Predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study

Introduction

Pulmonary arterial hypertension (PAH) is a major cause of mortality in connective tissue disease (CTD). We sought to quantify survival and determine factors predictive of mortality in a cohort of patients with CTD-associated PAH (CTD-PAH) in the current era of advanced PAH therapy.

Methods

Patients with right heart catheter proven CTD-PAH were recruited from six specialised PAH treatment centres across Australia and followed prospectively. Using survival methods including Cox proportional hazards regression, we modelled for all-cause mortality. Independent variables included demographic, clinical and hemodynamic data.

Results

Among 117 patients (104 (94.9%) with systemic sclerosis), during 2.6 ± 1.8 (mean ± SD) years of follow-up from PAH diagnosis, there were 32 (27.4%) deaths. One-, two- and three-year survivals were 94%, 89% and 73%, respectively. In multiple regression analysis, higher mean right atrial pressure (mRAP) at diagnosis (hazard ratio (HR) = 1.13, 95% CI: 1.04 to 1.24, P = 0.007), lower baseline six-minute walk distance (HR = 0.64, 95% CI: 0.43 to 0.97, P = 0.04), higher baseline World Health Organization functional class (HR = 3.42, 95% CI: 1.25 to 9.36, P = 0.04) and presence of a pericardial effusion (HR = 3.39, 95% CI: 1.07 to 10.68, P = 0.04) were predictive of mortality. Warfarin (HR = 0.20, 95% CI: 0.05 to 0.78, P = 0.02) and combination PAH therapy (HR = 0.20, 95% CI: 0.05 to 0.83, P = 0.03) were protective.

Conclusions

In this cohort of CTD-PAH patients, three-year survival was 73%. Independent therapeutic predictors of survival included warfarin and combination PAH therapy. Our findings suggest that anticoagulation and combination PAH therapy may improve survival in CTD-PAH. This observation merits further evaluation in randomised controlled trials.     

Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A1 adenosine receptor

To investigate whether altered function of adenosine receptors could contribute to sinus node or atrioventricular (AV) nodal dysfunction in conscious mammals, we studied transgenic (TG) mice with cardiac-specific overexpression of the A1 adenosine receptor (A1AR). A Holter ECG was recorded in seven freely moving littermate pairs of mice during normal activity, exercise (5 min of swimming), and 1 h after exercise. TG mice had lower maximal heart rates (HR) than wild-type (WT) mice (normal activity: 437 +/- 18 vs. 522 +/- 24 beats/min, P < 0.05; exercise: 650 +/- 13 vs. 765 +/- 28 beats/min, P < 0.05; 1 h after exercise: 588 +/- 18 vs. 720 +/- 12 beats/min, P < 0.05; all values are means +/- SE). Mean HR was lower during exercise (589 +/- 16 vs. 698 +/- 34 beats/min, P < 0.05) and after exercise (495 +/- 16 vs. 592 +/- 27 beats/min, P < 0.05). Minimal HR was not different between genotypes. HR variability (SD of RR intervals) was reduced by 30% (P < 0.05) in TG compared with WT mice. Pertussis toxin (n = 4 pairs, 150 microg/kg ip) reversed bradycardia after 48 h. TG mice showed first-degree AV nodal block (PQ interval: 42 +/- 2 vs. 37 +/- 2 ms, P < 0.05), which was diminished but not abolished by pertussis toxin. Isolated Langendorff-perfused TG hearts developed spontaneous atrial arrhythmias (3 of 6 TG mice vs. 0 of 9 WT mice, P < 0.05). In conclusion, A1AR regulate sinus nodal and AV nodal function in the mammalian heart in vivo. Enhanced expression of A1AR causes sinus nodal and AV nodal dysfunction and supraventricular arrhythmias.     

Arterial baroreflex control of heart rate during exercise in postural tachycardia syndrome.

Patients with postural tachycardia syndrome (POTS) have excessive tachycardia without hypotension during orthostasis as well as exercise. We tested the hypothesis that excessive tachycardia during exercise in POTS is not related to abnormal baroreflex control of heart rate (HR). Patients (n = 13) and healthy controls (n = 10) performed graded cycle exercise at 25, 50, and 75 W in both supine and upright positions while arterial pressure (arterial catheter) and HR (ECG) were measured. Baroreflex sensitivity of HR was assessed by bolus intravenous infusion of phenylephrine at each workload. In both positions, HR was higher in the patients than the controls during exercise. Supine baroreflex sensitivity (HR/systolic pressure) in POTS patients was -1.3 +/- 0.1 beats.min(-1).mmHg(-1) at rest and decreased to -0.6 +/- 0.1 beats.min(-1).mmHg(-1) during 75-W exercise, neither significantly different from the controls (P > 0.6). In the upright position, baroreflex sensitivity in POTS patients at rest (-1.4 +/- 0.1 beats.min(-1).mmHg(-1)) was higher than the controls (-1.0 +/- 0.1 beats.min(-1).mmHg(-1)) (P < 0.05), and it decreased to -0.1 +/- 0.04 beats.min(-1).mmHg(-1) during 75-W exercise, lower than the controls (-0.3 +/- 0.09 beats.min(-1).mmHg(-1)) (P < 0.05). The reduced arterial baroreflex sensitivity of HR during upright exercise was accompanied by greater fluctuations in systolic and pulse pressure in the patients than in the controls with 56 and 90% higher coefficient of variations, respectively (P < 0.01). However, when baroreflex control of HR was corrected for differences in HR, it was similar between the patients and controls during upright exercise. These results suggest that the tachycardia during exercise in POTS was not due to abnormal baroreflex control of HR.     

One-year health status outcomes of unstable angina versus myocardial infarction: a prospective, observational cohort study of ACS survivors

Background

Unstable angina (UA) patients have lower mortality and reinfarction risks than ST-elevation (STEMI) or non-ST elevation myocardial infarction (NSTEMI) patients and, accordingly, receive less aggressive treatment. Little is known, however, about the health status outcomes (angina, physical function, and quality of life) of UA versus MI patients among survivors of an ACS hospitalization.

Methods

In a cohort of 1,192 consecutively enrolled ACS survivors from two Kansas City hospitals, we evaluated the associations between ACS presentation (UA, NSTEMI, and STEMI) and one-year health status (angina, physical functioning and quality of life), one-year cardiac rehospitalization rates, and two-year mortality outcomes, using multivariable regression modeling.

Results

After multivariable adjustment for demographic, hospital, co-morbidity, baseline health status, and treatment characteristics, UA patients had a greater prevalence of angina at 1 year than STEMI patients (adjusted relative risk [RR] = 1.42; 95% CI [1.06, 1.90]) and similar rates as NSTEMI patients (adjusted RR = 1.1; 95% CI [0.85, 1.42]). In addition, UA patients fared no better than MI patients in Short Form-12 physical component scores (UA vs. STEMI score difference -0.05 points; 95% CI [-2.41, 2.3]; UA vs. NSTEMI score difference -1.91 points; 95% CI [-4.01, 0.18]) or Seattle Angina Questionnaire quality of life scores (UA vs. STEMI score difference -1.39 points; 95% CI [-5.63, 2.85]; UA vs. NSTEMI score difference -0.24 points 95% CI [-4.01, 3.54]). Finally, UA patients had similar rehospitalization rates as MI patients (UA vs. STEMI adjusted hazard ratio [HR] = 1.31; 95% CI [0.86, 1.99]; UA vs. NSTEMI adjusted HR = 1.03; 95% CI [0.73, 1.47]), despite better 2-year survival (UA vs. STEMI adjusted HR = 0.51; 95% confidence interval (CI) [0.28, 0.95]; UA vs. NSTEMI adjusted HR = 0.40; 95% CI [0.24, 0.65]).

Conclusion

Although UA patients have better survival rates, they have similar or worse one-year health status outcomes and cardiac rehospitalization rates as compared with MI patients. Clinicians should be aware of the adverse health status outcome risks for UA patients and consider close monitoring for the opportunity to improve their health status and minimize the need for subsequent rehospitalization.     

Ambulatory ECG-based T-wave alternans and heart rate turbulence can predict cardiac mortality in patients with myocardial infarction with or without diabetes mellitus

ABSTRACT: BACKGROUND: Many patients who survive a myocardial infarction (MI) remain at risk of sudden cardiac death despite revascularization and optimal medical treatment. We used the modified moving average (MMA) method to assess the utility of T-wave alternans (TWA) and heart rate turbulence (HRT) as risk markers in MI patients with or without diabetes mellitus (DM). METHODS: We prospectively enrolled 248 consecutive patients: 96 with MI (post-MI patients); 77 MI with DM (post-MI + DM patients); 75 controls without cardiovascular disease (group control). Both TWA and HRT were measured on ambulatory electrocardiograms (AECGs). HRT was assessed by two parameters [BOX DRAWINGS LIGHT HORIZONTAL] turbulence onset (TO) and turbulence slope (TS). HRT was considered positive when both TO [GREATER-THAN OR EQUAL TO]0% and TS [LESS-THAN OR EQUAL TO]2.5 ms/R-R interval were met. The endpoint was cardiac mortality. RESULTS: TWA values differed significantly between MI and controls. Post-MI + DM patients had higher TWA values than post-MI patients (58 [PLUS-MINUS SIGN] 21 muV VS 52 [PLUS-MINUS SIGN] 18 muV, P = 0.029). Impaired HRT--increased TO and decreased TS were observed in MI patients with or without DM. During follow-up of 578 [PLUS-MINUS SIGN] 146 days, cardiac death occurred in ten patients and three of them suffered sudden cardiac death (SCD). Multivariate analysis determined that a HRT-positive outcome [HR (95% CI): 5.01, 1.33--18.85; P = 0.017], as well as the combination of abnormal TWA ([GREATER-THAN OR EQUAL TO]47 muV) and positive HRT had significant association with the endpoint [HR (95% CI): 9.08, 2.21--37.2; P = 0.002)]. CONCLUSION: This study indicates that AECGs-based TWA and HRT can predict cardiac mortality in MI patients with or without DM. Combined analysis TWA and HRT may be a convenient and useful method of identifying patients at high risk for cardiovascular death.     

Reduced stroke volume during exercise in postural tachycardia syndrome.

Postural tachycardia syndrome (POTS) is characterized by excessive tachycardia without hypotension during orthostasis. Most POTS patients also report exercise intolerance. To assess cardiovascular regulation during exercise in POTS, patients (n = 13) and healthy controls (n = 10) performed graded cycle exercise at 25, 50, and 75 W in both supine and upright positions while arterial pressure (arterial catheter), heart rate (HR; measured by ECG), and cardiac output (open-circuit acetylene breathing) were measured. In both positions, mean arterial pressure, cardiac output, and total peripheral resistance at rest and during exercise were similar in patients and controls (P > 0.05). However, supine stroke volume (SV) tended to be lower in the patients than controls at rest (99 +/- 5 vs. 110 +/- 9 ml) and during 75-W exercise (97 +/- 5 vs. 111 +/- 7 ml) (P = 0.07), and HR was higher in the patients than controls at rest (76 +/- 3 vs. 62 +/- 4 beats/min) and during 75-W exercise (127 +/- 3 vs. 114 +/- 5 beats/min) (both P < 0.01). Upright SV was significantly lower in the patients than controls at rest (57 +/- 3 vs. 81 +/- 6 ml) and during 75-W exercise (70 +/- 4 vs. 94 +/- 6 ml) (both P < 0.01), and HR was much higher in the patients than controls at rest (103 +/- 3 vs. 81 +/- 4 beats/min) and during 75-W exercise (164 +/- 3 vs. 131 +/- 7 beats/min) (both P < 0.001). The change (upright - supine) in SV was inversely correlated with the change in HR for all participants at rest (R(2) = 0.32), at 25 W (R(2) = 0.49), 50 W (R(2) = 0.60), and 75 W (R(2) = 0.32) (P < 0.01). These results suggest that greater elevation in HR in POTS patients during exercise, especially while upright, was secondary to reduced SV and associated with exercise intolerance.     

Noninvasive Doppler-derived myocardial performance index in rats with myocardial infarction: validation and correlation by conductance catheter

The rodent model of myocardial infarction (MI) is extensively used in heart failure studies. However, long-term follow-up of echocardiographic left ventricular (LV) function parameters such as the myocardial performance index (MPI) and its ratio with the fractional shortening (LVFS/MPI) has not been validated in conjunction with invasive indexes, such as those derived from the conductance catheter (CC). Sprague-Dawley rats with left anterior descending coronary artery ligation (MI group, n = 9) were compared with a sham-operated control group (n = 10) without MI. Transthoracic echocardiography (TTE) was performed every 2 wk over an 8-wk period, after which classic TTE parameters, especially MPI and LVFS/MPI, were compared with invasive indexes obtained by using a CC. Serial TTE data showed significant alterations in the majority of the noninvasive functional and structural parameters (classic and novel) studied in the presence of MI. Both MPI and LVFS/MPI significantly (P < 0.05 for all reported values) correlated with body weight (r = -0.58 and 0.76 for MPI and LVFS/MPI, respectively), preload recruitable stroke work (r = -0.61 and 0.63), LV end-diastolic pressure (LVEDP) (r = 0.82 and -0.80), end-diastolic volume (r = 0.61 and -0.58), and end-systolic volume (r = 0.46 and -0.48). Forward stepwise linear regression analysis revealed that, of all variables tested, LVEDP was the only independent determinant of MPI (r = 0.84) and LVFS/MPI (r = 0.83). We conclude that MPI and LVFS/MPI correlate strongly and better than the classic noninvasive TTE parameters with established, invasively assessed indexes of contractility, preload, and volumetry. These findings support the use of these two new noninvasive indexes for long-term analysis of the post-MI LV remodeling.     

Validation of the wall motion score and myocardial performance indexes as novel techniques to assess cardiac function in mice after myocardial infarction

The aim of this study was to determine the feasibility and accuracy of wall motion score index (WMSI) and myocardial performance index (MPI) for measuring regional and global left ventricular (LV) function with use of high-resolution echocardiography after myocardial infarction (MI) in mice. In 48 mice, myocardial infarction was induced by ligation in the middle of the left anterior descending coronary artery. Echocardiography was performed under anesthesia at baseline and 1 mo after MI. WMSI was analyzed by a 16-segment model on short-axis views, and wall motion was scored as 1 for normal, 2 for hypokinetic, 3 for akinetic, 4 for dyskinetic, and 5 for aneurysmal. WMSI was calculated as the sum of scores divided by the total number of segments. MPI was calculated on the basis of isovolumetric contraction time (IVCT), isovolumetric relaxation time (IVRT), and ejection time (ET): MPI = (IVCT + IVRT)/ET. We measured LV ejection fraction (LVEF), end-systolic and end-diastolic volumes (ESV and EDV), fractional shortening (FS), and infarct size (IS). LVEF at 4 wk after MI was reduced at 32.8 +/- 9.0%. Linear correlation analyses showed that WMSI (1.6 +/- 0.3) correlated with LVEF (r = -0.84, P < 0.0005), FS (r = -0.43, P = 0.003), and IS (34.3 +/- 15.3%, r = 0.86, P < 0.0005). MPI (0.67 +/- 0.09) correlated with LVEF (r = -0.67, P < 0.0005) and IS (r = 0.72, P < 0.0005). MPI also correlated with mitral inflow velocity (r = -0.68, P < 0.0005) and deceleration time (r = -0.42, P = 0.003). Stepwise regression analysis revealed that WMSI was independently associated with IS. IS, FS, mitral inflow velocity, and deceleration time were independent determinants of MPI. In conclusion, echocardiographic assessments of WMSI and MPI in mice are feasible and correlate strongly with two-dimensional measurement of LV function and IS. These novel parameters provide additional noninvasive assessment of regional and global LV function in mice after MI.     

Pharmacogenetic Risk Stratification in Angiotensin-Converting Enzyme Inhibitor-Treated Patients with Congestive Heart Failure: A Retrospective Cohort Study

Background

Evidence for pharmacogenetic risk stratification of angiotensin-converting enzyme inhibitor (ACEI) treatment is limited. Therefore, in a cohort of ACEI-treated patients with congestive heart failure (CHF), we investigated the predictive value of two pharmacogenetic scores that previously were found to predict ACEI efficacy in patients with ischemic heart disease and hypertension, respectively. Score A combined single nucleotide polymorphisms (SNPs) of the angiotensin II receptor type 1 gene (rs275651 and rs5182) and the bradykinin receptor B1 gene (rs12050217). Score B combined SNPs of the angiotensin-converting enzyme gene (rs4343) and ABO blood group genes (rs495828 and rs8176746).

Methods

Danish patients with CHF enrolled in the previously reported Echocardiography and Heart Outcome Study were included. Subjects were genotyped and categorized according to pharmacogenetic scores A and B of ≤1, 2 and ≥3 each, and followed for up to 10 years. Difference in cumulative incidences of cardiovascular death and all-cause death were assessed by the cumulative incidence estimator. Survival was modeled by Cox proportional hazard analyses.

Results

We included 667 patients, of whom 80% were treated with ACEIs. Differences in cumulative incidences of cardiovascular death (P = 0.346 and P = 0.486) and all-cause death (P = 0.515 and P = 0.486) were not significant for score A and B, respectively. There was no difference in risk of cardiovascular death or all-cause death between subjects with score A ≤1 vs. 2 (HR 1.03 [95% CI 0.79–1.34] and HR 1.11 [95% CI 0.88–1.42]), score A ≤1 vs. ≥3 (HR 0.80 [95% CI 0.59–1.08] and HR 0.91 [95% CI 0.70–1.20]), score B ≤1 vs. 2 (HR 1.02 [95% CI 0.78–1.32] and HR 0.98 [95% CI 0.77–1.24]), and score B ≤1 vs. ≥3 (HR 1.03 [95% CI 0.75–1.41] and HR 1.05 [95% CI 0.79–1.40]), respectively.

Conclusions

We found no association between either of the analyzed pharmacogenetic scores and fatal outcomes in ACEI-treated patients with CHF.     

A new technique for assessing arterial pressure wave forms and central pressure with tissue Doppler

Background

Arterial diameters enlarge in response to wall thickening, plaques, and many atherosclerotic risk factors. We hypothesized that right common carotid artery (RCCA) diameter would be independently associated with cardiac disease and improve risk discrimination.

Methods

In a middle-aged, biracial population (baseline n = 11225), we examined associations between 1 standard deviation increments of baseline RCCA diameter with prevalent myocardial infarction (MI) and incident cardiac events (MI or cardiac death) using logistic regression and Cox proportional hazards models, respectively. Areas under the receiver operator characteristic curve (AUC) were used to estimate model discrimination.

Results

MI was present in 451 (4%) participants at baseline (1987–89), and incident cardiac events occurred among 646 (6%) others through 1999. Adjusting for IMT, RCCA diameter was associated with prevalent MI (female OR = 2.0, 95%CI = 1.61–2.49; male OR = 1.16, 95% CI = 1.04–1.30) and incident cardiac events (female HR = 1.75, 95% CI = 1.51–2.02; male HR = 1.27, 95% CI = 1.15–1.40). Associations were attenuated but persisted after adjustment for risk factors (not including IMT) (prevalent MI: female OR = 1.73, 95% CI = 1.40–2.14; male OR = 1.14, 95% CI = 1.02–1.28, and incident cardiac events: female HR = 1.26, 95% CI = 1.08–1.48; male HR = 1.19, 95% CI = 1.08–1.32). After additional adjustment for IMT, diameter was associated with incident cardiac events in women (HR = 1.18, 95% CI = 1.00–1.40) and men (HR = 1.17, 95% CI = 1.06–1.29), and with prevalent MI only in women (OR = 1.73; 95% CI = 1.37–2.17). In women, when adjustment was limited, diameter models had larger AUC than other models.

Conclusion

RCCA diameter is an important correlate of cardiac events, independent of IMT, but adds little to overall risk discrimination after risk factor adjustment.     

Heart rate reduction with ivabradine prevents the global phenotype of left ventricular remodeling

The aim of this study was to investigate the effect of chronic heart rate (HR) reduction with the hyperpolarization-activated current inhibitor ivabradine on the global phenotype of left ventricular (LV) remodeling in a ligated rat model. Seven days after coronary artery ligation, Wistar rats received ivabradine (10 mg · kg(-1) · day(-1) administered in drinking water) [myocardial infarction + ivabradine (MI+IVA), n = 22] or vehicle only (drinking water) (MI, n = 20) for 90 days. A sham group (n = 20) was included for model validation. MI+IVA rats had 12% lower HR (P < 0.01), improved LV volumes, 15% higher LV ejection fraction (LVEF, P < 0.01) than MI rats, and 33% reductions in both plasma atrial natriuretic peptide (ANP, P = 0.052) and cardiac hydroxyproline. Using patch-clamp, action potential duration was reduced and transient outward current density increased (P < 0.05). Cardiac energy metabolism was also improved (+33% creatine phosphate, P < 0.001; +15% ATP; and +9% energy charge, P < 0.05). Significant correlations were found between HR and parameters of cardiac metabolism, ANP, and LVEF (all P < 0.05). The HR-reducing properties of ivabradine prevent changes in the global phenotype of LV remodeling in the rat, optimize energy consumption, and avoid electrophysiological and structural remodeling.     

心电图左心室劳损和左心室肥厚对主动脉瓣狭窄患者预后的影响

目的:探讨心电图左心室劳损(LV)和左心室肥厚(LVH)对无症状主动脉瓣狭窄患者预后的影响。方法:到我院治疗的主动脉瓣狭窄患者766例,心电图左心室劳损和左心室肥厚的预测值用Sokolow-Lyon(SL)电压标准和Cornell电压-时间(CVDP)标准评估,通过对其他预后协变量调整并进行评价。结果:心电图左心室劳损患者的心肌梗死的累计发生率显著高于非心电图劳损的患者(HR=2.7,95%CI:1.4-5.3,P=0.006)。与非心电图左心室肥厚的患者比较,SL标准与CVDP标准联用诊断的左心室肥厚患者心力衰竭的风险显著增加(95%CI:4.7-26.4,P0.001);行主动脉瓣置换术风险显著增加(95%CI:1.6-3.2,P0.001);非致死性梗死、心力衰竭或心血管死亡的复合终点风险也显著增加(95%CI:1.2-3.7,P0.05)。结论:心电图LV和LVH是无症状主动脉瓣狭窄患者预后不良的独立预测因子。     

Parental mortality rates in a western country after the death of a child: assessment of the role of the child's sex

Background: Loss of a child has been associated with elevated mortality rates in parents. Studies that focus on the influence of the child's sex on parental mortality are sparse.Objective: The main objective of the present study was to reevaluate the combined impact of the parents' and child's sex within a larger sample and focus on adverse health effects as an objective measure of possible long-term effects of maladaptive grief reactions.Methods: For the time period between 1980 and 1996, all children in Denmark who died before 18 years of age were identified. Parents who had lost a child were identified as the bereaved (exposed) group. Mortality rates of parents within the same-sex parent-child dyad were compared with mortality rates of parents within the opposite-sex parent-child dyad. Separate analyses were performed for bereaved fathers and for bereaved mothers, and additional analyses were conducted to examine the sole effect of the child's sex, irrespective of parental gender. A Cox proportional hazards regression model was used to estimate the hazard ratios (HRs) with 95% CIs.Results: The study population consisted of 21,062 parents (mean age at entry, 32 years; 11,221 mothers, 9841 fathers). Bereaved parents who had lost a child of the same sex had similar overall mortality as bereaved parents who had lost a child of the opposite sex (HR = 1.02; 95% CI, 0.85–1.22). Similar findings were observed for mortality due to natural death (HR = 0.96; 95% CI, 0.78–1.18) or mortality due to unnatural death (HR = 1.22; 95% CI, 0.84–1.77). Bereaved fathers who had lost a son had similar mortality as those bereaved by the death of a daughter (HR = 1.10; 95% CI, 0.86–1.40). Bereaved mothers who had lost a daughter had similar mortality as those bereaved by the death of a son (HR = 0.93; 95% CI, 0.70–1.22). Bereaved parents who had lost a son had mortality rates similar to those who had lost a daughter (HR = 1.09; 95% CI, 0.91–1.31). The interactions between grouping variable and sex of parents were not significant, indicating that the differential effect of losing a child based on sex of the child was not greater for fathers than for mothers.Conclusions: The results of this study revealed no significant effect of sex of the deceased child on mortality in these bereaved parents. The results might differ if this study was replicated in a population with a different grief culture and, more importantly, different gender schemas.     

Cause-Specific Cardiovascular Risk Associated with Nonsteroidal Anti-Inflammatory Drugs among Myocardial Infarction Patients - A Nationwide Study

Background

Non steroidal anti-inflammatory drugs (NSAIDs) increase mortality and morbidity after myocardial infarction (MI). We examined cause-specific mortality and morbidity associated with NSAIDs in a nationwide cohort of MI patients.

Methods and Results

By individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark, patients aged >30 years admitted with first-time MI during 1997–2009 and their subsequent NSAID use were identified. The risk of three cardiovascular specific endpoints: cardiovascular death, the composite of coronary death and nonfatal MI, and the composite of fatal and nonfatal stroke, associated with NSAID use was analyzed by Cox proportional hazard analyses. Of 97,698 patients included 44.0% received NSAIDs during follow-up. Overall use of NSAIDs was associated with an increased risk of cardiovascular death (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.36–1.49). In particular use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with increased risk of cardiovascular death (HR 1.96 [1.79–2.15] and HR1.66 [1.44–1.91], respectively) with a dose dependent increase in risk. Use of ibuprofen was associated with increased risk of cardiovascular death (HR 1.34[1.26–1.44]), whereas naproxen was associated with the lowest risk of (e.g., HR 1.27[1.01–1.59].

Conclusion

Use of individual NSAIDs is associated with different cause-specific cardiovascular risk and in particular rofecoxib and diclofenac were associated with increased cardiovascular morbidity and mortality. These results support caution with use of all NSAIDs in patients with prior MI.     

Vascular Disease and Risk Stratification for Ischemic Stroke and All-Cause Death in Heart Failure Patients without Diagnosed Atrial Fibrillation: A Nationwide Cohort Study

Background

Stroke and mortality risk among heart failure patients previously diagnosed with different manifestations of vascular disease is poorly described. We conducted an observational study to evaluate the stroke and mortality risk among heart failure patients without diagnosed atrial fibrillation and with peripheral artery disease (PAD) or prior myocardial infarction (MI).

Methods

Population-based cohort study of patients diagnosed with incident heart failure during 2000–2012 and without atrial fibrillation, identified by record linkage between nationwide registries in Denmark. Hazard rate ratios of ischemic stroke and all-cause death after 1 year of follow-up were used to compare patients with either: a PAD diagnosis; a prior MI diagnosis; or no vascular disease.

Results

39,357 heart failure patients were included. When compared to heart failure patients with no vascular disease, PAD was associated with a higher 1-year rate of ischemic stroke (adjusted hazard rate ratio [HR]: 1.34, 95% confidence interval [CI]: 1.08–1.65) and all-cause death (adjusted HR: 1.47, 95% CI: 1.35–1.59), whereas prior MI was not (adjusted HR: 1.00, 95% CI: 0.86–1.15 and 0.94, 95% CI: 0.89–1.00, for ischemic stroke and all-cause death, respectively). When comparing patients with PAD to patients with prior MI, PAD was associated with a higher rate of both outcomes.

Conclusions

Among incident heart failure patients without diagnosed atrial fibrillation, a previous diagnosis of PAD was associated with a significantly higher rate of the ischemic stroke and all-cause death compared to patients with no vascular disease or prior MI. Prevention strategies may be particularly relevant among HF patients with PAD.     

Hydrogen sulfide and its possible roles in myocardial ischemia in experimental rats.

The role of hydrogen sulfide (H(2)S) in myocardial infarction (MI) has not been previously studied. We therefore investigated the effect of H(2)S in a rat model of MI in vivo. Animals were randomly divided into three groups (n = 80) and received either vehicle, 14 micromol/kg of sodium hydrosulfide (NaHS), or 50 mg/kg propargylglycine (PAG) everyday for 1 wk before surgery, and the treatment was continued for a further 2 days after MI when the animals were killed. The mortality was 35% in vehicle-treated, 40% in PAG-treated, and 27.5% in NaHS-treated (P < 0.05 vs. vehicle) groups. Infarct size was 52.9 +/- 3.5% in vehicle-treated, 62.9 +/- 7.6% in PAG-treated, and 43.4 +/- 2.8% in NaHS-treated (P < 0.05 vs. vehicle) groups. Plasma H(2)S concentration was significantly increased after MI (59.2 +/- 7.16 microM) compared with the baseline concentration (i.e., 38.2 +/- 2.07 microM before MI; P < 0.05). Elevated plasma H(2)S after MI was abolished by treatment of animals with PAG (39.2 +/- 5.02 microM). We further showed for the first time cystathionine-gamma-lyase protein localization in the myocardium of the infarct area by using immunohistochemical staining. In the hypoxic vascular smooth muscle cells, we found that cell death was increased under the stimuli of hypoxia but that the increased cell death was attenuated by the pretreatment of NaHS (71 +/- 1.2% cell viability in hypoxic vehicle vs. 95 +/- 2.3% in nonhypoxic control; P < 0.05). In conclusion, endogenous H(2)S was cardioprotective in the rat model of MI. PAG reduced endogenous H(2)S production after MI by inhibiting cystathionine-gamma-lyase. The results suggest that H(2)S might provide a novel approach to the treatment of MI.     

Similar Cardiovascular Outcomes Between Insulin Detemir and Insulin Glargine In Type 2 Diabetic Patients With Extremely Atherosclerotic Cardiovascular Disease Risks

Objective: The cardiovascular outcomes of insulin detemir in patients with type 2 diabetes mellitus (T2DM) after acute coronary syndrome (ACS) or acute ischemic stroke (AIS) are unclear. The aim of our real-life cohort study was to evaluate the cardiovascular outcomes of insulin detemir (IDet) versus insulin glargine (IGlar) in T2DM patients after ACS or AIS.Methods: A retrospective cohort study was conducted between June 1, 2005, and December 31, 2013, utilizing the Taiwan National Health Insurance Research Database. A total of 3,129 ACS or AIS patients were eligible for the analysis. Clinical outcomes were evaluated by comparing 1,043 subjects receiving IDet with 2,086 propensity score-matched subjects who received IGlar. The primary composite outcome included cardiovascular (CV) death, nonfatal myocardial infarction (MI) and nonfatal stroke.Results: The primary composite outcome occurred in 322 patients (30.9%) in the IDet group and 604 patients (29.0%) in the IGlar group (hazard ratio [HR], 1.12; 95% confidence interval [CI], 0.95 to 1.32) with a mean follow-up of 2.4 years. No significant differences were observed for CV death (HR, 1.09; 95% CI, 0.86 to 1.38), nonfatal MI (HR, 0.88; 95% CI, 0.66 to 1.19), and nonfatal stroke (HR, 1.15; 95% CI, 0.97 to 1.35). There were similar risks of all-cause mortality, hospitalization for heart failure and revascularization between the IDet group and the IGlar group (P = .647, .115, and .390 respectively).Conclusion: Compared with IGlar, in T2DM patients after ACS or AIS, IDet was not associated with increased risks of CV death, nonfatal MI, or nonfatal stroke.Abbreviations: ACS = acute coronary syndrome; AIS = acute ischemic stroke; ASCVD = atherosclerotic cardiovascular disease; CI = confidence interval; CV = cardiovascular; DKA = diabetic ketoacidosis; HHF = hospitalization for heart failure; HHS = hyperosmolar hyperglycemic state; HR = hazard ratio; IDet = insulin detemir; IGlar = insulin glargine; MI = myocardial infarction; NHIRD = National Health Insurance Research Database; PCI = percutaneous coronary intervention; PSM = propensity score matching; T2DM = type 2 diabetes mellitus     

影响复杂性Stanford B型主动脉夹层院内死亡的危险因素分析

目的:探讨复杂性Stanford B型主动脉夹层患者院内死亡的危险因素。方法:回顾性分析2010年1月至2015年6月急诊收治入院的98例复杂性Stanford B型主动脉夹层患者的住院病例资料,对可能影响复杂Stanford B型主动脉夹层院内死亡的15项临床病理因素:患者年龄、性别、治疗方式、发病至就诊时间、既往是否有高血压病史、就诊时收缩压、入院时是否合并肺部感染、慢性肾功能不全、既往结缔组织病、主动脉扩张、急性肾损伤、心包积液、胸腔积液、腹腔积液、心肌灌注、肠系膜动脉灌注、下肢灌注,进行单因素和多因素回归分析。结果:单因素分析结果显示:患者年龄、就诊时收缩压、治疗方式、急性肾损伤、心肌灌注不良、心包积液、主动脉扩张、下肢灌注不良与院内死亡有关(P0.1)。经COX多因素回归分析结果显示:TEVAR治疗(HR=8.437CI 1.048-67.925 P=0.045),心包积液(HR=4.010 CI 1.675-9.598 P=0.002),下肢灌注不良(HR=3.133 CI 1.083-9.064 P=0.035)与院内死亡有关(P0.05)。结论:心包积液及下肢灌注不良可使复杂性Stanford B型主动脉夹层患者院内死亡率增加,而TEVAR可有效改善患者早期预后。     

Multivessel versus Single Vessel Angioplasty in Non-ST Elevation Acute Coronary Syndromes: A Systematic Review and Metaanalysis

Background

Multivessel disease is common in acute coronary syndrome patients. However, if multivessel percutaneous coronary intervention is superior to culprit-vessel angioplasty has not been systematically addressed.

Methods

A metaanalysis was conducted including studies that compared multivessel angioplasty with culprit-vessel angioplasty among non-ST elevation ACS patients. Since all studies were observational adjusted estimates of effects were used. Pooled estimates of effects were computed using the generic inverse of variance with a random effects model.

Results

Twelve studies were included (n = 117,685). Median age was 64.1 years, most patients were male, 29.3% were diabetic and 36,9% had previous myocardial infarction. Median follow-up was 12 months. There were no significant differences in mortality risk (HR 0.79; 95% CI 0.58 to 1.09; I² 67.9%), with moderate inconsistency. Also, there were no significant differences in the risk of death or MI (HR 0.90; 95% CI 0.69 to 1.17; I² 62.3%), revascularization (HR 0.76; 95% CI 0.55 to 1.05; I² 49.9%) or in the combined incidence of death, myocardial infarction or revascularization (HR 0.83; 95% CI 0.66 to 1.03; I² 70.8%). All analyses exhibited a moderate degree of inconsistency. Subgroup analyses by design reduced the inconsistency of the analyses on death or myocardial infarction, revascularization and death, myocardial infarction or revascularization. There was evidence of publication bias (Egger’s test p = 0.097).

Conclusion

Routine multivessel angioplasty in non-ST elevation acute coronary syndrome patients with multivessel disease was not superior to culprit-vessel angioplasty. Randomized controlled trials comparing safety and effectiveness of both strategies in this setting are needed.     

Effects of exercise and passive head-up tilt on fractal and complexity properties of heart rate dynamics

tk;1Passive head-up tilt and exercise result in specific changes in the spectral characteristics of heart rate (HR) variability as a result of reduced vagal and enhanced sympathetic outflow. Recently analytic methods based on nonlinear system theory have been developed to characterize the nonlinear features in HR dynamics. This study was designed to assess the changes in the fractal and complexity measures of HR behavior during the passive head-up tilt and during exercise. Fractal exponent (alpha(1)) and approximate entropy (ApEn), measures of short-term correlation properties and overall complexity of HR, respectively, along with spectral components of HR variability were analyzed during a passive head-up tilt test (n = 10) and a low-intensity steady-state exercise (n = 20) in healthy subjects. We observed that alpha(1) increased during the tilt test (from 0.85 +/- 0.22 to 1.48 +/- 0.20; P < 0.001) and during the exercise (from 1.00 +/- 0.22 to 1.37 +/- 0. 14; P < 0.001). ApEn also increased during the exercise (from 1.04 +/- 0.11 to 1. 11 +/- 0.08; P < 0.05), but it did not change during the tilt test. The normalized high-frequency spectral component decreased and the low-frequency component increased similarly during both the exercise and the tilt test (P < 0.001 for all). Exercise and passive tilt result in an increase of short-term fractal correlation properties of HR dynamics, which is related to changes in the balance between the low- and high-frequency oscillations in controlled situations. Overall complexity of HR dynamics increases during exercise but not during passive tilt.