patients with chronic kidney disease (CKD), particularly those on dialysis, while sudden cardiac death (SCD) might be responsible for as many as 60% of SCD in patients undergoing dialysis. Studies have demonstrated a number of factors occurring in hemodialysis (HD) that could lead to cardiac arrhythmias. Patients with CKD undergoing HD are at high risk of ventricular arrhythmia and SCD since changes associated with renal failure and hemodialysis-related disorders overlap. Antiarrhythmic therapy is much more difficult in patients with CKD, but the general principles are similar to those in patients with normal renal function - at first, the cause of arrhythmias should be found and eliminated. Also the choice of therapy is narrowed due to the altered pharmacokinetics of many drugs resulting from renal failure, neurotoxicity of certain drugs and their complex interactions. Cardiac pacing in elderly patients is a common method of treatment. Assessment of patients’ prognosis is important when deciding whether to implant complex devices. There are reports concerning greater risk of surgical complications, which depends also on the extent of the surgical site. The decision concerning implantation of a pacing system in patients with CKD should be made on the basis of individual assessment of the patient.
Arrhythmias; Chronic kidney disease; Renal failure; Sudden cardiac death
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.
To examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population.
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
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).
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.
Sudden cardiac death; B-type natriuretic peptide; BNP; NT-proBNP
The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that implantable cardioverterdefibrillator (ICD) therapy reduces all-cause mortality in patients with New York Heart Association class II/III heart failure and a left ventricular ejection fraction ≤35% on optimal medical therapy. Whether ICD therapy reduced sudden death caused by ventricular tachyarrhythmias without affecting heart failure deaths in this population is unknown.
Methods and Results
SCD-HeFT randomized 2521 subjects to placebo, amiodarone, or shock-only, single-lead ICD therapy. Over a median follow-up of 45.5 months, a total of 666 deaths occurred, which were reviewed by an Events Committee and initially categorized as cardiac or noncardiac. Cardiac deaths were further adjudicated as resulting from sudden death presumed to be ventricular tachyarrhythmic, bradyarrhythmia, heart failure, or other cardiac causes. ICD therapy significantly reduced cardiac mortality compared with placebo (adjusted hazard ratio, 0.76; 95% confidence interval, 0.60 to 0.95) and tachyarrhythmia mortality (adjusted hazard ratio, 0.40; 95% confidence interval, 0.27 to 0.59) and had no impact on mortality resulting from heart failure or noncardiac causes. The cardiac and tachyarrhythmia mortality reductions were evident in subjects with New York Heart Association class II but not in subjects with class III heart failure. The reduction in tachyarrhythmia mortality with ICD therapy was similar in subjects with ischemic and nonischemic disease. Compared with placebo, amiodarone had no significant effect on any mode of death.
ICD therapy reduced cardiac mortality and sudden death presumed to be ventricular tachyarrhythmic in SCD-HeFT and had no effect on heart failure mortality. Amiodarone had no effect on all-cause mortality or its cause-specific components, except an increase in non-cardiac mortality in class III patients.
cardiomyopathy; death, sudden; heart failure; mortality; tachyarrhythmias
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.
risk stratification; sudden cardiac death; prevention; treatment
Omega-3 polyunsaturated fatty acids (PUFA) may modulate autonomic control of the heart because omega-3 PUFA is abundant in the brain and other nervous tissue as well as in cardiac tissue. This might partly explain why omega-3 PUFA offer some protection against sudden cardiac death (SCD). The autonomic nervous system is involved in the pathogenesis of SCD. Heart rate variability (HRV) can be used as a non-invasive marker of cardiac autonomic control and a low HRV is a predictor for SCD and arrhythmic events. Studies on HRV and omega-3 PUFA have been performed in several populations such as patients with ischemic heart disease, patients with diabetes mellitus, patients with chronic renal failure, and in healthy subjects as well as in children. The studies have demonstrated a positive association between cellular content of omega-3 PUFA and HRV and supplementation with omega-3 PUFA seems to increase HRV which could be a possible explanation for decreased risk of arrhythmic events and SCD sometimes observed after omega-3 PUFA supplementation. However, the results are not consistent and further research is needed.
omega-3 polyunsaturated fatty acids; sudden cardiac death; autonomic function; heart rate variability
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.
The aim of this study was to determine characteristics of patients with sudden cardiac arrest (SCA) and/or sudden cardiac death (SCD). We need an effective risk stratification method for SCD in patients without low left ventricular ejection fraction (LVEF).
The study population of this cross-sectional study consisted of 241 patients with SCA or SCD who were admitted to an academic hospital, in Tehran, Iran, from 2011 through 2012. SCD was defined as unexpected death from cardiac causes, heralded by abrupt loss of consciousness within one hour of the onset of acute changes in cardiovascular status, or an unobserved death in which the patient was seen and known to be doing well within the previous 24 hours. Survivors of aborted SCD were also included in the study. Clinical and paraclinical characteristics as well as emergency department complications of patients were recorded.
The mean age of population was 66.0 ± 16.5 (17 to 90 years). Among the patients, 166 (68.9 %) were male, 50 (20.7%) were smoker, 77 (32.0%) had hypertension, 47 (19.5%) had diabetes mellitus, 21 (8.7%) had hyperlipidemia, and 32 (13.3%) had renal insufficiency. According to New York Health Association (NYHA) functional class, 31 (12.9%) patients were asymptomatic, 42 (17.4) and 99 (41.1%) subjects were in NYHA I and II, respectively and only 69 (28.6%) patients were in NYHA III or IV. In this study, presenting arrhythmia was pulseless electrical activity or asystole which was observed in 130 (53.9%) subjects. Ventricular tachycardia (VT) or ventricular fibrillation (VF) was seen in 53 (22%) patients. Cardiopulmonary resuscitation in emergency room was successful only in 46 (19.1%) subjects.
Low ejection fraction (EF) may be an independent predictor of sudden cardiac death in patients, but it is not enough. While implantable cardioverter defibrillators can save lives, we are lacking effective risk stratification and prevention methods for the majority of patients without low EF who will experience SCD.
Death; Sudden Cardiac Arrest; Sudden Cardiac Death
Background: Electrocardiographic early repolarization (ER) occurring in <5% of general/atherosclerotic populations, is a marker of sudden cardiac death (SCD). The prevalence of ER in chronic kidney disease (CKD) patients, in whom SCD is common, is unknown. We aimed to determine the prevalence, contributing factors, and relationship of ER to all-cause mortality and progression to dialysis in CKD patients.
Methods: A retrospective study of 197 patients with stage 3–5 CKD. Full demographic data were collected including cardiovascular risk factors and history. All patients underwent a 12-lead ECG, analysed for the presence of ER and other ECG findings. ER was defined as elevation of the QRS-ST junction (J point) by at least 0.1 mV from baseline with slurring/notching of the QRS complex. The primary and secondary endpoints were all cause mortality and progression to dialysis respectively at 1 year. To control for the effects of CKD, we evaluated the ECGs of 39 healthy renal transplant donors (RTD).
Results: CKD patients had a mean age of 61.5 (±16.1). Prevalence of ER in pre-dialysis patients with CKD stage 4 and 5 was higher than in RTD (26.4 vs. 7.7%, p = 0.02). ER frequency increased with CKD stage (stage 3: 7.7%, stage 4: 29.7%, and pre-dialysis stage 5: 24.6%), but decreased in dialysis patients (13%). On multivariate analysis only the QRS duration was a significant independent predictor of ER (OR 0.97, 95% CI, 0.94–0.99, p = 0.01). At 1-year follow-up, there were 24 (12%) deaths in the patients with CKD of whom 5 (21%) had ER. ER was not a predictor of all cause mortality (p = 1.00) and had no effects on the rate of progression to dialysis (p = 0.67).
Conclusions: ER is more common in pre-dialysis CKD patients, compared to healthy RTD but is not associated with increased 1-year mortality or entry onto dialysis programs. Further longitudinal studies are indicated to determine whether this increased prevalence of ER is associated with the rate of SCD seen in this population.
early repolarization; chronic kidney disease; sudden cardiac death; dialysis; mortality
Concentric left ventricular hypertrophy (LVH) is independently associated with increased risk of sudden cardiac death (SCD). Some animal models of LVH display specific alterations of the myocardial interstitium that could increase myocardial vulnerability to ventricular arrhythmias, but these merit evaluation in humans with LVH and SCD.
Methods and Results
Twelve consecutive patients with isolated LVH and SCD (LVH+SCD) in the absence of hypertrophic cardiomyopathy, coronary disease, or other cardiac structural abnormality were ascertained in the Oregon Sudden Unexpected Death Study. Detailed postmortem comparisons were conducted with 18 controls who had isolated LVH and unnatural deaths (Control Group A) and 6 controls who had structurally normal hearts and unnatural deaths (Control Group B). Postmortem left ventricular myocardial sections were obtained for measurement of collagen volume fraction, characterization of gap junctions, and quantification of collagen subtypes. Heart weight normalized to body weight was higher in LVH+SCD cases (6.9±1.2 g/kg) than in Control Group A (5.3±1.4 g/kg) and Control Group B (4.2±0.3 g/kg); P=0.001. Collagen volume fraction was also higher in LVH+SCD cases (3.1±0.4) than in Control Group A (2.3±0.4) and Control Group B (1.6±0.3); P=0.0002. The relative amount of collagen III was significantly higher in LVH+SCD cases (33.0±4.4%) than in Control Group A (20.9±4.3%) and Control Group B (13.4±3.5%); P=0.0001. There was an overall increase in the number of connexin 43–labeled gap junctions with increasing myocyte size. No subject was found to have high-risk hypertrophic cardiomyopathy mutations.
In addition to the expected increase in myocardial mass and overall collagen content, SCD with isolated LVH was associated with relative abundance of type III collagen, a novel finding that warrants further mechanistic evaluation. (J Am Heart Assoc. 2012;1:e001511 doi: 10.1161/JAHA.111.001511.)
death, sudden; collagen; hypertrophy; myocardium; remodeling
Over a three year period we have used haemodialysis and haemofiltration in parallel with cardiopulmonary bypass in 26 patients. Impaired renal function and excessive fluid retention have been the main indications. Patients on haemodialysis programmes for end stage renal failure did not require further dialysis until at least the third postoperative day, when they could tolerate the haemodynamic disturbance of dialysis. In the other patients these techniques proved valuable in reversing the effects of haemodilution and in controlling the concentration of serum potassium. Our experience has confirmed that haemodialysis and haemofiltration in parallel with cardiopulmonary bypass are useful adjuncts in the perioperative management of patients with impaired renal function undergoing open heart surgery. The techniques are also effective in correcting the fluid retention and biochemical imbalance in patients with congestive cardiac failure, including those with heart transplants.
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.
homoarginine; ornithine; arginine; children; carotid vascular structure
NG,NG-dimethyl-l-arginine (ADMA) and NG-methyl-l-arginine (NMMA) are endogenous inhibitors of nitric oxide synthase (NOS). In contrast, NG,N′G-dimethyl-Larginine (SDMA) possesses only a weak inhibitory potency towards neuronal NOS and it is known to limit nitric oxide (NO) production by competing with l-arginine for cellular uptake. The inhibition of NOS is associated with endothelial dysfunction in cardiovascular diseases as well in chronic renal failure. l-Homoarginine (HArg), a structural analog of l-arginine (Arg), is an alternative but less efficient substrate for NOS. Besides, it inhibits arginase, leading to an increased availability of l-arginine for NOS to produce NO. However, its relation with cardiovascular disease remains unclear. To date, several analytical methods for the quantitative determination of Arg, HArg, NMMA, AMDA, and SDMA in biological samples have been described. Here, we present a simple, fast, and accurate HPLC-ESI-MS/MS method which allows both the simultaneous determination and quantification of these compounds without needing derivatization, and the possibility to easily modulate the chromatographic separation between HArg and NMMA (or between SDMA and ADMA). Data on biological samples revealed the feasibility of the method, the minimal sample preparation, and the fast run time which make this method very suitable and accurate for analysis in the basic and clinical settings.
homoarginine; arginine; NMMA; ADMA; SDMA
Homoarginine inhibits the growth of Escherichia coli B, but not of E. coli K-12. These two strains also differ in regard to repressibility of the arginine-forming enzymes. In K-12, arginine acts as a repressor whereas in B it does not. The latter difference is determined by different alleles of a regulator gene, arg R. In K-12 × B crosses, it was shown that the genetic determinant for homoarginine sensitivity is closely linked to or identical with arg R. Homoarginine-resistant mutants of B were isolated. The biochemical mechanism of homoarginine inhibition is not known. However, whether or not a strain is sensitive to homoarginine seems to depend on the intracellular level of arginine. In B this level is relatively low and inflexible as a result of the action of a repressor whose formation is determined by the B-specific allele of arg R.
Recent studies have demonstrated an association between moderate kidney dysfunction and sudden cardiac death in people with cardiovascular disease.
Methods and Results
The study was a longitudinal analysis among 4465 participants from the Cardiovascular Health Study without prevalent cardiovascular disease at baseline. Cystatin C and creatinine were measured from baseline sera. SCD was defined as a sudden pulseless condition from a cardiac origin in a previously stable individual that occurred out of the hospital or in the emergency room. The association between cystatin C tertiles and SCD was determined with multivariate Cox proportional hazards. A similar analysis compared SCD incidence across creatinine-based eGFR tertiles. Over a median follow-up of 11.2 years, 91 adjudicated SCD events occurred. The annual incidence of SCD events increased across cystatin C tertiles: 10 events per 10,000 person years in tertile 1, 25 events per 10,000 person years in tertile 2 and 32 events per 10,000 person years in the highest cystatin C tertile. These associations persisted after multivariate adjustment: [HR = 2.72, 95% CI (1.44–5.16) in tertile 2 and HR = 2.67, 95% CI (1.33–5.35) in tertile 3]. After multivariate adjustment, the rate of SCD also increased in a linear distribution across creatinine-based eGFR tertiles: 15 events per 10,000 person years in tertile 1, 22 events per 10,000 person years in tertile 2 and 27 events per 10,000 person years in tertile 3. No significant associations, however, remained between creatinine-based eGFR and SCD after multivariable adjustment.
Impaired kidney function, as measured by cystatin C, has an independent association with SCD risk among elderly persons without clinical cardiovascular disease.
Cystatin C; kidney; sudden cardiac death; epidemiology
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited genetic disease characterized by compensatory pathological left ventricle (LV) hypertrophy due to sarcomere dysfunction. In an important proportion of patients with HCM, the site and extent of cardiac hypertrophy results in severe obstruction to LV outflow tract (LVOT), contributing to disabling symptoms and increasing the risk of sudden cardiac death (SCD). In patients with progressive and/or refractory symptoms despite optimal pharmacological treatment, invasive therapies that diminish or abolish LVOT obstruction relieve heart failure-related symptoms, improve quality of life and could be associated with long-term survival similar to that observed in the general population. The gold standard in this respect is surgical septal myectomy, which might be supplementary associated with a reduction in SCD. Percutaneous techniques, particularly alcohol septal ablation (ASA) and more recently radiofrequency (RF) septal ablation, can achieve LVOT gradient reduction and symptomatic benefit in a large proportion of HOCM patients at the cost of a supposedly limited septal myocardial necrosis and a 10-20% risk of chronic atrioventricular block. After an initial period of enthusiasm, standard DDD pacing failed to show in randomized trials significant LVOT gradient reductions and objective improvement in exercise capacity. However, case reports and recent small pilot studies suggested that atrial synchronous LV or biventricular (biV) pacing significantly reduce LVOT obstruction and improve symptoms (acutely as well as long-term) in a large proportion of severely symptomatic HOCM patients not suitable to other gradient reduction therapies. Moreover, biV/LV pacing in HOCM seems to be associated with significant LV reverse remodelling.
hypertrophic obstructive cardiomyopathy; intraventricular gradient; biventricular pacing; reverse remodelling
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.
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.
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.
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.
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.
Death; sudden; defibrillation; tachyarrhythmias; risk factors; QRS duration
Sudden cardiac death (SCD) can be the first manifestation of cardiovascular disease. Development of screening methods for higher / lower risk is critical.
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.
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.
Results support a potential role for 24-hour Holter recordings to identify older adults at increased or lower risk of SCD.
Sudden death; risk stratification; ambulatory ECG monitoring; heart rate variability; heart rate turbulence; T-wave alternans; arrhythmias; population-dwelling elderly
Heart failure (HF) patients have a high risk of death, and implantable cardioverter defibrillators (ICDs) are effective in preventing sudden cardiac death (SCD). However, a certain percentage of patients may not be immediate candidates for ICDs, particularly those having a short duration of risk or an uncertain amount of risk. This includes the newly diagnosed patients, as well as those on the cardiac transplant list or NYHA class IV heart failure patients who do not already have an ICD. In these patients, a wearable cardioverter defibrillator (WCD) may be used until long term risk of SCD is defined. The purpose of this study was to determine the incidence of SCD in this population, and the efficacy of early defibrillation by a WCD.
Ten enrolling centers identified 89 eligible HF patients who were either listed for cardiac transplantation, diagnosed with dilated cardiomyopathy, or receiving inotropic medications. Data collected included medical history, device records, and outcomes (including 90 day mortality).
Out of 89 patients, final data on 82 patients has been collected. Patients wore the device for 75±58 days. Mean age was 56.8±13.2, and 72% were male. Most patients (98.8%) were diagnosed with dilated cardiomyopathy with a low ejection fraction (<40%) and twelve were listed for cardiac transplantation. Four patients were on inotropes. There were no sudden cardiac arrests or deaths during the study. Interestingly, 41.5% of patients were much improved after WCD use, while 34.1% went on to receive an ICD.
In conclusion, the WCD monitored HF patients until further assessment of risk. The leading reasons for end of WCD use were improvement in left ventricular ejection fraction (LVEF) or ICD implantation if there was no significant improvement in LVEF.
Heart failure; Wearable cardioverter defibrillator; Sudden cardiac death
Background. The association between parathyroid hormone (PTH) level and mortality in dialysis patients is controversial. We hypothesized that wasting, a common condition potentially related to adynamic bone disease, modifies the association of PTH with mortality and cardiovascular events (CVE), respectively.
Methods. We analysed data from 1255 diabetic haemodialysis patients, participating in the German Diabetes and Dialysis Study between 1998 and 2004. The patients were stratified by the presence or absence of wasting (albumin ≤3.8 versus albumin >3.8 g/dL; BMI ≤23 versus BMI >23 kg/m2). Using Cox regression analyses, we calculated the risks of (1) all-cause mortality and (2) CVE according to baseline PTH levels. All analyses were adjusted for age, sex, atorvastatin treatment, duration of dialysis, comorbidity, HbA1c, phosphate, calcium, blood pressure, haemoglobin and C-reactive protein.
Results. Patients had a mean age of 66 ± 8 years, and 54% were male. Among patients without wasting (albumin >3.8 g/dL, n = 586), the risks of death and CVE during 4 years of follow-up significantly increased by 23% and 20% per unit increase in logPTH. Patients in the highest PTH tertile had a 74% higher risk of death (HRadj 1.74, 95% CI 1.27–2.40) and a 49% higher risk of CVE (HRadj 1.49, 95% CI 1.05–2.11) compared to patients in the lowest PTH tertile. In contrast, no effect was found in patients with wasting. Accordingly, additional analyses in strata of BMI showed that PTH significantly impacted on death and CVE [HR(logPTH)adj 1.15 and 1.14, respectively] only in patients without, but not in patients with, wasting.
Conclusions. Wasting modifies the association of PTH with adverse outcomes in diabetic dialysis patients. High PTH levels are of concern in the patients without wasting, while the effect of PTH on mortality is nullified in the patients with wasting.
cardiovascular events; haemodialysis; mortality; parathyroid hormone; wasting
Patterns of medical resource use near the end of life may differ across modes of death. We characterized patterns of inpatient resource use and direct costs for patients with HF who died of sudden cardiac death (SCD), HF, other cardiovascular causes, or noncardiovascular causes during the last year of life. Data were from a randomized trial exercise training in patients with HF. Mode of death was adjudicated by an end point committee. We used generalized estimating equations to compare hospitalizations, inpatient days, and inpatient costs incurred during the final year of life among patients who died of different causes, adjusting for clinical and treatment characteristics. Of 2331 patients enrolled in the trial, 231 died after at least 1 year of follow-up with an adjudicated mode of death, including 72 of SCD, 80 of HF, 34 of other cardiovascular causes, and 45 of noncardiovascular causes. Patients who died of SCD were younger, had less severe HF, and incurred fewer hospitalizations, fewer inpatient days, and lower inpatient costs than patients who died of other causes. After adjustment for patient characteristics, inpatient resource use varied by 2 to 4 times across modes of death, suggesting that cost-effectiveness analyses of interventions that reduce mortality from SCD compared with other causes should incorporate mode-specific end-of-life costs. In conclusion, resource use and associated medical costs in the last year of life differed markedly among patients with HF who experienced SCD and patients who died of other causes.
Costs and Cost Analysis; Death; Sudden; Cardiac; Heart Failure