Closed loop stimulation in patients with chronic heart failure and severe chronotropic incompetence: Responders versus non-responders.

BACKGROUND: Clinical effects of rate-adaptive pacing (RAP) are unpredictable and highly variable among cardiac resynchronization therapy (CRT) patients with chronotropic incompetence. Physiologic sensors such as Closed Loop Stimulation (CLS), measuring intracardiac impedance changes (surrogate for ventricular contractility), may add clinical benefit and help identify predictors of response to RAP. The objective of the present BIOlCREATE study subanalysis was to identify criteria for selection of CRT patients who are likely to respond positively to CLS-based RAP. METHODS: In the randomized, crossover BIO|CREATE study, CRT patients with severe chronotropic incompetence and NYHA class II/III were randomized to CLS with conventional upper sensor rate programming or to no RAP for 1 month, followed by crossover for another month. At 1-month and 2-month follow-ups, patients underwent treadmill-based cardiopulmonary exercise test. Positive CLS response was defined as a ≥ 5% reduction in ventilatory efficiency slope. Eight of 17 patients (47%) were CLS responders. In this subanalysis, we compared responders and non-responders to explore outcomes, mechanisms, and predictors. RESULTS: All cardiopulmonary variables, health-related quality of life, patient activity status, and NT-proBNP concentration showed favorable trend in CLS responders and unfavorable trend in non-responders, underlining the need to find predictors. Following all analyses, we recommend CLS in heart failure patients with improved left ventricular ejection fraction (LVEF >40%, after a ≥ 10-point increase from a CRT-pre-implant value of ≤40%), corresponding to 'HFimpEF' in the universal classification system. CONCLUSION: HFimpEF patients are likely to benefit from CLS-based RAP, in contrast to 'HFrEF' (heart failure with reduced LVEF [≤40%]).

Impact of closed loop stimulation on prognostic cardiopulmonary variables in patients with chronic heart failure and severe chronotropic incompetence: a pilot, randomized, crossover study.

AIMS: Clinical effects of rate-adaptive pacing in heart failure patients with chronotropic incompetence (CI) undergoing cardiac resynchronization therapy (CRT) remain unclear. Closed loop stimulation (CLS) is a new rate-adaptive sensor in CRT devices. We evaluated the effectiveness of CLS in CRT patients with severe CI, focusing primarily on key prognostic variables assessed by cardiopulmonary exercise (CPX) testing. METHODS AND RESULTS: In the randomized, crossover, multicentre BIO|CREATE study, 20 CRT patients with severe CI and NYHA Class II/III (60%/40%) were randomized 1:1 to the sequence DDD-40 mode to DDD-CLS mode, or the sequence DDD-CLS mode to DDD-40 mode (1 month in each mode). Patients underwent symptom-limited treadmill-based CPX test in each mode. An improvement (decrease) of the ventilatory efficiency (VE) slope of ≥5% during CLS was regarded as positive response to CLS. Seventeen patients with full data sets had a mean intra-individual VE slope change of -1.8 ± 3.0 (-4.1%) with CLS (P = 0.23). Eight patients (47%) were CLS responders, with a -6.1 ± 2.7 (-16.4%) slope change (P = 0.029). Compared to non-responders, CLS responders had a higher left ventricular (LV) ejection fraction (46 ± 3 vs. 36 ± 9%; P = 0.0070), smaller end-diastolic LV volume (121 ± 34 vs. 181 ± 41 mL; P = 0.0085), smaller end-systolic LV volume (65 ± 23 vs. 114 ± 39 mL; P = 0.0076), and were predominantly in NYHA Class II (P = 0.0498). CONCLUSION: The data of the present pilot study are compatible with the notion that CLS activation may improve VE slope in CRT patients with severe CI and less advanced heart failure. Further research is needed to determine the long-term clinical outcomes of CLS.

Streamlining cardiopulmonary exercise testing for use as a screening and tracking tool in primary care.

Cardiopulmonary exercise testing (CPET) using a spectrum of different approaches demonstrates usefulness for objectively assessing patient disease severity in clinical and research settings. Still, an absence of trained specialists and/or improper data interpretation techniques can pose major limitations to the effective use of CPET for the clinical classification of patients. This study aimed to test an automated disease likelihood scoring algorithm system based on cardiopulmonary responses during a simplified step-test protocol. For patients with heart failure (HF), pulmonary hypertension (PAH), obstructive lung disease (OLD), or restrictive lung disease (RLD), we compared patient scores stratified into one of four "silos" generated from our novel algorithm system against patient evaluations provided by expert clinicians. Patients with HF (n = 12), PAH (n = 9), OLD (n = 16), or RLD (n = 10) performed baseline pulmonary function testing followed by submaximal step-testing. Breath-by-breath measures of ventilation and gas exchange, in addition to oxygen saturation and heart rate were collected continuously throughout testing. The algorithm demonstrated close alignment with patient assessments provided by clinical specialists: HF (r = 0.89, P < 0.01); PAH (r = 0.88, P < 0.01); OLD (r = 0.70, P < 0.01); and RLD (r = 0.88, P < 0.01). Furthermore, the algorithm was capable of differentiating major disease from other disease pathologies. Thus, in a clinically relevant manner, these data suggest this simplified automated disease algorithm scoring system used during step-testing to identify the likelihood that patients have HF, PAH, OLD, or RLD closely correlates with patient assessments conducted by trained clinicians.

Algorithm for Predicting Disease Likelihood From a Submaximal Exercise Test.

We developed a simplified automated algorithm to interpret noninvasive gas exchange in healthy subjects and patients with heart failure (HF, n = 12), pulmonary arterial hypertension (PAH, n = 11), chronic obstructive lung disease (OLD, n = 16), and restrictive lung disease (RLD, n = 12). They underwent spirometry and thereafter an incremental 3-minute step test where heart rate and SpO2 respiratory gas exchange were obtained. A custom-developed algorithm for each disease pathology was used to interpret outcomes. Each algorithm for HF, PAH, OLD, and RLD was capable of differentiating disease groups (P < .05) as well as healthy cohorts (n = 19, P < .05). In addition, this algorithm identified referral pathology and coexisting disease. Our primary finding was that the ranking algorithm worked well to identify the primary referral pathology; however, coexisting disease in many of these pathologies in some cases equally contributed to the cardiorespiratory abnormalities. Automated algorithms will help guide decision making and simplify a traditionally complex and often time-consuming process.

Clinical feasibility of exercise-based A-V interval optimization for cardiac resynchronization: a pilot study.

BACKGROUND: One-third of eligible patients fail to respond to cardiac resynchronization therapy (CRT). Current methods to "optimize" the atrio-ventricular (A-V) interval are performed at rest, which may limit its efficacy during daily activities. We hypothesized that low-intensity cardiopulmonary exercise testing (CPX) could identify the most favorable physiologic combination of specific gas exchange parameters reflecting pulmonary blood flow or cardiac output, stroke volume, and left atrial pressure to guide determination of the optimal A-V interval. METHODS: We assessed relative feasibility of determining the optimal A-V interval by three methods in 17 patients who underwent optimization of CRT: (1) resting echocardiographic optimization (the Ritter method), (2) resting electrical optimization (intrinsic A-V interval and QRS duration), and (3) during low-intensity, steady-state CPX. Five sequential, incremental A-V intervals were programmed in each method. Assessment of cardiopulmonary stability and potential influence on the CPX-based method were assessed. RESULTS: CPX and determination of a physiological optimal A-V interval was successfully completed in 94.1% of patients, slightly higher than the resting echo-based approach (88.2%). There was a wide variation in the optimal A-V delay determined by each method. There was no observed cardiopulmonary instability or impact of the implant procedure that affected determination of the CPX-based optimized A-V interval. CONCLUSIONS: Determining optimized A-V intervals by CPX is feasible. Proposed mechanisms explaining this finding and long-term impact require further study.

Effects of atrioventricular and interventricular delays on gas exchange during exercise in patients with heart failure.

BACKGROUND: Cardiac resynchronization therapy (CRT) has been an important treatment for heart failure. However, it is controversial as to whether an individualized approach to altering AV and VV timing intervals would improve outcomes. Changes in respiratory patterns and gas exchange are dynamic and may be influenced by timing delays. Light exercise enhances the heart and lung interactions. Thus, in this study we investigated changes in non-invasive gas exchange by altering AV and VV timing intervals during light exercise. METHODS: Patients (n = 20, age 66 ± 9 years) performed two walking tests post-implantation. The protocol evaluated AV delays (100, 120, 140, 160 and 180 milliseconds), followed by VV delays (0, -20 and -40 milliseconds) while gas exchange was assessed. RESULTS: There was no consistent group pattern of change in gas exchange variables across AV and VV delays (p > 0.05). However, there were modest changes in these variables on an individual basis with variations in VE/VCO2 averaging 10%; O2 pulse 11% and PETCO2 5% across AV delays, and 4%, 8% and 2%, respectively, across VV delays. Delays that resulted in the most improved gas exchange differed from nominal in 17 of 20 subjects. CONCLUSION: Gas exchange measures can be improved by optimization of AV and VV delays and thus could be used to individualize the approach to CRT optimization.

Use of noninvasive gas exchange to track pulmonary vascular responses to exercise in heart failure.

We determined whether a non-invasive gas exchange based estimate of pulmonary vascular (PV) capacitance [PVCAP = stroke volume (SV) × pulmonary arterial pressure (Ppa)] (GXCAP) tracked the PV response to exercise in heart-failure (HF) patients. Pulmonary wedge pressure (Ppw), Ppa, PV resistance (PVR), and gas exchange were measured simultaneously during cycle exercise in 42 HF patients undergoing right-heart catheterization. During exercise, PETCO2 and VE/VCO2 were related to each other (r = -0.93, P < 0.01) and similarly related to mean Ppa (mPpa) (r = -0.39 and 0.36; P < 0.05); PETCO2 was subsequently used as a metric of mPpa. Oxygen pulse (O2 pulse) tracked the SV response to exercise (r = 0.91, P < 0.01). Thus, GXCAP was calculated as O2 pulse × PETCO2. During exercise, invasively determined PVCAP and non-invasive GXCAP were related (r = 0.86, P < 0.01), and GXCAP correlated with mPpa and PVR (r = -0.46 and -0.54; P < 0.01). In conclusion, noninvasive gas exchange measures may represent a simple way to track the PV response to exercise in HF.

A multivariable index for grading exercise gas exchange severity in patients with pulmonary arterial hypertension and heart failure.

Patients with pulmonary arterial hypertension (PAH) and heart failure (HF) display many abnormalities in respiratory gas exchange. These abnormalities are accentuated with exercise and track with disease severity. However, use of gas exchange measures in day-to-day clinical practice is limited by several issues, including the large number of variables available and difficulty in data interpretation. Moreover, maximal exercise testing has limitations in clinical populations due to their complexity, patient anxiety and variability in protocols and cost. Therefore, a multivariable gas exchange index (MVI) that integrates key gas exchange variables obtained during submaximal exercise into a severity score that ranges from normal to severe-very-severe is proposed. To demonstrate the usefulness of this index, we applied this to 2 groups (PAH, n = 42 and HF, n = 47) as well as to age matched healthy controls (n = 25). We demonstrate that this score tracks WHO classification and right ventricular systolic pressure in PAH (r = 0.53 and 0.73, P ≤ 0.01) and NYHA and cardiac index in HF (r = 0.49 and 0.74, P ≤ 0.01). This index demonstrates a stronger relationship than any single gas exchange variable alone. In conclusion, MVI obtained from light, submaximal exercise gas exchange is a useful approach to simplify data interpretation in PAH and HF populations.

Ventilatory expired gas at constant-rate low-intensity exercise predicts adverse events and is related to neurohormonal markers in patients with heart failure.

BACKGROUND: Ventilatory efficiency (VE/VCO(2) ratio) and the partial pressure of end-tidal carbon dioxide (P(ET)CO(2)), obtained during moderate to high levels of physical exertion demonstrate prognostic value in heart failure (HF). The present investigation assesses the clinical utility of these variables during low-intensity exercise. METHODS AND RESULTS: One hundred and thirty subjects diagnosed with HF underwent a 2-minute, constant-rate treadmill session at 2 miles per hour. Both the VE/VCO(2) ratio and P(ET)CO(2) were recorded during exercise (30-second average) and their change (Delta) from rest. B-type and atrial natriuretic peptide (BNP and ANP) were also determined. Only P(ET)CO(2) and DeltaP(ET)CO(2) emerged from the multivariate Cox regression. Receiver operating characteristic curve analysis revealed the prognostic classification schemes were significant with thresholds of < or >or=34 mm Hg (hazard ratio: 4.2, 95% CI: 2.2-8.0, P < .001) and < or >or=1 mm Hg (hazard ratio: 3.5, 95% CI: 1.9-6.6, P < .001) being optimal for P(ET)CO(2) and DeltaP(ET)CO(2), respectively. Moreover, subjects with a P(ET)CO(2)>or=34 mm Hg had a significantly lower BNP (214.1 +/- 431.9 vs. 1110.5 +/- 1854.0 pg/mL, P=.005) and ANP (108.2 +/- 103.6 vs. 246.2 +/- 200.4 pg/mL, P < .001). CONCLUSIONS: The results of this pilot study indicate ventilatory expired gas analysis during a short bout of low-intensity exercise may provide insight into prognosis and cardiac stability.

D-ribose aids advanced ischemic heart failure patients.

Patients with advanced heart failure are exercise intolerant. Low cellular energy levels in the failing heart have been proposed. Energy enhancing substrates have revealed mixed results. Ribose, a pentose monosaccharide, has shown to replenish low myocardial energy levels, improving cardiac dysfunction following ischemia, and improving ventilation efficiency in patients with heart failure. As current pharmaceuticals do not address cellular energy levels, this study was designed to investigate the role of ribose on ventilation at anaerobic threshold in congestive heart failure patients. d-ribose (5 gms/dose, tid) was assessed in 16 NYHA class III-IV, heart failure patients with VO(2), tidal volume/VCO(2), heart rate/tidal volume evaluated at 8 weeks. All patients had a significant improvement in ventilatory parameters at anaerobic threshold, along with a 44% Weber class improvement. Ribose improved the ventilatory exercise status in advanced heart failure patients.

D-Ribose improves diastolic function and quality of life in congestive heart failure patients: a prospective feasibility study.

Patients with chronic coronary heart disease often suffer from congestive heart failure (CHF) despite multiple drug therapies. D-Ribose has been shown in animal models to improve cardiac energy metabolism and function following ischaemia. This was a prospective, double blind, randomized, crossover design study, to assess the effect of oral D-ribose supplementation on cardiac hemodynamics and quality of life in 15 patients with chronic coronary artery disease and CHF. The study consisted of two treatment periods of 3 weeks, during which either oral D-ribose or placebo was administered followed by a 1-week wash out period, and then administration of the other supplement. Assessment of myocardial functional parameters by echocardiography, quality of life using the SF-36 questionnaire and functional capacity using cycle ergometer testing was performed. The administration of D-ribose resulted in an enhancement of atrial contribution to left ventricular filling (40+/-11 vs. 45+/-9%, P=0.02), a smaller left atrial dimension (54+/-20 vs. 47+/-18 ml, P=0.02) and a shortened E wave deceleration (235+/-64 vs. 196+/-42, P=0.002) by echocardiography. Further, D-ribose also demonstrated a significant improvement of the patient's quality of life (417+/-118 vs. 467+/-128, P< or =0.01). In comparison, placebo did not result in any significant echocardiographic changes or in quality of life. This feasibility study in patients with coronary artery disease in CHF revealed the beneficial effects of D-ribose by improving diastolic functional parameters and enhancing quality of life.

Right Atrial Thrombi and Depressed Right Atrial Appendage Function After Cardioversion of Atrial Fibrillation.

BACKGROUND: It has been shown that cardioversion of atrial fibrillation may result in left atrial chamber and appendage dysfunction and cause new thrombi in the left atrium. The aim of this prospective study was to investigate right atrial appendage function and assess the incidence of new right atrial thrombi after electrical cardioversion. METHODS: Transthoracic echocardiography was performed in 25 patients 4 h before and at 24 h and 7 days after electrical cardioversion to determine right and left atrial mechanical function (internal atrial defibrillation, n = 16; external electrical cardioversion, n = 9), as assessed by peak A wave velocities derived from the transtricuspid and transmitral velocity profiles. In addition, transesophageal echocardiography was performed 4 h before and 24 h after cardioversion to evaluate postcardioversion thrombus formation in the right and left atrial chambers and to assess right and left atrial appendage function. The degree of spontaneous echo contrast was noted, and peak emptying velocities of the appendages were measured before and after cardioversion. RESULTS: Peak emptying velocities of both the right atrial appendage (mean +/- SD, 0.23 +/- 0.1 vs 0.32 +/- 0.11 m/sec; P = 0.02) and the left atrial appendage (0.3 +/- 0.15 vs 0.4 +/- 0.15 m/sec; P = 0.01) were significantly lower 24 h after cardioversion compared with 4 h before cardioversion, respectively. The degree of spontaneous echo contrast increased in the left atrium after cardioversion from 1.0 +/- 1.2 to 1.9 +/- 2.1 (P = 0.02), and in the right atrium, it increased from 0.8 +/- 1.1 to 1.2 +/- 1.1 (P = 0.1) after cardioversion. Peak A wave transtricuspid velocity increased from 0.26 +/- 0.05 m/sec at 24 h to 0.38 +/- 0.06 m/sec (P = 0.001) after 7 days; respective values for transmitral peak A wave velocity were 0.39 +/- 0.15 and 0.54 +/- 0.16 m/sec (P = 0.009). No thrombi were found in either the right or left atrium before cardioversion. In two patients, new thrombi in the right atrium were detected 24 h after internal atrial defibrillation. Thrombi were located at the superior rim of the fossa ovalis in both patients with patent foramen ovale. Another patient had developed a thrombus in the left atrial appendage. CONCLUSIONS: Electrical cardioversion may not only cause left atrial chamber and appendage dysfunction and left atrial thrombi but also lead to depressed right atrial appendage function and the generation of new thrombi in the body of the right atrium.