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.

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 Disease in Older Women.

Cardiovascular disease is the major cause of death in women. Older women remain at risk for coronary artery disease/cardiovascular disease, but risk-modifying behavior can improve outcomes. Women have a different symptom profile and have been underdiagnosed and undertreated as compared with men. Although older women are underrepresented in trials, clinicians should be more attuned to the prevention, diagnosis, and treatment of cardiovascular disease in older women.

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.

Exercise blood pressure, cardiorespiratory fitness and mortality risk.

OBJECTIVE: To assess the cardiorespiratory fitness (CRF) impact on the association between exercise blood pressure (BP) and mortality risk. PATIENTS AND METHODS: We assessed CRF in 15,004 US Veterans (mean age 57.5 ± 11.2 years) who completed a standardized treadmill test between January 1, 1988 and July 28, 2017 and had no evidence of ischemia. They were classified as Unfit or Fit according to the age-specific metabolic equivalents (METs) achieved <50% (6.2 ± 1.6 METs; n = 8440) or ≥ 50% (10.5 ± 2.4 METs; n = 6264). To account for the impact of resting systolic BP (SBP) on outcomes, we calculated the difference (Peak SBP-Resting SBP) and termed it SBP-Reserve. We noted a significant increase in mortality associated with SBP-Reserve ≤52 mmHg and stratified the cohort accordingly (SBP-Reserve ≤52 mmHg and > 52 mmHg). We applied multivariable Cox models to estimate hazard ratios (HR) and 95% confidence interval (CIs) for outcomes. RESULTS: Mortality risk was significantly elevated only in Unfit individuals with SBP-Reserve ≤52 mmHg compared to those with SBP-Reserve >52 mmHg (HR = 1.35; CI: 1.24-1.46; P < 0.001). We then assessed the CRF and SBP-Reserve interaction on mortality risk with Fit individuals with SBP-Reserve >52 mmHg serving as the referent. Mortality risk was 92% higher (HR = 1.92%; 95% CI: 1.77-2.09; P < 0.001) in Unfit individuals with SBP-Reserve ≤52 mmHg and 47% higher (HR = 1.47; 95% CI: 1.33-1.62; P < 0.001) in those with SBP-Reserve >52 mmHg. CONCLUSION: Low CRF was associated with increased mortality risk regardless of peak exercise SBP. The risk was substantially higher in individuals unable to augment their exercise SBP >52 mmHg beyond resting levels.

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.

High Lp(a) associated with very premature coronary heart disease.

Although high levels of Lp(a) have become increasingly recognized as a risk factor for coronary heart disease (CHD), its association with very premature CHD (ie, younger than 30 years) is unclear. We present a case of a young woman with very high levels of Lp(a) in whom accelerated CHD is unlikely to be accounted for by traditional risk factors.

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.

Preoperative antibiotics and cardiovascular implantable electronic device infection: A cohort study in veterans.

BACKGROUND: Cefazolin is used as standard preoperative prophylaxis for a variety of surgical procedures that involve the skin. In contrast, vancomycin is recommended for a minority of patients, specifically those with an IgE-mediated allergy to beta-lactams and considered in patients with known colonization with methicillin-resistant Staphylococcus aureus or at high risk for such. Vancomycin, however, has been overprescribed, has nephrotoxicity risk, and may be less effective due to its inferior coverage of methicillin-susceptible S. aureus and lack of Gram-negative coverage. This study was performed to assess whether vancomycin use was associated with an increased incidence of cardiovascular implantable electronic device infection (CIEDI) as compared to that of cefazolin or other antistaphylococcal beta-lactam antibiotics. METHODS: The VA Informatics and Computing Infrastructure database, which included all veterans who underwent CIED placement or revision between 2008 and 2015, was used. A logistic regression model was constructed to estimate the adjusted odds of CIEDI. RESULTS: Overall, 10,454 CIED procedures were included, and 98% of them were performed in men with a mean age of 71 ± 12 years. The logistic regression analysis showed that vancomycin use alone or in combination with other antibiotics was associated with an increased risk of CIEDI (odds ratio 2.99 [1.76-5.06], P-value < 0.001), after controlling for other effects. CONCLUSIONS: Our study revealed that among patients who received surgical site infection prophylaxis for CIED placement or revision, there was: (1) an unanticipated high rate of vancomycin use, and (2) a threefold increase in the incidence of subsequent CIEDI among vancomycin recipient.

Statin use and the risk of cardiovascular implantable electronic device infection: A cohort study in a veteran population.

BACKGROUND: The rate of cardiovascular implantable electronic device infection (CIEDI) has increased, despite the use of perioperative antibiotics at the time of device placement or revision. This is due, in part, to the presence of multiple comorbid conditions in an elderly population, in general, who require CIED. Statins may have an antibacterial effect, although there is currently no evidence that the likelihood of CIEDI has been impacted by statin use. METHODS: A retrospective cohort study was performed to assess whether statins are associated with a reduced risk of CIEDI. The VA Informatics and Computing Infrastructure (VINCI) database, which includes all veterans who underwent CIED placement between 2008 and 2015, was used. A logistic regression model was constructed to estimate the adjusted risk of CIEDI among patients who were receiving statins after adjusting for confounding factors. RESULTS: Overall, 18,970 CIED procedures were included, and 98% of them were performed in men with a mean age of 71 ± 11 years. The rate of diabetes mellitus, heart failure, advanced chronic kidney diseases, CIEDI, positive methicillin-resistant Staphylococcus aureus nasal colonization, and statin use were 23%, 15.7%, 3.3%, 1.14%, 12.6%, and 56%, respectively. The logistic regression analysis showed that statins were significantly associated with a reduced risk of CIEDI; after controlling for other effects, the reduction was 66% (odds ratio 0.34 [0.2-0.59], P-value < 0.001). The effect of statins was confirmed by propensity score analysis. CONCLUSIONS: Our study showed that among patients receiving statins who had undergone CIED placement, there was a 66% reduction in subsequent CIEDI.

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.

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.

Self-reported post-exertional fatigue in Gulf War veterans: roles of autonomic testing.

To determine if objective evidence of autonomic dysfunction exists from a group of Gulf War veterans with self-reported post-exertional fatigue, we evaluated 16 Gulf War ill veterans and 12 Gulf War controls. Participants of the ill group had self- reported, unexplained chronic post-exertional fatigue and the illness symptoms had persisted for years until the current clinical study. The controls had no self-reported post-exertional fatigue either at the time of initial survey nor at the time of the current study. We intended to identify clinical autonomic disorders using autonomic and neurophysiologic testing in the clinical context. We compared the autonomic measures between the 2 groups on cardiovascular function at both baseline and head-up tilt, and sudomotor function. We identified 1 participant with orthostatic hypotension, 1 posture orthostatic tachycardia syndrome, 2 distal small fiber neuropathy, and 1 length dependent distal neuropathy affecting both large and small fiber in the ill group; whereas none of above definable diagnoses was noted in the controls. The ill group had a significantly higher baseline heart rate compared to controls. Compound autonomic scoring scale showed a significant higher score (95% CI of mean: 1.72-2.67) among ill group compared to controls (0.58-1.59). We conclude that objective autonomic testing is necessary for the evaluation of self-reported, unexplained post-exertional fatigue among some Gulf War veterans with multi-symptom illnesses. Our observation that ill veterans with self-reported post-exertional fatigue had objective autonomic measures that were worse than controls warrants validation in a larger clinical series.

How Should Implantable Cardioverter-Defibrillator Lead Failures be Managed and What is the Role of Lead Extraction?

Despite remarkable advances in design, implantable cardioverter-defibrillator (ICD) leads remain the component most susceptible to failure, which often leads to substantial adverse clinical outcomes. This article focuses on management strategies when ICD lead systems fail. Two cases involving management decisions for ICD lead failures are presented and discussed. One involves a common mode of presentation, inappropriate shocks. The second involves an alert in a patient with a complex system and multiple comorbidities. Although a systematic approach is outlined, management decisions must be balanced by a risk-and-benefit assessment of the individual patient.