Identification and outcomes of KDIGO-defined chronic kidney disease in 1.4 million U.S. Veterans with heart failure.

AIMS: According to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline, the definition of chronic kidney disease (CKD) requires the presence of abnormal kidney structure or function for >3 months with implications for health. CKD in patients with heart failure (HF) has not been defined using this definition, and less is known about the true health implications of CKD in these patients. The objective of the current study was to identify patients with HF who met KDIGO criteria for CKD and examine their outcomes. METHODS AND RESULTS: Of the 1 419 729 Veterans with HF not receiving kidney replacement therapy, 828 744 had data on ≥2 ambulatory serum creatinine >90 days apart. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 (n = 185 821) or urinary albumin-to-creatinine ratio (uACR) >30 mg/g (n = 32 730) present twice >3 months apart. Normal kidney function (NKF) was defined as eGFR ≥60 ml/min/1.73 m2, present for >3 months, without any uACR >30 mg/g (n = 365 963). Patients with eGFR <60 ml/min/1.73 m2 were categorized into four stages: 45-59 (n = 72 606), 30-44 (n = 74 812), 15-29 (n = 32 077), and <15 (n = 6326) ml/min/1.73 m2. Five-year all-cause mortality occurred in 40.4%, 57.8%, 65.6%, 73.3%, 69.7%, and 47.5% of patients with NKF, four eGFR stages, and uACR >30mg/g (albuminuria), respectively. Compared with NKF, hazard ratios (HR) (95% confidence intervals [CI]) for all-cause mortality associated with the four eGFR stages and albuminuria were 1.63 (1.62-1.65), 2.00 (1.98-2.02), 2.49 (2.45-2.52), 2.28 (2.21-2.35), and 1.22 (1.20-1.24), respectively. Respective age-adjusted HRs (95% CIs) were 1.13 (1.12-1.14), 1.36 (1.34-1.37), 1.87 (1.84-1.89), 2.24 (2.18-2.31) and 1.19 (1.17-1.21), and multivariable-adjusted HRs (95% CIs) were 1.11 (1.10-1.12), 1.24 (1.22-1.25), 1.46 (1.43-1.48), 1.42 (1.38-1.47), and 1.13 (1.11-1.16). Similar patterns were observed for associations with hospitalizations. CONCLUSION: Data needed to define CKD using KDIGO criteria were available in six out of ten patients, and CKD could be defined in seven out of ten patients with data. HF patients with KDIGO-defined CKD had higher risks for poor outcomes, most of which was not explained by abnormal kidney structure or function. Future studies need to examine whether CKD defined using a single eGFR is characteristically and prognostically different from CKD defined using KDIGO criteria.

Barriers and Facilitators Associated With Remote Monitoring Adherence Among Veterans With Pacemakers and Implantable Cardioverter-Defibrillators: Qualitative Cross-Sectional Study.

BACKGROUND: The Heart Rhythm Society strongly recommends remote monitoring (RM) of cardiovascular implantable electronic devices (CIEDs) because of the clinical outcome benefits to patients. However, many patients do not adhere to RM and, thus, do not achieve these benefits. There has been limited study of patient-level barriers and facilitators to RM adherence; understanding patient perspectives is essential to developing solutions to improve adherence. OBJECTIVE: We sought to identify barriers and facilitators associated with adherence to RM among veterans with CIEDs followed by the Veterans Health Administration. METHODS: We interviewed 40 veterans with CIEDs regarding their experiences with RM. Veterans were stratified into 3 groups based on their adherence to scheduled RM transmissions over the past 2 years: 6 fully adherent (≥95%), 25 partially adherent (≥65% but <95%), and 9 nonadherent (<65%). As the focus was to understand challenges with RM adherence, partially adherent and nonadherent veterans were preferentially weighted for selection. Veterans were mailed a letter stating they would be called to understand their experiences and perspectives of RM and possible barriers, and then contacted beginning 1 week after the letter was mailed. Interviews were structured (some questions allowing for open-ended responses to dive deeper into themes) and focused on 4 predetermined domains: knowledge of RM, satisfaction with RM, reasons for nonadherence, and preferences for health care engagement. RESULTS: Of the 44 veterans contacted, 40 (91%) agreed to participate. The mean veteran age was 75.3 (SD 7.6) years, and 98% (39/40) were men. Veterans had been implanted with their current CIED for an average of 4.4 (SD 2.8) years. A total of 58% (23/40) of veterans recalled a discussion of home monitoring, and 45% (18/40) reported a good understanding of RM; however, when asked to describe RM, their understanding was sometimes incomplete or not correct. Among the 31 fully or partially adherent veterans, nearly all were satisfied with RM. Approximately one-third recalled ever being told the results of a remote transmission. Among partially or nonadherent veterans, only one-fourth reported being contacted by a Department of Veterans Affairs health care professional regarding not having sent a remote transmission; among those who had troubleshooted to ensure they could send remote transmissions, they often relied on the CIED manufacturer for help (this experience was nearly always positive). Most nonadherent veterans felt more comfortable engaging in RM if they received more information or education. Most veterans were interested in being notified of a successful remote transmission and learning the results of their remote transmissions. CONCLUSIONS: Veterans with CIEDs often had limited knowledge about RM and did not recall being contacted about nonadherence. When they were contacted and troubleshooted, the experience was positive. These findings provide opportunities to optimize strategies for educating and engaging patients in RM.

Changes in Cardiorespiratory Fitness and Survival in Patients With or Without Cardiovascular Disease.

BACKGROUND: The association between cardiorespiratory fitness (CRF) and mortality risk is based mostly on 1 CRF assessment. The impact of CRF change on mortality risk is not well-defined. OBJECTIVES: This study sought to evaluate changes in CRF and all-cause mortality. METHODS: We assessed 93,060 participants aged 30-95 years (mean 61.3 ± 9.8 years). All completed 2 symptom-limited exercise treadmill tests, 1 or more years apart (mean 5.8 ± 3.7 years) with no evidence of overt cardiovascular disease. Participants were assigned to age-specific fitness quartiles based on peak METS achieved on the baseline exercise treadmill test. Additionally, each CRF quartile was stratified based on CRF changes (increase, decrease, no change) observed on the final exercise treadmill test. Multivariable Cox models were used to estimate HRs and 95% CIs for all-cause mortality. RESULTS: During a median follow-up of 6.3 years (IQR: 3.7-9.9 years), 18,302 participants died with an average yearly mortality rate of 27.6 events per 1,000 person-years. In general, changes in CRF ≥1.0 MET were associated with inverse and proportionate changes in mortality risk regardless of baseline CRF status. For example, a decline in CRF of >2.0 METS was associated with a 74% increase in risk (HR: 1.74; 95% CI: 1.59-1.91) for low-fit individuals with CVD, and 69% increase (HR: 1.69; 95% CI: 1.45-1.96) for those without CVD. CONCLUSIONS: Changes in CRF reflected inverse and proportional changes in mortality risk for those with and without CVD. The impact of relatively small CRF changes on mortality risk has considerable clinical and public health significance.

Imaging modality for left ventricular ejection fraction estimation and effect of implantable cardioverter-defibrillator on mortality in patients with heart failure.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) improve outcomes in patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≤35%. Less is known about whether outcomes varied between the 2 noninvasive imaging modalities used to estimate LVEF-2-dimensional echocardiography (2DE) and multigated acquisition radionuclide ventriculography (MUGA)-which use different principles (geometric vs count-based, respectively). OBJECTIVE: The purpose of this study was to examine whether the effect of ICD on mortality in patients with HF and LVEF ≤35% varied on the basis of LVEF measured by 2DE or MUGA. METHODS: Of the 2521 patients with HF with LVEF ≤35% in the Sudden Cardiac Death in Heart Failure Trial, 1676 (66%) were randomized to either placebo or ICD, of whom 1386 (83%) had LVEF measured by 2DE (n = 971) or MUGA (n = 415). Hazard ratios (HRs) and 97.5% confidence intervals (CIs) for mortality associated with ICD were estimated overall, checking for interaction, and within the 2 imaging subgroups. RESULTS: Of the 1386 patients in the present analysis, all-cause mortality occurred in 23.1% (160 of 692) and 29.7% (206 of 694) of patients randomized to ICD or placebo, respectively (HR 0.77; 97.5% CI 0.61-0.97), which is consistent with that in 1676 patients in the original report. HRs (97.5% CIs) for all-cause mortality in the 2DE and MUGA subgroups were 0.79 (0.60-1.04) and 0.72 (0.46-1.11), respectively (P = .693 for interaction). Similar associations were observed for cardiac and arrhythmic mortalities. CONCLUSION: We found no evidence that in patients with HF and LVEF ≤35%, the effect of ICD on mortality varied by the noninvasive imaging method used to measure LVEF.

Hydroxychloroquine and Risk of Long QT Syndrome in Rheumatoid Arthritis: A Veterans Cohort Study With Nineteen-Year Follow-up.

OBJECTIVE: Recent evidence suggests that hydroxychloroquine use is not associated with higher 1-year risk of long QT syndrome (LQTS) in patients with rheumatoid arthritis (RA). Less is known about its long-term risk, the examination of which was the objective of this study. METHODS: We conducted a propensity score-matched active-comparator safety study of hydroxychloroquine in 8,852 veterans (mean age 64 ± 12 years, 14% women, 28% Black) with newly diagnosed RA. A total of 4,426 patients started on hydroxychloroquine and 4,426 started on another nonbiologic disease-modifying antirheumatic drug (DMARD) and were balanced on 87 baseline characteristics. The primary outcome was LQTS during 19-year follow-up through December 31, 2019. RESULTS: Incident LQTS occurred in 4 (0.09%) and 5 (0.11%) patients in the hydroxychloroquine and other DMARD groups, respectively, during the first 2 years. Respective 5-year incidences were 17 (0.38%) and 6 (0.14%), representing 11 additional LQTS events in the hydroxychloroquine group (number needed to harm 403; [95% confidence interval (95% CI)], 217-1,740) and a 181% greater relative risk (95% CI 11%-613%; P = 0.030). Although overall 10-year risk remained significant (hazard ratio 2.17; 95% CI 1.13-4.18), only 5 extra LQTS occurred in hydroxychloroquine group over the next 5 years (years 6-10) and 1 over the next 9 years (years 11-19). There was no association with arrhythmia-related hospitalization or all-cause mortality. CONCLUSIONS: Hydroxychloroquine use had no association with LQTS during the first 2 years after initiation of therapy. There was a higher risk thereafter that became significant after 5 years of therapy. However, the 5-year absolute risk was very low, and the absolute risk difference was even lower. Both risks attenuated during longer follow-up. These findings provide evidence for long-term safety of hydroxychloroquine in patients with RA.

Cardiovascular Safety of Hydroxychloroquine in US Veterans With Rheumatoid Arthritis.

OBJECTIVE: Hydroxychloroquine (HCQ) may prolong the QT interval, a risk factor for torsade de pointes, a potentially fatal ventricular arrhythmia. This study was undertaken to examine the cardiovascular safety of HCQ in patients with rheumatoid arthritis (RA). METHODS: We conducted an active comparator safety study of HCQ in a propensity score-matched cohort of 8,852 US veterans newly diagnosed as having RA between October 1, 2001 and December 31, 2017. Patients were started on HCQ (n = 4,426) or another nonbiologic disease-modifying antirheumatic drug (DMARD; n = 4,426) after RA diagnosis, up to December 31, 2018, and followed up for 12 months after therapy initiation, up to December 31, 2019. RESULTS: Patients had a mean ± SD age of 64 ± 12 years, 14% were women, and 28% were African American. The treatment groups were balanced with regard to 87 baseline characteristics. There were 3 long QT syndrome events (0.03%), 2 of which occurred in patients receiving HCQ. Of the 56 arrhythmia-related hospitalizations (0.63%), 30 occurred in patients in the HCQ group (hazard ratio [HR] associated with HCQ 1.16 [95% confidence interval (95% CI) 0.68-1.95]). All-cause mortality occurred in 144 (3.25%) and 136 (3.07%) of the patients in the HCQ and non-HCQ groups, respectively (HR associated with HCQ 1.06 [95% CI, 0.84-1.34]). During the first 30 days of follow-up, there were no long QT syndrome events, 2 arrhythmia-related hospitalizations (none in the HCQ group), and 13 deaths (6 in the HCQ group). CONCLUSION: Our findings indicate that the incidence of long QT syndrome and arrhythmia-related hospitalization is low in patients with RA during the first year after the initiation of HCQ or another nonbiologic DMARD. We found no evidence that HCQ therapy is associated with a higher risk of adverse cardiovascular events or death.

Outcomes of Premature Ventricular Contraction-Cardiomyopathy in the Veteran Population: A Secondary Analysis of the CHF-STAT Study.

OBJECTIVES: This study sought to assess the rate and outcomes of premature ventricular contractions (PVC)-cardiomyopathy from the CHF-STAT (Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure) trial, a population with cardiomyopathy (left ventricular [LV] ejection fraction of <40%) and frequent PVCs (>10 PVCs per hour). BACKGROUND: PVCs are associated with heart failure and PVC-cardiomyopathy. The prevalence of PVC-cardiomyopathy and outcome benefits of PVC suppression are not clear. METHODS: A secondary analysis of the CHF-STAT study was performed to compare the rate of successful PVC suppression (≥80% PVC reduction), LV recovery (defined as improvement in LV ejection fraction of ≥10% points), and PVC-cardiomyopathy between amiodarone and placebo groups at 6 months. PVC-cardiomyopathy was defined if both PVC reduction of ≥80% and LV ejection fraction improvement of ≥10% were present at 6 months. Cardiac events (death or resuscitated cardiac arrest) were compared between PVC-cardiomyopathy versus non-PVC-cardiomyopathy during a 5-year follow-up. RESULTS: The rates of successful PVC suppression and LV recovery were significantly higher in the amiodarone (72% and 39%, respectively) when compared to the placebo group (12% and 16%, respectively; p < 0.001), regardless of cardiomyopathy etiology. PVC-cardiomyopathy was present in 29% and 1.8% of patients in the amiodarone and placebo groups, respectively (p < 0.001). Similar PVC-cardiomyopathy rates were found in ischemic (24% amiodarone vs. 2% placebo; p < 0.001) and nonischemic populations (41% amiodarone vs. 1.5% placebo; p < 0.001). Death and resuscitated cardiac arrest were significantly lower in patients with PVC-cardiomyopathy and those treated with amiodarone. CONCLUSIONS: The overall prevalence of PVC-cardiomyopathy in the CHF-STAT study was significant regardless of ischemic substrate (29%, overall population; 41%, nonischemic cardiomyopathy). Treatment of PVC-cardiomyopathy with amiodarone is likely to improve survival in this high-risk population.

Digoxin Initiation and Outcomes in Patients with Heart Failure (HFrEF and HFpEF) and Atrial Fibrillation.

BACKGROUND: Digoxin reduces the risk of heart failure hospitalization but has no effect on mortality in patients with heart failure without atrial fibrillation in the randomized controlled trial setting. Observational studies of digoxin use in patients with atrial fibrillation have suggested a higher risk for poor outcomes. Less is known about this association in patients with heart failure and atrial fibrillation, the examination of which was the objective of the current study. METHODS: We conducted an observational propensity score-matched study of predischarge digoxin initiation in 1768 hospitalized patients with heart failure and atrial fibrillation in the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry, balanced on 56 baseline characteristics (mean age, 79 years; 55% women; 7% African American). Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were estimated for the 884 patients initiated on digoxin compared with 884 not initiated on digoxin. RESULTS: HRs (95% CIs) for 30-day, 2-year, and 4-year all-cause mortality were 0.80 (0.55-1.18; P = .261), 0.94 (0.87-1.16; P = .936), and 1.01 (0.90-1.14; P = .729), respectively. Respective HRs (95% CIs) for heart failure readmission were 0.67 (0.49-0.92; P = .014), 0.81 (0.69-0.94; P = .005), and 0.85 (0.74-0.97; P = .022), and those for all-cause readmission were 0.78 (0.64-0.96; P = .016), 0.90 (0.81-1.00; P = .057), and 0.91 (0.83-1.01; P = .603). These associations were homogeneous between patients with left ventricular ejection fraction ≤45% vs >45%. CONCLUSIONS: Among hospitalized older patients with heart failure (HFrEF and HFpEF) and atrial fibrillation, initiation of digoxin was associated with a lower risk of heart failure readmission but had no association with mortality.

Impact of Hospice and Palliative Care Service Utilization on All-Cause 30-Day Readmission Rate for Older Adults Hospitalized with Heart Failure.

BACKGROUND: Acute decompensated heart failure (HF) is the leading cause for hospital readmission. Large-scale sustainable interventions to reduce readmission rate have not been fully explored or proven effective. OBJECTIVE: We studied the impact of hospice and palliative care service utilization on 30-day all-cause hospital readmissions for patients with HF. METHODS AND RESULTS: Data were retrieved from the Department of Veterans Affairs Corporate Data Warehouse. The study included 238 116 HF admissions with primary diagnosis of HF belonging to 130 812 patients. Among these patients, 2592 had hospice and palliative care utilizations and 68 245 patients did not. Rehospitalization was calculated within 30 days of index hospitalization. Propensity scores were used to match hospice and nonhospice patients on demographics, Charlson comorbidity categories, and 30-day survival. In the matched group, logistic regression was used to estimate effects of hospice on readmission, controlling for any covariates that had failed to balance. The average age of the matched patients was 74 years old, 14% were African American, 75% Caucasian, 2% Asian, and 17% female. After propensity matching, the odds ratio for readmission was 1.29. The 95% confidence interval for the odds was 1.13 to 1.48, suggesting that veterans receiving services have a higher chance of readmission. CONCLUSION: In a large cohort study of older US Veterans, utilization of hospice and palliative care services was associated with a higher 30-day all-cause readmission rate among hospitalized patients with HF. Further prospective studies should be conducted to confirm results and test generalizability outside the Veterans Affairs system of care.

Cardiorespiratory fitness, body mass index and heart failure incidence.

AIMS: Obesity is associated with increased risk of heart failure (HF). This risk may be modulated by improved cardiorespiratory fitness (CRF) as CRF is associated with favourable health outcomes. Thus, we assessed the interaction between body mass index (BMI), CRF and HF. METHODS AND RESULTS: Cardiorespiratory fitness and BMI were assessed in 20 254 US male veterans (mean age 58.0 ± 11.3 years), who completed a maximal exercise treadmill test between 1987 and 2017. All had no evidence of ischaemia or HF prior to the exercise test. They were classified based on age-stratified quartiles of peak metabolic equivalents (METs) achieved as: least-fit (4.5 ± 1.3), low-fit (6.7 ± 1.3), moderate-fit (8.1 ± 1.1), and high-fit (11.2 ± 2.4); and according to BMI as normal weight (18.5-24.9 kg/m2 ), overweight (25-29.9 kg/m2 ), and obese (≥ 30.0 kg/m2 ). During a median follow-up of 13.4 years, there were 2979 HF events (10.8 events/1000 person-years). HF risk was significantly higher in the obese category [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.10-1.36; P < 0.001], but was no longer significant after further adjustment for METs. When compared to the least-fit, HF risk declined progressively with increased CRF within all BMI categories. The risk was 63% (HR 0.37, 95% CI 0.30-0.47; P < 0.001), 66% (HR 0.37, 95% CI 0.28-0.40; P < 0.001), and 73% (HR 0.27, 95% CI 0.22-0.34; P < 0.001) lower for high-fit individuals within normal weight, overweight and obese categories, respectively. CONCLUSIONS: Increased CRF was associated with progressively lower HF risk regardless of BMI, suggesting that the elevated HF risk associated with obesity may be modulated by improved CRF.

Association between lifetime risk of atrial fibrillation and mortality in the oldest old.

BACKGROUND: Age is the strongest predictor of atrial fibrillation (AF), yet little is known about AF incidence in the oldest old. HYPOTHESIS: AF incidence declines after age 90 years, and morbidity is compressed into a brief period at the end of life. METHODS: In this retrospective, longitudinal cohort study of patients (born 1905-1935), we examined cumulative lifetime incidence of AF and its impact on mortality. Data included records from 1 062 610 octogenarians, 317 161 nonagenarians, and 3572 centenarians. Kaplan-Meier curves were used to estimate cumulative incidence of AF by age group, incidence rates were compared using log-rank tests, and Cox proportional hazards model was used to estimate unadjusted hazard ratios. The primary outcome was AF incidence at age > 80 years; the secondary outcome was mortality. RESULTS: The cumulative AF incidence rate was 5.0% in octogenarians, 5.4% in nonagenarians, and 2.3% in centenarians. Octogenarians and nonagenarians had a higher risk of AF incidence compared to centenarians (adjusted hazard ratio 8.74, 95% confidence interval [CI]: 6.31-12.04; and 2.98, 95% CI: 2.17-4.1, respectively). The lowest hazard ratio for mortality in patients with AF compared to those without was 2.3 (95% CI: 2.3-2.4) in patients who were on antiplatelet and anticoagulant medication and had a score of 0 on the Elixhauser comorbidity index score. CONCLUSIONS: Although AF incidence increased with age, being a centenarian was associated with reduced incidence and compression of morbidity. Patients with AF had a higher adjusted mortality rate. However, data suggest that a regimen of anticoagulants and antiplatelets may reduce risk of mortality in patients over 80 with an AF diagnosis.

A case of influenza type a myocarditis that presents with ST elevation MI, cardiogenic shock, acute renal failure, and rhabdomyolysis and with rapid recovery after treatment with oseltamivir and intra-aortic balloon pump support.

We present a 59-year-old black male with history of type-1 diabetes and alcohol abuse. Patient became critically ill after a 5-day period of burning throat discomfort. On arrival patient was lethargic, in cardiogenic shock with a blood pressure of 81/47mmHg. Immediate diagnoses included diabetic ketoacidosis, acute renal failure, and possible septic shock. He was intubated, resuscitated with intravenous fluids, maintained on three inotropic agents, and given empiric wide spectrum antibiotics. An ECG showed a new ST elevation MI and an echocardiogram showed severe LV dysfunction. Cardiac catheterization showed clean coronaries. With appropriate treatment patient recovered 10days later.

Characteristics and Incidence of Chronic Illness in Community-Dwelling Predominantly Male U.S. Veteran Centenarians.

OBJECTIVES: To assess the incidence of chronic illness and its effect on veteran centenarians. DESIGN: Retrospective longitudinal cohort study. SETTING: United States Veterans Affairs Corporate Data Warehouse (CDW). PARTICIPANTS: Community-dwelling veterans born between 1910 and 1915 who survived to at least age 80 (N = 86,892; 31,121 octogenarians, 52,420 nonagenarians, 3,351 centenarians). MEASUREMENTS: The Kaplan-Meier method was used to estimate cumulative incidence of chronic conditions according to age group. Incidence rates were compared using the log-rank test. Cox proportional hazards models were used to estimate unadjusted hazard ratios. RESULTS: Ninety-seven percent of Centenarians were male, 88.0% were white, 31.8% were widowed, 87.5% served in World War II, and 63.9% did not have a service-related disability. The incidence rates of chronic illnesses were higher in octogenarians than centenarians (atrial fibrillation, 15.0% vs 0.6%, P < .001; heart failure, 19.3% vs 0.4%, P < .001; chronic obstructive pulmonary disease, 17.9% vs 0.6%, P < .001; hypertension, 29.6% vs 3.0%, P < .001; end-stage renal disease, 7.2% vs 0.1%, P < .001; malignancy, 14.1% vs 0.6%, P < .001; diabetes mellitus, 11.1% vs 0.4%, P < .001; stroke, 4.6% vs 0.4%, P < .001) and in nonagenarians than centenarians (atrial fibrillation, 13.2% vs 3.5%, P < .001; heart failure, 15.8% vs 3.3%, P < .001; chronic obstructive pulmonary disease, 11.8% vs 3.5%, P < .001; hypertension, 27.2% vs 12.8%, P < .001; end-stage renal disease, 11.9% vs 4.5%, P < .001; malignancy, 8.6% vs 2.3%, P < .001; diabetes mellitus, 7.5% vs 2.2%, P < .001; and stroke, 3.5% vs 1.3%, P < .001). CONCLUSION: In a large cohort of predominantly male community-dwelling elderly veterans, centenarians had a lower incidence of chronic illness than those in their 80s and 90s, demonstrating similar compression of morbidity and extension of health span observed in other studies.

Cardiorespiratory Fitness and Incidence of Major Adverse Cardiovascular Events in US Veterans: A Cohort Study.

OBJECTIVE: To assess the association between exercise capacity and the risk of major adverse cardiovascular events (MACEs). PATIENTS AND METHODS: A symptom-limited exercise tolerance test was performed to assess exercise capacity in 20,590 US veterans (12,975 blacks and 7615 whites; mean ± SD age, 58.2±11.0 years) from the Veterans Affairs medical centers in Washington, District of Columbia, and Palo Alto, California. None had a history of MACE or evidence of ischemia at the time of or before their exercise tolerance test. We established quintiles of cardiorespiratory fitness (CRF) categories based on age-specific peak metabolic equivalents (METs) achieved. We also defined the age-specific MET level associated with no risk for MACE (hazard ratio [HR], 1.0) and formed 4 additional CRF categories based on METs achieved below (least fit and low fit) and above (moderately fit and highly fit) that level. Multivariate Cox models were used to estimate HR and 95% CIs for mortality across fitness categories. RESULTS: During follow-up (median, 11.3 years; range, 0.3-33.0 years), 2846 individuals experienced MACEs. The CRF-MACE association was inverse and graded. The risk for MACE declined precipitously for those with a CRF level of 6.0 METs or higher. When considering CFR categories based on the age-specific MET threshold, the risk increased for those in the 2 CFR categories below that threshold (HR, 1.95; 95% CI, 1.73-2.21 and HR, 1.41; 95% CI, 1.27-1.56 for the least-fit and low-fit individuals, respectively) and decreased for those above it (HR, 0.77; 95% CI, 0.68-0.87 and HR, 0.57; 95% CI, 0.48-0.67 for moderately fit and highly fit, respectively). CONCLUSION: Increased CRF is inversely and independently associated with the risk for MACE. When an age-specific MET threshold was defined, the risk for MACE increased significantly for those below that threshold and decreased for those above it (P<.001).

Exercise Capacity and Atrial Fibrillation Risk in Veterans: A Cohort Study.

OBJECTIVE: To assess the association between exercise capacity and the risk of developing atrial fibrillation (AF). PATIENTS AND METHODS: A symptom-limited exercise tolerance test was conducted to assess exercise capacity in 5962 veterans (mean age, 56.8±11.0 years) from the Veterans Affairs Medical Center, Washington, DC. None had evidence of AF or ischemia at the time of or before undergoing their exercise tolerance test. We established 4 fitness categories based on age-stratified quartiles of peak metabolic equivalent task (MET) achieved: least fit (4.9±1.10 METs; n=1446); moderately fit (6.7±1.0 METs; n=1490); fit (7.9±1.0 METs; n=1585), and highly fit (9.3±1.2 METs; n=1441). Multivariable Cox proportional hazards regression models were used to compare the AF-exercise capacity association between fitness categories. RESULTS: During a median follow-up period of 8.3 years, 722 (12.1%) individuals developed AF (14.5 per 1000 person-years; 95% CI, 13.9-15.9 per 1000 person-years). Exercise capacity was inversely related to AF incidence. The risk was 21% lower (hazard ratio, 0.79; 95% CI, 0.76-0.82) for each 1-MET increase in exercise capacity. Compared with the least fit individuals, hazard ratios were 0.80 (95% CI, 0.67-0.97) for moderately fit individuals, 0.55 (95% CI, 0.45-0.68) for fit individuals, and 0.37 (95% CI, 0.29-0.47) for highly fit individuals. Similar trends were observed in those younger than 65 years and those 65 years or older. CONCLUSION: Increased fitness is inversely and independently associated with the reduced risk of developing AF. The decrease in risk was graded and precipitous with only modest increases in exercise capacity. These findings counter previous suggestions that even moderate increases in physical activity, as recommended by national and international guidelines, increase the risk of AF, with marked protection against AF noted with increasing levels of fitness.

SCD-HeFT: Use of R-R interval statistics for long-term risk stratification for arrhythmic sudden cardiac death.

BACKGROUND: In the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), a significant fraction of the patients with congestive heart failure ultimately did not die suddenly of arrhythmic causes. Patients with CHF will benefit from better tools to identify if implantable cardioverter-defibrillator (ICD) therapy is needed. OBJECTIVES: We aimed to identify predictor variables from baseline SCD-HeFT patients' R-R intervals that correlate to arrhythmic sudden cardiac death (SCD) and mortality and to design an ICD therapy screening test. METHODS: Ten predictor variables were extracted from prerandomization Holter data from 475 patients enrolled in the ICD arm of the SCD-HeFT by using novel and traditional heart rate variability methods. All variables were correlated to SCD using the Mann-Whitney-Wilcoxon test and receiver operating characteristic analysis. ICD therapy screening tests were designed by minimizing the cost of false classifications. Survival analysis, including log-rank test and Cox models, was also performed. RESULTS: A short-term fractal exponent, α1, and a long-term fractal exponent, α2, from detrended fluctuation analysis, the ratio of low- to high-frequency power, the number of premature ventricular contractions per hour, and the heart rate turbulence slope are all statistically significant for predicting the occurrences of SCD (P < .001) and survival (log-rank, P < .01). The most powerful multivariate predictor tool using the Cox proportional hazards regression model was α2 with a hazard ratio of 0.0465 (95% confidence interval 0.00528-0.409; P < .01). CONCLUSION: Predictor variables extracted from R-R intervals correlate to the occurrences of SCD and distinguish survival functions among patients with ICDs in SCD-HeFT. We believe that SCD prediction models should incorporate Holter-based R-R interval analysis to refine ICD patient selection, especially to exclude patients who are unlikely to benefit from ICD therapy.

Drug-induced post-repolarization refractoriness as an antiarrhythmic principle and its underlying mechanism.

AIMS: We hypothesized that amiodarone (AM), unlike d-sotalol (DS) (a 'pure' Class III agent), not only prolongs the action potential duration (APD) but also causes post-repolarization refractoriness (PRR), thereby preventing premature excitation and providing superior antiarrhythmic efficacy. METHODS AND RESULTS: We tested this hypothesis in 31 patients with inducible ventricular tachycardia (VT) during programmed stimulation with the use of the 'Franz' monophasic action potential (MAP) catheter with simultaneous pacing capability. We determined the effective refractory period (ERP) for each of three extrastimuli (S2-S4) and the corresponding MAP duration at 90% repolarization (APD90), both during baseline and on randomized therapy with either DS (n = 15) or AM (n = 16). We defined ERP > APD90 as PRR and ERP < APD90 as 'encroachment' on repolarization. A revised computer action potential model was developed to help explain the mechanisms of these in-vivo human-heart phenomena. Encroachment but not PRR was present in all patients at baseline and during DS treatment (NS vs. baseline), and VT was non-inducible in only 2 of 15 DS patients. In contrast, in 12 of 16 AM patients PRR was present (P < 0.001 vs. baseline), and VT was no longer inducible. Our model (with revised sodium channel kinetics) reproduced encroachment and drug-induced PRR. CONCLUSION: Both, AM and DS, prolonged APD90 but only AM produced PRR and prevented encroachment of premature extrastimuli. Our computer simulations suggest that PRR is due to altered kinetics of the slow inactivation of the rapid sodium current. This may contribute to the high antiarrhythmic efficacy of AM.

Atrial tachyarrhythmias temporally precede fluid accumulation in implantable device patients.

BACKGROUND: The complex relationship between heart failure and atrial tachyarrhythmias (AT/atrial fibrillation [AF]) is not well understood. We examined the temporal association between changes in intrathoracic impedance, suggesting thoracic fluid accumulation, and AT/AF occurrence in cardiac resynchronization therapy-defibrillator and implantable cardioverter defibrillator (ICD) patients. METHODS: A retrospective analysis was conducted on stored implantable device data to identify patients with automatic monitoring of daily AT/AF burden and intrathoracic impedance. Daily population trends in AT/AF burden before and after a fluid index threshold crossing (FIC) were determined. RESULTS: A total of 73,018 patients (68 ± 12 years, 51% ICD, 75% male) were evaluated over 18.6 ± 11.5 months. Kaplan-Meier analysis indicated a significantly higher probability of FIC events in the first month following the onset of persistent AT/AF when compared to a matched group without persistent AT/AF (hazard ratio [HR] 1.65, 95% confidence interval [CI] [1.58, 1.72], P < 0.001). Conversely, patients were significantly more likely to experience an episode of persistent AF in the first month after the FIC event (HR 1.32, 95% CI [1.08, 1.63], P = 0.008). The probability of a fluid index crossing within 30 days of the onset of persistent AT/AF was significantly lower in a subgroup of patients with adequate rate control (35.8% [34.3-37.4%] vs 42.0% [39.6-44.6%]; HR 1.24 [1.13-1.36]). CONCLUSION: Thoracic fluid accumulation, as indicated by decreasing intrathoracic impedance, was more likely to occur immediately after the onset of persistent AT/AF, especially in the presence of inadequate rate control. Likewise, the onset of persistent AT/AF was more likely following a decrease in intrathoracic impedance.