Objectives This study was designed to assess the clinical course and to identify risk factors for life-threatening events in patients with long-QT syndrome (LQTS) with normal corrected QT (QTc) ...intervals. Background Current data regarding the outcome of patients with concealed LQTS are limited. Methods Clinical and genetic risk factors for aborted cardiac arrest (ACA) or sudden cardiac death (SCD) from birth through age 40 years were examined in 3,386 genotyped subjects from 7 multinational LQTS registries, categorized as LQTS with normal-range QTc (≤440 ms n = 469), LQTS with prolonged QTc interval (>440 ms n = 1,392), and unaffected family members (genotyped negative with ≤440 ms n = 1,525). Results The cumulative probability of ACA or SCD in patients with LQTS with normal-range QTc intervals (4%) was significantly lower than in those with prolonged QTc intervals (15%) (p < 0.001) but higher than in unaffected family members (0.4%) (p < 0.001). Risk factors ACA or SCD in patients with normal-range QTc intervals included mutation characteristics (transmembrane-missense vs. nontransmembrane or nonmissense mutations: hazard ratio: 6.32; p = 0.006) and the LQTS genotypes (LQTS type 1:LQTS type 2, hazard ratio: 9.88; p = 0.03; LQTS type 3:LQTS type 2, hazard ratio: 8.04; p = 0.07), whereas clinical factors, including sex and QTc duration, were associated with a significant increase in the risk for ACA or SCD only in patients with prolonged QTc intervals (female age >13 years, hazard ratio: 1.90; p = 0.002; QTc duration, 8% risk increase per 10-ms increment; p = 0.002). Conclusions Genotype-confirmed patients with concealed LQTS make up about 25% of the at-risk LQTS population. Genetic data, including information regarding mutation characteristics and the LQTS genotype, identify increased risk for ACA or SCD in this overall lower risk LQTS subgroup.
Long QT Syndrome in Adults Sauer, Andrew J., BS; Moss, Arthur J., MD; McNitt, Scott, MS ...
Journal of the American College of Cardiology,
01/2007, Letnik:
49, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Long QT Syndrome in Adults Andrew J. Sauer, Arthur J. Moss, Scott McNitt, Derick R. Peterson, Wojciech Zareba, Jennifer L. Robinson, Ming Qi, Ilan Goldenberg, Jenny B. Hobbs, Michael J. Ackerman, ...Jesaia Benhorin, W. Jackson Hall, Elizabeth S. Kaufman, Emanuela H. Locati, Carlo Napolitano, MD, Silvia G. Priori, Peter J. Schwartz, Jeffrey A. Towbin, G. Michael Vincent, Li Zhang The clinical course and risk factors for cardiac events in genotype-confirmed adult patients with long QT syndrome (LQTS) were investigated. The severity of LQTS in adulthood can be risk stratified with information regarding genotype, gender, corrected QT duration, and history of cardiac events. Beta-blockers effectively reduce but do not eliminate the risk of both syncopal and life-threatening cardiac events in adult patients with mutation-confirmed LQTS.
Long QT Syndrome and Pregnancy Seth, Rahul, MD; Moss, Arthur J., MD; McNitt, Scott, MS ...
Journal of the American College of Cardiology,
03/2007, Letnik:
49, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Long QT Syndrome and Pregnancy Rahul Seth, Arthur J. Moss, Scott McNitt, Wojciech Zareba, Mark L. Andrews, Ming Qi, Jennifer L. Robinson, Ilan Goldenberg, Michael J. Ackerman, Jesaia Benhorin, ...Elizabeth S. Kaufman, Emanuela H. Locati, Carlo Napolitano, Silvia G. Priori, Peter J. Schwartz, Jeffrey A. Towbin, G. Michael Vincent, Li Zhang The risk of experiencing an adverse cardiac event, including syncope, aborted cardiac arrest, and sudden death, during and after pregnancy was analyzed for women who had their first birth from 1980 to 2003 (n = 391). Compared with a time period before a woman’s first conception, the pregnancy time was associated with a reduced risk of cardiac events and an increased risk during the 9-month postpartum period, especially among women with the LQT2 genotype. Beta-blockers were associated with a reduction in cardiac events during the high-risk postpartum time period.
Background The ODYSSEY COMBO I study ( http://clinicaltrials.gov/show/NCT01644175 ) evaluated efficacy and safety of alirocumab as add-on therapy to stable maximally tolerated daily statin with or ...without other lipid-lowering therapy in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia. Methods This multicenter, phase 3, randomized (2:1 alirocumab vs placebo), double-blind, 52-week trial enrolled 316 patients with established coronary heart disease or coronary heart disease risk equivalents and hypercholesterolemia. Alirocumab (75 mg every 2 weeks Q2W) or placebo Q2W was self-administered subcutaneously via 1 mL prefilled pen. The alirocumab dose was increased to 150 mg Q2W (also 1 mL) at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥70 mg/dL. The primary efficacy end point was percent change in LDL-C from baseline to week 24 (intention-to-treat analysis). Results At week 24, estimated mean (95% CI) changes in LDL-C from baseline were −48.2% (−52.0% to −44.4%) and −2.3% (−7.6% to 3.1%) for alirocumab and placebo, respectively, an estimated mean (95% CI) difference of −45.9% (−52.5% to −39.3%) ( P < .0001). Low-density lipoprotein cholesterol <70 mg/dL was achieved by 75% alirocumab versus 9% placebo patients at week 24. At week 12, 83.2% of evaluable alirocumab-treated patients remained on 75-mg Q2W. Treatment-emergent adverse events were comparable between groups. Conclusions Alirocumab treatment achieved a significantly greater reduction in LDL-C and allowed a greater proportion of patients to achieve LDL-C goals, versus placebo after 24 weeks in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia at baseline despite receiving maximally tolerated statin with or without other lipid-lowering therapy. The frequency of treatment-emergent adverse events and study medication discontinuations were generally comparable between treatment groups.
The role of pneumonectomy after neoadjuvant therapy for stage IIIA non-small cell lung cancer (NSCLC) remains uncertain.
Patients who underwent pneumonectomy for clinical stage IIIA NSCLC were ...abstracted from the National Cancer Database. Individuals treated with neoadjuvant therapy, followed by resection, were compared with those who underwent resection, followed by adjuvant therapy. Logistic regression was performed to identify factors associated with 30-day mortality. A Cox proportional hazards model was fitted to identify factors associated with survival.
Pneumonectomy for stage IIIA NSCLC with R0 resection was performed in 1,033 patients; of these, 739 (71%) received neoadjuvant therapy, and 294 (29%) underwent resection, followed by adjuvant therapy. The two groups were well matched for age, gender, race, income, Charlson comorbidity score, and tumor size. The 30-day mortality rate in the neoadjuvant group was 7.8% (57 of 739). Median survival was similar between the two groups: 25.9 months neoadjuvant vs 31.3 months adjuvant (p = 0.74). A multivariable logistic regression model for 30-day mortality demonstrated that increasing age, annual income of less than $35,000, nonacademic facility, and right-sided resection were associated with an elevated risk of 30-day mortality. A multivariable Cox model for survival demonstrated that increasing age was predictive of shorter survival and that administration of neoadjuvant therapy did not confer a survival advantage over adjuvant therapy (p = 0.59).
Most patients who require pneumonectomy for clinical stage IIIA NSCLC receive neoadjuvant chemoradiotherapy, without an improvement in survival. In these patients, primary resection, followed by adjuvant chemoradiotherapy, may provide equivalent long-term outcomes.
Men and women with type 2 long QT syndrome (LQT2) exhibit time-dependent differences in the risk for cardiac events. We hypothesized that data regarding the location of the disease-causing mutation ...in the KCNH2 channel may affect gender-specific risk in LQT2.
This study sought to risk-stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information.
The risk for life-threatening cardiac events from birth through age 40 years (comprising aborted cardiac arrest ACA or sudden cardiac death SCD) was assessed among 1,166 LQT2 male (n = 490) and female (n = 676) patients by the location of the LQTS-causing mutation in the KCNH2 channel (prespecified in the primary analysis as pore-loop vs. non-pore-loop).
During follow-up, the cumulative probability of life-threatening cardiac events years was significantly higher among LQT2 women (26%) as compared with men (14%; P <.001). Multivariate analysis showed that the risk for life-threatening cardiac events was not significantly different between women with and without pore-loop mutations (hazard ratio 1.20; P =.33). In contrast, men with pore-loop mutations displayed a significant >2-fold higher risk of a first ACA or SCD as compared with those with non-pore-loop mutations (hazard ratio 2.18; P = .01). Consistently, women experienced a high rate of life-threatening events regardless of mutation location (pore-loop: 35%, non-pore-loop: 23%), whereas in men the rate of ACA or SCD was high among those with pore-loop mutations (28%) and relatively low among those with non-pore-loop mutations (8%).
Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in LQT2.
Elevated lipoprotein(a) Lp(a) is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to ...proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between alirocumab and controls. We evaluated the effect of alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with alirocumab 75/150-mg Q2W and 29% with alirocumab 150-mg Q2W (all comparisons p <0.0001 vs controls). Reductions were sustained over 78 to 104 weeks. Lp(a) reductions with alirocumab were independent of race, gender, presence of familial hypercholesterolemia, baseline Lp(a), and LDL-C concentrations, or use of statins. In conclusion, in addition to marked reduction in LDL-C, alirocumab leads to a significant and sustained lowering of Lp(a).
Men and women with type 1 long QT syndrome (LQT1) exhibit time-dependent differences in the risk for cardiac events.
We hypothesized that sex-specific risk for LQT1 is related to the location and ...function of the disease-causing mutation in the KCNQ1 gene.
The risk for life-threatening cardiac events (comprising aborted cardiac arrest ACA or sudden cardiac death SCD) from birth through age 40 years was assessed among 1051 individuals with LQT1 (450 men and 601 women) by the location and function of the LQT1-causing mutation (prespecified as mutations in the intracellular domains linking the membrane-spanning segments ie, S2-S3 and S4-S5 cytoplasmic loops involved in adrenergic channel regulation vs other mutations).
Multivariate analysis showed that during childhood (age group: 0-13 years) men had >2-fold (P < .003) increased risk for ACA/SCD than did women, whereas after the onset of adolescence the risk for ACA/SCD was similar between men and women (hazard ratio = 0.89 P = .64). The presence of cytoplasmic-loop mutations was associated with a 2.7-fold (P < .001) increased risk for ACA/SCD among women, but it did not affect the risk among men (hazard ratio 1.37; P = .26). Time-dependent syncope was associated with a more pronounced risk-increase among men than among women (hazard ratio 4.73 P < .001 and 2.43 P = .02, respectively), whereas a prolonged corrected QT interval (≥ 500 ms) was associated with a higher risk among women than among men.
Our findings suggest that the combined assessment of clinical and mutation location/functional data can be used to identify sex-specific risk factors for life-threatening events for patients with LQT1.
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in developed and developing countries. Despite decades of effort, unhealthy lifestyle habits and ASCVD risk factor levels ...remain high and are increasing in many population groups. A new approach to ASCVD prevention is needed. Multiple lines of evidence from animal and human studies suggest that atherosclerosis regression and normalization of vessel function can occur when low-density lipoprotein cholesterol (LDL-C) lowering occurs early in the course of atherosclerosis or when very aggressive LDL-C lowering occurs somewhat later. We propose a new paradigm focused on curing atherosclerosis early in the course of the disease. An approach that resets the vascular aging clock composed of initial regression therapy followed by periodic retreatment to suppress atherosclerosis development may be possible, with the ultimate goal of preventing subsequent ASCVD events. Proof-of-concept studies are needed to determine: 1) the optimal age and/or extent of atherosclerosis for intervention and LDL-C–lowering therapy; 2) the intensity and duration of therapy for inducing atherosclerosis regression; and 3) documenting the normalization of vascular function. Ultimately, this new paradigm will need to be evaluated in ASCVD outcomes trials.
Objectives To determine the relationship between non–high-density lipoprotein cholesterol (HDL-C) lowering and coronary heart disease (CHD) risk reduction for various lipid-modifying therapies. ...Background Non–HDL-C is the second lipid target of therapy after low-density lipoprotein cholesterol (LDL-C). Methods Randomized placebo or active-controlled trials were evaluated. The effect of mean non–HDL-C reduction on the relative risk of nonfatal myocardial infarction and CHD death was estimated using Bayesian random-effects meta-analysis models adjusted for study duration. Cochrane's Q was used to test for heterogeneity. Results Inclusion criteria were met by 14 statin (n = 100,827), 7 fibrate (n = 21,647), and 6 niacin (n = 4,445) trials, and 1 trial each of a bile acid sequestrant (n = 3,806), diet (n = 458), and ileal bypass surgery (n = 838). For statins, each 1% decrease in non–HDL-C resulted in an estimated 4.5-year CHD relative risk of 0.99 (95% Bayesian confidence interval: 0.98 to 1.00). The fibrate model did not differ from the statin model (Bayes factor K = 0.49) with no evidence of heterogeneity. The niacin model was moderately different from the statin model (K = 7.43), with heterogeneity among the trials (Q = 11.8, 5 df; p = 0.038). The only niacin monotherapy trial (n = 3,908) had a 1:1 relationship between non–HDL-C and risk reduction. No consistent relationships were apparent for the 5 small trials of niacin in combination. The 95% confidence intervals for the single trials of diet, bile acid sequestrants, and surgery also included the 1:1 relationship. Conclusions Non–HDL-C is an important target of therapy for CHD prevention. Most lipid-modifying drugs used as monotherapy have an ≈1:1 relationship between percent non–HDL-C lowering and CHD reduction.
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