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Chronotropic incompetence (CI) in patients with heart failure is common and associated with impaired exercise intolerance and adverse outcomes. This study sought to determine the effects of closed loop stimulation (CLS) rate-adaptive pacing on functional capacity in patients with heart failure with reduced ejection fraction (HFrEF) and CI implanted with cardiac resynchronization therapy (CRT) devices. A randomized, blinded, cross-over designed trial enrolled patients with HFrEF and CI implanted with a Biotronik CRT-D to complete a quality of life questionnaire, 6-min walk distance (6MWD), and cardiopulmonary exercise testing after two programmed periods: 1-week period of CLS and 1-week period of standard accelerometer (DDDR). Nine patients (6 males, mean age 71.4 years, 7 with New York Heart Association Class III, mean ejection fraction 39 ± 8%) were enrolled. Quality of life trended higher in CLS as compared to DDDR (550.8 ± 123.9 vs 489.3 ± 164.9, p = 0.06). There were no differences between CLS and DDDR in 6MWD (293.1 ± 90.2 m vs 315.1 ± 95.5 m, p = 0.52), peak heart rate (HR) 110.7 ± 14.7 bpm vs 109.7 bpm ± 14.1, p = 0.67), or peak VO2 (12.3 ± 4.9 ml/kg/min vs 12.9 ± 5.9, p = 0.47). As tests were submaximal as indicated by low respiratory exchange ratios (0.98 ± 0.11 vs 1.0 ± 0.8, p = 0.35), VE/VCO2 slope also showed no difference between CLS and DDDR (35.8 ± 5.6 vs 35.4 ± 5.7, p = 0.65). Five patients (56%) preferred CLS programming (p = 1.0). In patients with HFrEF and CI implanted with a CRT-D, peak HR, peak VO2, and 6MWD were equivalent, while there was a trend toward improved quality of life in CLS as compared to DDDR. URL: https://www.clinicaltrials.gov . Unique identifier: NCT02693262.

Cardiac amyloidosis is characterized by extracellular protein fibril deposition in the myocardium leading to restrictive heart failure. Both atrial and ventricular arrhythmias, along with conduction disease, are common in cardiac amyloidosis, and are often highly symptomatic and poorly tolerated. Many commonly used therapeutics such as beta-blockers, calcium-channel blockers, and digoxin may be poorly tolerated and lead to clinical decompensation in this population, adding complexity to the co-management of these conditions. In addition, studies have shown that atrial fibrillation with cardiac amyloidosis carries a high risk of stroke and systemic embolism, making anticoagulation indicated in all patients regardless of CHA2DS2-VASc score. Ventricular arrhythmias are common, whereas an implantable cardioverter-defibrillator has not been shown to improve survival. Conduction disease is also common and permanent pacemaker placement is often needed. High-quality evidence and guideline recommendations are limited with regard to the management of arrhythmias in cardiac amyloidosis. Providers are often left to clinical experience and expert consensus to aid in decision-making. In this focused review, we outline current guideline recommendations, summarize both historical and contemporary data, and describe evidence-based strategies for managing arrhythmias and their sequelae in patients with cardiac amyloidosis.

Background: Predicting mortality is important in patients with heart failure (HF). However, current strategies for predicting risk are only modestly successful, likely because they are derived from statistical analysis methods that fail to capture prognostic information in large data sets containing multi-dimensional interactions. Methods and results: We used a machine learning algorithm to capture correlations between patient characteristics and mortality. A model was built by training a boosted decision tree algorithm to relate a subset of the patient data with a very high or very low mortality risk in a cohort of 5822 hospitalized and ambulatory patients with HF. From this model we derived a risk score that accurately discriminated between low and high-risk of death by identifying eight variables (diastolic blood pressure, creatinine, blood urea nitrogen, haemoglobin, white blood cell count, platelets, albumin, and red blood cell distribution width). This risk score had an area under the curve (AUC) of 0.88 and was predictive across the full spectrum of risk. External validation in two separate HF populations gave AUCs of 0.84 and 0.81, which were superior to those obtained with two available risk scores in these same populations. Conclusions: Using machine learning and readily available variables, we generated and validated a mortality risk score in patients with HF that was more accurate than other risk scores to which it was compared. These results support the use of this machine learning approach for the evaluation of patients with HF and in other settings where predicting risk has been challenging. (Less)

Left ventricular assist devices (LVADs) have revolutionized the therapy for advanced heart failure patients by improving the survival and quality of life. Despite all advancement, and improvement in LVAD technology, patients with implanted LVAD will face multiple challenges, including significant lifestyle modifications, complications associated with LVAD, and long-term management. One of the most crucial steps in improving the outcome of LVAD patients is the preparation of the patients and their caregivers before hospital discharge. These steps include adequate education of the patients and their caregivers, assessment of the home safety, referring to rehabilitation centers, and medically optimization of the patients before discharge. After discharge, patients will need close follow-ups. Patients, caregivers, and LVAD teams are responsible for managing blood pressure, driveline exit-site, and equipment. Most of the LVAD patients are on multiple medications, and there are unique pharmacological considerations that the LVAD patients and their caregivers need to be aware of; these include the anticoagulation therapy, antiplatelet therapy, and drug interactions. Caregivers are one of the essential members of the LVAD team. This chapter will review the outpatient challenges and management strategies for LVAD patients and their caregivers.

NEW FINDINGS What is the central question of this study? The venoarteriolar response (VAR) contributes substantially to the maintenance of orthostatic tolerance in humans. Despite its importance in haemodynamic homeostasis, the impact of ageing on the VAR remains understudied. What is the main finding and its importance? Older adults exhibit an augmented VAR in response to leg dependency. The age-related augmentation of the VAR might be linked with progressive increases of peripheral vascular resistance with ageing. We found a modest but significant correlation between the leg VAR and the morning blood pressure surge in older adults. Augmented leg VAR might contribute to the blood pressure elevation in the early morning. ABSTRACT The venoarteriolar response (VAR) is a non-adrenergic, non-baroreflex-mediated mechanism of vasoconstriction, which has been proposed to contribute ∼45% of the increase in total peripheral resistance during orthostasis. Despite its importance in human cardiovascular control during orthostatic stress, there is no information available regarding the impact of age and sex on the VAR or its role in diurnal blood pressure (BP) variation. We studied 33 (15 women) young (mean ± SD; 28 ± 4 years old) and 26 (12 women) older (71 ± 3 years old) healthy individuals. Brachial and femoral blood flow were measured using Doppler ultrasound. The percentage reduction in vascular conductance (blood flow/mean BP) during 4 min of limb dependency (35-40 cm below the heart level) was used to assess the VAR. The morning surge in BP was assessed using 24 h ambulatory BP monitoring. Peak VAR in the lower limb, but not in the upper limb, was significantly higher in the older than the younger adults (33 ± 4 versus 26 ± 6%, older versus young; P < 0.05). There was no sex difference in the VAR in either the young or the older group. A greater leg VAR was related to a greater morning surge in BP in older adults (r = -0.4, P = 0.02) but not in the young adults (r = -0.26, P = 0.1). Thus, advancing age enhances the VAR in the lower limb and is associated with the morning blood pressure surge in older adults. Sex does not affect this local axonal reflex in healthy humans.

Introduction For patients with end-stage hereditary transthyretin (TTR) cardiac amyloidosis, heart or heart-liver transplant can be considered. Due to advances in treatment, liver transplant may no longer be necessary, even if concomitant polyneuropathy is present as there are novel therapies that may halt, and in some cases reverse the burden of disease. We present a case of mixed phenotype TTR amyloidosis (cardiac involvement and polyneuropathy) successfully treated with orthotopic heart transplant (OHT) and patisiran therapy. Case Report A 73-year-old previously healthy African American male was referred for evaluation due to new-onset dyspnea. Electrocardiogram revealed atrial flutter with a controlled ventricular response. Echocardiogram was notable for severe biventricular hypertrophy, severe biatrial enlargement, severely depressed ejection fraction, and a pericardial effusion. An endomyocardial biopsy confirmed amyloid deposits. Mass spectrometry and genetic testing confirmed the presence of a pathogenic mutation in the TTR gene. During that same time period, the patient reported neuropathy. Nerve conduction studies revealed decrement in conduction consistent with an amyloid polyneuropathy. Despite initiation of tafamidis, the patient's clinical picture deteriorated, and he eventually required initiation of inotropes as a bridge to OHT. He successfully underwent OHT and was discharged home soon after. His immediate and long-term post-operative course was uneventful up until 10 months post-transplant, when the patient began to report worsening symptoms of neuropathy. Neurologic evaluation confirmed the clinical presence of an amyloid polyneuropathy, previously supported by nerve conduction studies. The patient was initiated on patisiran, an anti-transthyretin RNA interference agent, approximately one-year following transplant. At 18 months, the patient reports stability of his polyneuropathy symptoms and has not had any complications from patisiran infusions. Summary In patients undergoing OHT for hereditary TTR cardiac amyloidosis with concomitant polyneuropathy, post-transplant treatment with patisiran can be considered to halt progression of polyneuropathy. Effects on other organs including the transplanted heart may also be favorable, although this area is absent supporting data.

Background The practice of induction therapy with either rabbit anti-thymocyte globulin (r-ATG) or interleukin-2 receptor antagonists (IL-2RA) is common among heart transplant recipients. However, its benefits in the setting of contemporary maintenance immunosuppression with tacrolimus/mycophenolic acid (TAC/MPA) are unknown. Methods We compared post-transplant mortality among three induction therapy strategies (r-ATG vs IL2-RA vs no induction) in a retrospective cohort analysis of heart transplant recipients maintained on TAC/MPA in the Organ Procurement Transplant Network (OPTN) database between the years 2006 and 2015. We used a multivariable model adjusting for clinically important co-morbidities, and a propensity score analysis using the inverse probability weighted (IPW) method in the final analysis. Results In multivariable IPW analysis, r-ATG (HR = 1.23; 95% CI = 1.05-1.46, P = 0.01) remained significantly associated with a higher mortality. There was a trend toward having a higher mortality in the IL2-RA (HR = 1.11; 95% CI = 1.00-1.24, P = 0.06) group. Subgroup analyses failed to show a patient survival benefit in using either r-ATG or IL2-RA among any of the subgroups analyzed. Conclusion In this contemporary cohort of heart transplant recipients receiving TAC/MPA, neither r-ATG nor IL2-RA were associated with a survival benefit. On the contrary, adjusted analyses showed a significantly higher mortality in the r-ATG group and a trend toward higher mortality in the IL2-RA group. While caution is needed in interpreting treatment effects in an observational cohort, these data call into question the benefit of induction therapy as a common practice and highlight the need for more studies.

The effects of closed loop stimulation (CLS) on functional capacity in patients with heart failure with reduced ejection fraction (HFrEF) and chronotropic incompetence (CI) implanted with cardiac resynchronization therapy (CRT) is unknown. A randomized, blinded, cross-over designed trial enrolled

Author(s): Ho, Gordon; Tran, Hao A; Urey, Marcus A; Adler, Eric D; Pretorius, Victor G; Hsu, Jonathan C

Background: Poor fitness in middle age is a risk factor for heart failure, particularly heart failure with a preserved ejection fraction. The development of heart failure with a preserved ejection fraction is likely mediated through increased left ventricular (LV) stiffness, a consequence of sedentary aging. In a prospective, parallel group, randomized controlled trial, we examined the effect of 2 years of supervised high-intensity exercise training on LV stiffness. Methods: Sixty-one (48% male) healthy, sedentary, middle-aged participants (53±5 years) were randomly assigned to either 2 years of exercise training (n=34) or attention control (control; n=27). Right heart catheterization and 3-dimensional echocardiography were performed with preload manipulations to define LV end-diastolic pressure-volume relationships and Frank-Starling curves. LV stiffness was calculated by curve fit of the diastolic pressure-volume curve. Maximal oxygen uptake (Vo 2 max) was measured to quantify changes in fitness. Results: Fifty-three participants completed the study. Adherence to prescribed exercise sessions was 88±11%. Vo 2 max increased by 18% (exercise training: pre 29.0±4.8 to post 34.4±6.4; control: pre 29.5±5.3 to post 28.7±5.4, group×time P P =0.0018), whereas there was no change in controls (group×time P P =0.83). Exercise increased LV end-diastolic volume (group×time P P =0.007). Conclusions: In previously sedentary healthy middle-aged adults, 2 years of exercise training improved maximal oxygen uptake and decreased cardiac stiffness. Regular exercise training may provide protection against the future risk of heart failure with a preserved ejection fraction by preventing the increase in cardiac stiffness attributable to sedentary aging. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02039154.

Refractory atrial arrhythmias often require repeat catheter ablations causing decreased atrial compliance. Overtime, dyspnea may develop from secondary elevated pulmonary pressures because of a noncompliant left atrium (LA), referred to as the stiff LA syndrome. We present a case of a patient with a complicated arrhythmia history refractory to antiarrhythmic medications necessitating multiple ablations presenting with dyspnea on exertion. Cardiopulmonary exercise testing (CPET) with invasive hemodynamic measurement supported the diagnosis of stiff LA syndrome noticeable only during exercise. The patient is a 68-year-old male with a history of atrial arrhythmias refractory to anti-arrhythmic medications and repeat left atrial ablations who presents with exercise intolerance. A transthoracic echocardiogram showed preserved ejection fraction, biatrial enlargement, grade II diastolic dysfunction, and mildly elevated right ventricular systolic pressure, while a nuclear perfusion myocardial scan, cardiac computed tomography angiography, CPET, pulmonary function test, and ventilation-perfusion scan were unremarkable. Diuretics for presumed heart failure with preserved ejection fraction subsequently caused orthostatic symptoms. As such, he was referred for a repeat CPET with the addition …

Necrotizing autoimmune myopathy is a rare neuromuscular disorder characterized clinically by severe proximal limb muscle weakness and pathologically by necrotic muscle fibers with minimal inflammation. It is often associated with statin therapy, connective tissue diseases, and malignancy. Most have characteristic autoantibodies although a small subset present without myositis-specific autoantibodies. While cardiac involvement is rare, conduction abnormalities, diastolic dysfunction, and wall motion abnormalities have been reported. Severe cardiomyopathy from necrotizing autoimmune myopathy resulting in end-stage biventricular failure is extremely rare without a clear role for guideline-directed medical therapy. A 45-year-old man with hypothyroidism was admitted with several months of worsening proximal muscular weakness. He was found to have new severe biventricular dysfunction with conduction abnormalities during diagnostic work-up. Physical exam was notable for symmetric proximal muscle weakness in upper and lower extremities, sclerodactyly, elevated jugular venous distension, and lower extremity edema. Laboratory testing showed a creatine kinase of 3101 U/L, ANA 1:640, positive RNP antibodies, positive PM/Scl 100 antibodies. Anti-HMGCR antibodies and anti-SRP antibodies were negative. Lower extremity MRI showed diffuse bilateral symmetric myositis around the pelvis consistent with an inflammatory myopathy. EMG suggested irritable myopathy. Left thigh skeletal muscle biopsy showed necrotizing autoimmune myopathy with a paucity of inflammatory cells. Electrocardiogram revealed a right bundle branch block and 1st degree AV block. Frequent atrial and ventricular ectopic beats were seen on telemetry. Transthoracic echocardiogram showed biventricular failure with LVEF 23% and severe global hypokinesis. Cardiac MRI showed patchy foci of delayed subendocardial delayed enhancement. Endomyocardial biopsy did not reveal evidence of lymphocytic infiltration or ongoing myocarditis. Right heart catheterization was notable for elevated biventricular pressures with a cardiac index of 2.18. No obstructive coronary artery disease was seen on coronary angiogram. He was treated with intravenous immunoglobulins, methotrexate, and high-dose prednisone with improvement in proximal weakness. Low-dose spironolactone and lisinopril were started but could not be increased due to degree of hypotension. This case highlights a rare manifestation of an exceedingly rare autoimmune condition associated with high mortality. Given the variability of cardiac involvement in the disorder, a high clinical suspicion is needed to establish an early diagnosis and pursue aggressive treatment with up-front combination immunomodulating therapy, which has been associated with improved outcomes.

Predicting mortality in heart failure is critically important to patients, their providers, healthcare systems, and third-party payers alike. The ability to accurately assess mortality risk, however, has proven to be a difficult task. Previous risk scores have only had modest success due to one or

In a prospective, parallel group, randomized study, we examined the effect of two-years of high-intensity exercise training on integrated, dynamic (beat-by-beat), cardiovascular regulation incorporating (1) Starling mechanism, (2) arterial compliance, and (3) arterial-cardiac baroreflex function.

Tremendous advances in mechanical circulatory support have occurred during the past decade. The HeartMate II trials1,2 demonstrated that second-generation, continuous-flow (CF) left ventricular assist devices (LVADs) led to greater survival rates than first-generation, pulsatile devices for patients with advanced heart failure (HF). After Food and Drug Administration approval of the HeartMate II LVAD in 2008 as a bridge to transplant and in 2010 as destination therapy, axial CF-LVADs quickly replaced the HeartMate XVE, and the era of nonpulsatility was born.3 After publication of the Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure (ADVANCE) trial,4 the centrifugal-flow HeartWare VAD was introduced as an alternative to the HeartMate II trial for the bridge to transplant population, and now, >10 000 patients with HF have been implanted.3 Article see p 944 Although patients benefit from improvements in functional capacity and HF symptoms after CF-LVAD insertion,5 there is growing awareness of the risks associated with chronic exposure to minimally or entirely nonpulsatile blood flow. On a cellular and molecular level, nearly all CF-LVAD patients develop an acquired von Willebrand syndrome,6 which may increase the risk of nonsurgical, and more particularly, gastrointestinal bleeding. Indeed, the risk of bleeding seems to be inversely proportional to the degree of pulsatility in the system.7 Reductions in pulsatility also lead to maladaptations in neurohumoral pathways.8–10 For example, CF-LVADs are associated with a hyperadrenergic environment characterized by marked increases in sympathetic neural activity,8 which likely results from reductions in pulsatile distortion of the arterial baroreceptors. In addition, renin and aldosterone levels are higher than those observed in patients with pulsatile LVADs.9 Although it is not yet clear whether such neurohumoral abnormalities have adverse clinical consequences in this setting, it …