Predictors of long-term outcomes greater than 10 years after cardiac resynchronization therapy implantation.

BACKGROUND: Cardiac resynchronization therapy (CRT) is indicated in patients with medically refractory heart failure and wide QRS duration. While much is known about predictors of left ventricular (LV) remodeling after CRT implantation and short-term mortality, limited data exist on long-term outcomes after CRT placement. METHODS: We retrospectively reviewed all patients undergoing CRT implantation at our center between 2003 and 2008 and examined mortality using institutional electronic records, social security death index, and online obituary search. We included only patients with preimplant echoes with LV ejection fraction (LVEF) 35% or below. Variable selection was performed using stepwise regression and models were compared using goodness-of-fit criteria. A final model was validated with the bootstrap regression method. RESULTS: Out of the 877 CRT patients undergoing implantation during this time, 287 (32.7%) survived longer than 10 years. Significant (P < .05) predictors of survival in our multivariate model were age, left ventricular diastolic diameter, sex, presence of nonischemic vs ischemic cardiomyopathy, QRS duration, atrial fibrillation, BNP levels, and creatinine levels at the time of CRT implantation. A model using the odds ratios from these variables had a receiver operating curve with an area under the curve score of 0.816 (standard error, 0.019) at predicting survival or freedom from LVAD or heart transplant for longer than 10 years after CRT implantation. The specificity for factors 3 or above and 5 or above was 68% and 77%, respectively. CONCLUSION: A large proportion of patients are still alive 10 years after CRT implantation. Variables at the time of CRT implant can help provide prognostic information to patients and electrophysiologists to determine the long-term benefit and survival of patients after CRT implantation.

Optimizing Cardiac Resynchronization Therapy: an Update on New Insights and Advancements.

PURPOSE OF REVIEW: This review focuses on the current advancements in optimizing patient response to cardiac resynchronization therapy (CRT). RECENT FINDINGS: It has been well known that not every patient will derive benefit from CRT, and of those that do, there are varying levels of response. Optimizing CRT begins well before device implant and involves appropriate patient selection and an understanding of the underlying substrate. After implant, there are different CRT device programming options that can be enabled to help overcome barriers as to why a patient may not respond. Given the multifaceted components of optimizing CRT and the complex patient population, multi-subspecialty clinics have been developed bringing together specialists in heart failure, electrophysiology, and imaging. Data as to whether this results in better response rates and outcomes shows promise.

Effect of statins on skeletal muscle function.

BACKGROUND: Many clinicians believe that statins cause muscle pain, but this has not been observed in clinical trials, and the effect of statins on muscle performance has not been carefully studied. METHODS AND RESULTS: The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study assessed symptoms and measured creatine kinase, exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo was administered for 6 months to 420 healthy, statin-naive subjects. No individual creatine kinase value exceeded 10 times normal, but average creatine kinase increased 20.8±141.1 U/L (P<0.0001) with atorvastatin. There were no significant changes in several measures of muscle strength or exercise capacity with atorvastatin, but more atorvastatin than placebo subjects developed myalgia (19 versus 10; P=0.05). Myalgic subjects on atorvastatin or placebo had decreased muscle strength in 5 of 14 and 4 of 14 variables, respectively (P=0.69). CONCLUSIONS: These results indicate that high-dose atorvastatin for 6 months does not decrease average muscle strength or exercise performance in healthy, previously untreated subjects. Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins increase muscle complaints. Atorvastatin also increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects. This increase in creatine kinase should prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular performance. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00609063.

Sex-specific effect of aging on submaximal leg exercise hemodynamics in middle-aged and older adults.

The purpose of the study was to examine predictors of the leg hemodynamic response to exercise in middle- and older-aged men and women. Femoral artery blood flow (FBF), mean arterial pressure (MAP), and femoral vascular conductance (FVC, calculated as the quotient of FBF and MAP) were measured at rest and during 5 min of single knee-extensor exercise at ~10 W workload in healthy men (n = 31) and women (n = 32) (age 40-72 years). Age, menopausal status, maximal quadriceps strength, blood lipids, vitamin D levels, maximal oxygen uptake (VO(2max)), physical activity, blood pressure, estimated quadriceps muscle mass, and body mass index (BMI) were also assessed. The effect of age on FBF and FVC was negative and significant in men (r = -0.44 and -0.42 and p = 0.01 and 0.02, respectively) but was abolished by normalization to estimated quadriceps muscle (p = 0.18 and 0.73, respectively). There was no effect of age on leg hemodynamic responses to exercise in women (alone or normalized to quadriceps muscle), but menopausal status was a significant predictor of FVC and normalized FVC (p = 0.04 and 0.02, respectively). The multivariate model for exercising FVC in men (in order of strongest to weakest predictors) included quadriceps strength, BMI, resting FVC, age, and high-density lipoprotein cholesterol. The multivariate model for exercising FVC in women included quadriceps mass, systolic blood pressure, vitamin D, age, VO(2max), waist circumference, and physical activity score. These findings suggest that factors besides chronological age mediate exercising leg hemodynamics in middle-aged to older adults and that these factors are sex-specific.

Cardiac resynchronization therapy-heart failure (CRT-HF) clinic: A novel model of care.

BACKGROUND: Post-implant care of patients with heart failure (HF) undergoing cardiac resynchronization therapy (CRT) is not addressed in current HF or CRT guidelines and is often fragmented with poor communication between specialties. We sought to develop a new model of post-CRT care which could be implemented in busy clinical settings. METHODS AND RESULTS: We designed a novel, multidisciplinary approach to standardizing post CRT care. All patients receiving a CRT device at the Cleveland Clinic between March 2017 and August 2018 were invited to be seen in the clinic 6 months post implant. A one-time collaborative visit encompassing cardiac imaging, heart failure, and electrophysiology care was performed. We recorded the operational feasibility of the clinic in terms of patient throughput as well as patient characteristics, interventions, and new diagnoses made. Between September 2017 and February 2019, 150 patients were seen in the clinic. Of these, 125 patients had their index CRT implanted for standard indications and were included in the current analysis. Approximately 45 minutes were dedicated for each patient visit. Interventions in care were made in 95% of patients, with CRT non-responders offered a higher number of interventions as compared to responders (median 3 versus 2 interventions). Types of interventions were device-related (26% of population), medication-related (74%), and referral for alternate medical services (80%). CONCLUSIONS: Multidisciplinary post-implant care of patients with HF receiving CRT devices, regardless of CRT response status, is feasible and results in frequent medical interventions.

Effect of Cardiac Resynchronization Therapy on Left Ventricular Remodeling in Patients With Cardiac Sarcoidosis.

Cardiac resynchronization therapy (CRT) has been shown to be beneficial in patients with medically refractory heart failure. Although it has been found to be effective in a wide range of etiologies for nonischemic cardiomyopathy, its role in improving remodeling and survival of patients with cardiac sarcoidosis (CS) remains undefined. We performed a retrospective review of all patients at our institution with CS who underwent implantation of a CRT device from 2007 to 2017. The outcomes of this population were compared with the outcomes of a cohort of patients with nonischemic cardiomyopathy with an etiology other than sarcoidosis. Nineteen patients in our institution with CS underwent CRT implantation during the time period. This group was compared with 311 consecutive patients with other etiologies of nonischemic cardiomyopathy who underwent CRT implantation. CRT improved left ventricular ejection fraction (LVEF) from 28.8% to 35.9% (p <0.05) in CS, whereas it improved LVEF from 25% to 36.6% (p <0.01) in non-CS group (difference in means of 0.13). CRT significantly improved diastolic and systolic LV diameters, mitral regurgitation, and right ventricular systolic function in non-CS patients but failed to improve same parameters in CS patients. In conclusion, CRT significantly improved LVEF in patients with CS. There is no significant evidence that survival outcomes of CRT patients with CS are significantly worse than other etiologies of nonischemic cardiomyopathy.

The Effect of Atorvastatin on Habitual Physical Activity among Healthy Adults.

PURPOSE: Statin therapy can result in muscle pain, cramps, and weakness that may limit physical activity, although reports are mixed. We conducted a randomized control trial to examine the effect of atorvastatin on habitual physical activity levels in a large sample of healthy adults. METHODS: Participants (n = 418) were statin-naive adults (44.0 ± 16.1 yr (mean ± SD)) who were randomized and double-blinded to 80 mg · d(-1) of atorvastatin or placebo for 6 months. Accelerometers were worn for 96 h before and after drug treatment. Repeated-measures analysis tested physical activity levels after versus those before drug treatment among groups with age and VO2max as covariates. RESULTS: In the total sample, sedentary behavior increased (19.5 ± 5.1 min · d(-1)), whereas light-intensity (9.1 ± 3.0 min · d(-1)) and moderate-intensity (9.7 ± 2.8 min · d(-1)) physical activity decreased, as did total activity counts (17.8 ± 6.3 d × 10(-3)) over 6 months (P < 0.01), with no differences between groups. The atorvastatin group increased sedentary behavior (19.8 ± 7.4 min · d(-1)) and decreased light-intensity (10.7 ± 4.3 min · d(-1)) and moderate-intensity (8.5 ± 4.0 min · d(-1)) physical activity (P < 0.05). On the other hand, the placebo group increased sedentary behavior (19.2 ± 7.1 min · d(-1)) and decreased moderate-intensity (11.0 ± 3.8 min · d(-1)) and total physical activity counts (-23.8 ± 8.8 × 10(-3) d(-1)) (P < 0.05). CONCLUSIONS: Time being sedentary increased and physical activity levels decreased in the total sample over 6 months of drug treatment, independent of group assignment. Our results suggest that statins do not influence physical activity levels any differently from placebo, and the lack of inclusion of a placebo condition may provide insight into inconsistencies in the literature.

Atorvastatin Treatment Does Not Alter Pulse Wave Velocity in Healthy Adults.

Introduction. Both statins and regular physical activity (PA) reduce arterial stiffness. The present post hoc analysis examined if arterial stiffness was improved with high-dose atorvastatin treatment in healthy adults and whether PA levels magnified this response. We utilized data from a double-blind, random-assignment clinical trial investigating the effects of atorvastatin 80 mg/d for 6 mo on skeletal muscle symptoms. Methods. Central and peripheral arterial pulse wave velocity (PWV) were measured and PA levels assessed at baseline and 6 mo in subjects randomized to atorvastatin (n = 21, 9 men) or placebo (n = 29, 16 men). Results. Baseline participant characteristics, PWV, and PA levels were not different between treatments. Central (means ± SD; 8.7 ± 2.6 to 9.0 ± 2.5 m/sec) and peripheral PWV (9.9 ± 1.3 to 9.8 ± 1.6 m/sec) were unchanged from baseline following atorvastatin treatment (time × drug interaction: P ≥ 0.13). Similarly, PA levels were unaffected by time or treatment. In sex and age adjusted models, baseline levels of PA were not related to changes in PWV with atorvastatin treatment. Conclusion. These data indicate that high-dose atorvastatin treatment for 6 mo does not influence arterial stiffness in healthy adults. Participation in habitual PA did not magnify the vascular effects of statin therapy. This study was registered with ClinicalTrials.gov NCT00609063.

Effects of Atorvastatin on Resting and Peak Exercise Blood Pressure among Normotensive Men and Women.

Statins are the most widely prescribed and effective medication for reducing low density lipoprotein cholesterol. Statins may also lower resting blood pressure (BP); however, results are inconsistent. We sought to determine if the maximum dose of atorvastatin reduces resting BP and the peak systolic BP (SBP) achieved on a graded exercise stress test (GEST) among a large sample of 419 healthy men (48%) and women (52%). Subjects (419, 44.1 ± 0.8 yr) were double-blinded and randomized to 80 mg·d(-1) of atorvastatin (n = 202) or placebo (n = 217) for 6 mo. Among the total sample, there were no differences in resting BP (SBP, P = 0.30; diastolic BP [DBP], P = 0.69; mean arterial pressure (P = 0.76); or peak SBP on a GEST (P = 0.99)) over 6 mo, regardless of drug treatment group. However, among women on atorvastatin, resting SBP/DBP (3.7±1.5 mmHg, P = 0.01/3.2±0.9 mmHg, P = 0.02) and peak SBP on a GEST (6.5±1.5 mmHg, P = 0.04) were lower versus men. Atorvastatin lowered resting BP 3-4 mmHg and peak SBP on a GEST ~7 mmHg more among women than men over 6 mo of treatment. The inconsistent findings regarding the antihypertensive effects of statins may be partially explained by not accounting for sex effects.

25(OH) vitamin D is associated with greater muscle strength in healthy men and women.

PURPOSE: The purpose of the study was to examine the relation between serum 25-hydroxy vitamin D (25(OH)D) levels and muscle strength in 419 healthy men and women over a broad age range (20-76 yr). METHODS: Isometric and isokinetic strength of the arms and legs was measured using computerized dynamometry, and its relation to vitamin D was tested in multivariate models controlling for age, gender, resting HR, systolic blood pressure, diastolic blood pressure, body mass index, maximal oxygen uptake (VO(2max)), physical activity counts, and season of vitamin D measurement. RESULTS: Vitamin D was significantly associated with arm and leg muscle strength when controlling for age and gender. When controlling for other covariates listed previously, vitamin D remained directly related to both isometric and isokinetic arm strength but only to isometric leg strength. CONCLUSION: These data suggest that there may be a differential effect of vitamin D on upper and lower body strength. The mechanism for this difference remains unclear but could be related to differences in androgenic effects or to differences in vitamin D receptor expression. Our study supports a direct relation between vitamin D and muscle strength and suggests that vitamin D supplementation be evaluated to determine whether it is an effective therapy to preserve muscle strength in adults.

Increases in creatine kinase with atorvastatin treatment are not associated with decreases in muscular performance.

BACKGROUND: The present study examined if increases in creatine kinase (CK) levels during high-dose atorvastatin treatment are associated with changes in skeletal muscle function and symptoms. METHODS: The Effect of Statins on Muscle Performance study (STOMP) investigated the effects of atorvastatin 80 mg daily for 6 months on muscle performance, exercise capacity, and the incidence of statin-associated muscle complaints in healthy adults. RESULTS: CK levels increased with atorvastatin (n = 202) from 132.3 ± 120.9 U/L (mean ± SD) at baseline to 159.7 ± 170.4 and 153.1 ± 139.4 U/L at 3 and 6 months, respectively (P ≤ 0.002 for both). Changes in CK with atorvastatin treatment were not associated with changes in muscle function or the incidence of myalgia. More subjects on atorvastatin (n = 24) compared to placebo (n = 12 of 217) doubled their CK level at 6 months (P = 0.02). No differences in muscle function or physical activity were observed between atorvastatin-treated subjects who did or did not double their CK. CONCLUSIONS: Results of the present investigation extend the findings of STOMP by demonstrating that greater increases in CK levels with high-dose atorvastatin treatment did not deleteriously impact skeletal muscle function or predict skeletal muscle complaints. This study was registered at ClinicalTrials.gov (NCT00609063).

Atorvastatin increases exercise leg blood flow in healthy adults.

OBJECTIVES: We sought to examine the effect of atorvastatin therapy on exercise leg blood flow in healthy middle-aged and older-men and women. BACKGROUND: The vasodilatory response to exercise decreases in humans with aging and disease and this reduction may contribute to reduced exercise capacity. METHODS: We used a double-blind, randomly assigned, placebo-controlled protocol to assess the effect of atorvastatin treatment on exercising leg hemodynamics. We measured femoral artery blood flow (FBF) using Doppler ultrasound and calculated femoral vascular conductance (FVC) from brachial mean arterial pressure (MAP) before and during single knee-extensor exercise in healthy adults (ages 40-71) before (PRE) and after (POST) 6 months of 80 mg atorvastatin (A: 14 men, 16 women) or placebo (P: 14 men, 22 women) treatment. FBF and FVC were normalized to exercise power output and estimated quadriceps muscle mass. RESULTS: Atorvastatin reduced LDL cholesterol by approximately 50%, but not in the placebo group (p < 0.01). Atorvastatin also increased exercise FBF from 44.2 ± 19.0 to 51.4 ± 22.0 mL/min/W/kg muscle whereas FBF in the placebo group was unchanged (40.1 ± 16.0 vs. 39.5 ± 16.1) (p < 0.01). FVC also increased with atorvastatin from 0.5 ± 0.2 to 0.6 ± 0.2 mL/min/mmHg/W/kg muscle, but not in the placebo subjects (P: 0.4 ± 0.2 vs. 0.4 ± 0.2) (p < 0.01). CONCLUSIONS: High-dose atorvastatin augments exercising leg hyperemia. Statins may mitigate reductions in the exercise vasodilatory response in humans that are associated with aging and disease.

A randomized clinical trial to assess the effect of statins on skeletal muscle function and performance: rationale and study design.

Hydroxymethylglutaryl-coenzyme A reductase inhibitors or statins are the most effective medications for reducing elevated concentrations of low-density lipoprotein cholesterol (LDL-C). Statins reduce cardiac events in patients with coronary artery disease and previously healthy persons. Current recommendations for LDL-C treatment goals indicate that more patients will be treated with higher doses of these medications. Statins have been extremely well-tolerated in controlled clinical trials but are increasingly recognized to produce skeletal muscle myalgia, cramps, and weakness. The reported frequency of such mild symptoms is not clear, and muscle performance has not been examined with these medications. Accordingly, the present investigation, the Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study, will recruit approximately 440 healthy persons. Participants will be randomly assigned to treatment with atorvastatin 80 mg/d or placebo. Handgrip, elbow and knee isometric and isokinetic strength, knee extensor endurance, and maximal aerobic exercise performance will be determined at baseline. Participants will undergo repeat testing after 6 months of treatment or after meeting the study definition of statin myalgia. This study will determine the effect of statins on skeletal muscle strength, endurance, and aerobic exercise performance and may ultimately help clinicians better evaluate statin-related muscle and exercise complaints.