Olson, Thomas P.

Background— Afterload reduction is a cornerstone in the management of patients with heart failure (HF) and reduced ejection fraction. However, arterial load and the effect of HF therapies on afterload might vary between individuals. Tailoring vasoactive medicines to patients with HF based upon better understanding of arterial afterload may enable better individualization of therapy. Methods and Results— Subjects with HF and reduced ejection fraction underwent aggressive titration of vasoactive HF therapies with assessment of central aortic waveforms analyzed using pulse wave, wave separation, and arterial reservoir models. Clinical response to treatment was assessed using the 6-minute walk test distance, which increased in 25 subjects and decreased or remained unchanged in 13. Subjects with improvement on therapy displayed higher aortic pressure wave pulsatility (central pulse pressure [PP], reflected pressure wave, and reservoir pressure) at study entry compared with subjects without improvement (all P <0.05). Parameters derived by the arterial analysis methods were strongly correlated with one another and displayed similar ability to predict improvement. Aortic pressure pulsatility significantly decreased in subjects with functional improvement, whereas no change was observed in patients without functional improvement ( P for interaction <0.05). These differences in arterial load at baseline and on therapy were not apparent from conventional brachial artery cuff pressure assessments. Conclusions— Increased aortic pressure wave pulsatility and greater decrease in pulsatility on treatment are associated with functional improvement in patients with HF and reduced ejection fraction receiving aggressive vasodilator titration. These differences are not identifiable using brachial cuff pressures. Central aortic waveform analysis may enable better individualization of vasoactive therapies in chronic HF and reduced ejection fraction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00588692.

Background: Diagnosis of heart failure with preserved ejection fraction (HFpEF) is challenging and relies largely on demonstration of elevated cardiac filling pressures (pulmonary capillary wedge pressure). Current guidelines recommend use of natriuretic peptides (N-terminal pro-B type natriuretic peptide) and rest/exercise echocardiography (E/e′ ratio) to make this determination. Data to support this practice are conflicting. Methods: Simultaneous echocardiographic-catheterization studies were prospectively conducted at rest and during exercise in subjects with invasively proven HFpEF (n=50) and participants with dyspnea but no identifiable cardiac pathology (n=24). Results: N-Terminal pro-B type natriuretic peptide levels were below the level considered to exclude disease (≤125 pg/mL) in 18% of subjects with HFpEF. E/e′ ratio was correlated with directly measured pulmonary capillary wedge pressure at rest ( r =0.63, P <0.0001) and during exercise ( r =0.57, P <0.0001). Although specific, current guidelines were poorly sensitive, identifying only 34% to 60% of subjects with invasively proven HFpEF on the basis of resting echocardiographic data alone. Addition of exercise echocardiographic data (E/e′ ratio>14) improved sensitivity (to 90%) and thus negative predictive value, but decreased specificity (71%). Conclusions: Currently proposed HFpEF diagnostic guidelines on the basis of resting data are poorly sensitive. Adding exercise E/e′ data improves sensitivity and negative predictive value but compromises specificity, suggesting that exercise echocardiography may help rule out HFpEF. These results question the accuracy of current approaches to exclude HFpEF on the basis of resting data alone and reinforce the value of exercise testing using invasive and noninvasive hemodynamic assessments to definitively confirm or refute the diagnosis of HFpEF. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique Identifier: NCT01418248.

Cardiac output (CO) assessment as a basic hemodynamic parameter has been of interest in exercise physiology, cardiology, and anesthesiology. Noninvasive techniques available are technically challenging, and thus difficult to use outside of a clinical or laboratory setting. We propose a novel method of noninvasive CO assessment using a single, upper-arm cuff. The method uses the arterial pressure pulse wave signal acquired from the brachial artery during 20-s intervals of suprasystolic occlusion. This method was evaluated in a cohort of 12 healthy individuals (age, 27.7 ± 5.4 yr, 50% men) and compared with an established method for noninvasive CO assessment, the open-circuit acetylene method (OpCirc) at rest, and during low- to moderate-intensity exercise. CO increased from rest to exercise (rest, 7.4 ± 0.8 vs. 7.2 ± 0.8; low, 9.8 ± 1.8 vs. 9.9 ± 2.0; moderate, 14.1 ± 2.8 vs. 14.8 ± 3.2 l/min) as assessed by the cuff-occlusion and OpCirc techniques, respectively. The average error of experimental technique compared with OpCirc was −0.25 ± 1.02 l/min, Pearson’s correlation coefficient of 0.96 (rest + exercise), and 0.21 ± 0.42 l/min with Pearson’s correlation coefficient of 0.87 (rest only). Bland-Altman analysis demonstrated good agreement between methods (within 95% boundaries); the reproducibility coefficient (RPC) = 0.84 l/min with R2= 0.75 at rest and RPC = 2 l/min with R2= 0.92 at rest and during exercise, respectively. In comparison with an established method to quantify CO, the cuff-occlusion method provides similar measures at rest and with light to moderate exercise. Thus, we believe this method has the potential to be used as a new, noninvasive method for assessing CO during exercise.

Background Beta-2 adrenergic receptors (β 2 ARs) are located throughout the body including airway and alveolar cells. The β 2 ARs regulate lung fluid clearance through a variety of mechanisms including ion transport on alveolar cells and relaxation of the pulmonary lymphatics. We examined the effect of an inhaled β 2 -agonist (albuterol) on alveolar-capillary membrane conductance (DM) and pulmonary capillary blood volume ( V C ) in healthy humans. Methods We assessed the diffusing capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO) at baseline, 30 minutes, and 60 minutes following nebulized albuterol (2.5 mg, diluted in 3 mL normal saline) in 45 healthy subjects. Seventeen subjects repeated these measures following nebulized normal saline (age = 27 ± 9 years, height = 165 ± 21 cm, weight = 68 ± 12 kg, BMI = 26 ± 9 kg/m 2 ). Cardiac output (Q), heart rate, systemic vascular resistance (SVR), blood pressure, oxygen saturation, forced expiratory volume at one-second (FEV 1 ), and forced expiratory flow at 50% of forced vital capacity (FEF 50 ) were assessed at baseline, 30 minutes, and 60 minutes following the administration of albuterol or saline. Results Albuterol resulted in a decrease in SVR, and an increase in Q, FEV 1 , and FEF 50 compared to saline controls. Albuterol also resulted in a decrease in V C at 60 minutes post albuterol. Both albuterol and normal saline resulted in no change in DLCO or DM when assessed alone, but a significant increase was observed in DM when accounting for changes in V C . Conclusion These data suggest that nebulized albuterol improves pulmonary function in healthy humans, while nebulization of both albuterol and saline results in an increase in DM/ V C .

Although pathophysiological links between postmenopause and healthy aging remain unclear, both factors are associated with increased blood pressure and sympathetic nerve activity (SNA) in women. Activation of polymodal musculoskeletal neural afferents originating within adventia of venules modulates SNA and blood pressure control during exercise in healthy adults. We hypothesized transient subsystolic regional circulatory occlusion (RCO) during exercise sensitizes these afferents leading to augmented systemic vascular resistance (SVR)-mediated increased mean arterial pressure (MAP) in postmenopause vs. premenopause. Normotensive women in premenopause or postmenopause ( n = 14 and 14; ages: 30 ± 9 and 55 ± 7 yr, respectively; P < 0.01) performed: 1) peak exercise testing and 2) fixed-load cycling at 30% peak workload (48 ± 11 and 38 ± 6 W, respectively; P < 0.01), whereby the initial 3 min were control exercise without RCO (CTL), thereafter including 2 min of bilateral-thigh RCO to 20, 40, 60, 80, or 100 mmHg (randomized), with 2 min deflation between RCO. Both MAP (17 ± 4 vs. 4 ± 4%, P = 0.02) and SVR (16 ± 8 vs. −3 ± 8%, P = 0.04) increased at 80 mmHg from CTL in postmenopause vs. premenopause, respectively. However, cardiac index was similar in postmenopause vs. premenopause at 80 mmHg from CTL (1 ± 6 vs. 7 ± 6%, respectively; P = 0.15). There was no continuous effect of aging in MAP ( P = 0.12), SVR ( P = 0.07), or cardiac index ( P = 0.18) models. These data suggest transient locomotor subsystolic RCO sensitizes musculoskeletal afferents, which provoke increased SVR to generate augmented MAP during exercise in postmenopause. These observations provide a novel approach for understanding the age-independent variability in exercise blood pressure control across the normotensive adult pre- to postmenopause spectrum.

Background— Pulmonary hypertension and right ventricular (RV) dysfunction are common in patients with advanced heart failure with preserved ejection fraction (HFpEF), yet their underlying mechanisms remain poorly understood. We sought to examine RV–pulmonary artery (PA) functional reserve responses and RV–PA coupling at rest and during β-adrenergic stimulation in subjects with earlier stage HFpEF. Methods and Results— In a prospective trial, subjects with HFpEF (n=39) and controls (n=18) underwent comprehensive invasive and noninvasive hemodynamic assessment using high fidelity micromanometer catheters, echocardiography, and expired gas analysis at rest and during dobutamine infusion. HFpEF subjects displayed similar RV structure but significantly impaired RV systolic (lower RV d P /d t max /IP and s′) and diastolic function (higher RV τ) coupled with more severe pulmonary vascular disease, manifest by higher PA pressures, higher PA resistance, and lower PA compliance compared with controls. Dobutamine infusion caused greater pulmonary vasodilation in HFpEF compared with controls, with enhanced reductions in PA resistance, greater increase in PA compliance, and a more negative slope in the PA pressure–flow relationship when compared with controls (all P <0.001). RV–PA coupling analysis revealed that dobutamine improved RV ejection in HFpEF subjects through afterload reduction alone, rather than through enhanced contractility, indicating RV systolic reserve dysfunction. Conclusions— Pulmonary hypertension in early stage HFpEF is related to partially reversible pulmonary vasoconstriction coupled with RV systolic and diastolic dysfunction, even in the absence of RV structural remodeling. Pulmonary vascular tone is more favorably responsive to β-adrenergic stimulation in HFpEF than controls, suggesting a potential role for β-agonists in the treatment of patients with HFpEF and pulmonary hypertension. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01418248.

Background— Invasive hemodynamic exercise testing is commonly used in the evaluation of patients with suspected heart failure with preserved ejection fraction (HFpEF) or pulmonary hypertension. Saline loading has been suggested as an alternative provocative maneuver, but the hemodynamic changes induced by the 2 stresses have not been compared. Methods and Results— Twenty-six subjects (aged, 67±10 years; n=14 HFpEF; n=12 control) underwent right heart catheterization at rest, during supine exercise, and with acute saline loading in a prospective study. Exercise and saline each increased cardiac output and pressures in the right atrium, pulmonary artery, and pulmonary capillary wedge positions. Changes in heart rate, blood pressure, rate–pressure product, and cardiac output were greater with exercise compared with saline. In controls subjects, right atrial pressure, pulmonary arterial pressure, and pulmonary capillary wedge pressure increased similarly with saline and exercise, whereas in HFpEF subjects, exercise led to ≈2-fold greater increases in right atrial pressure (10±4 versus 6±3 mm Hg; P =0.02), pulmonary arterial pressure (22±8 versus 11±4 mm Hg; P =0.0001), and pulmonary capillary wedge pressure (18±5 versus 10±4 mm Hg; P <0.0001) compared with saline. Systolic reserve assessed by stroke work and cardiac power output was lower in HFpEF subjects with both exercise and saline. Systemic and pulmonary arterial compliances were enhanced with saline but reduced with exercise. Conclusions— Exercise elicits greater pulmonary capillary wedge pressure elevation compared with saline in HFpEF but not controls, suggesting that hemodynamic stresses beyond passive stiffness and increased venous return explain the development of pulmonary venous hypertension in HFpEF. Exercise testing is more sensitive than saline loading to detect hemodynamic derangements indicative of HFpEF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01418248.

Background Medication treatment decisions in heart failure ( HF ) are currently informed by measurements of brachial artery pressure, but ventricular afterload is more accurately represented by central aortic pressure, which differs from brachial pressure. We sought to determine whether aggressive titration of vasoactive medicines beyond goal‐directed heart failure medical therapy ( GDMT ) based upon aortic pressure improves exercise capacity and cardiovascular structure‐function. Methods and Results Subjects with chronic HF (n=50) underwent cardiopulmonary exercise testing, echocardiography, and arterial tonometry to measure aortic pressure and augmentation index, and were then randomized to aortic pressure‐guided treatment (active, n=23) or conventional therapy (control, n=27). Subjects returned for 6 monthly visits wherein GDMT was first optimized. Additional vasoactive therapies were then sequentially added with the goal to reduce aortic augmentation index to 0% (active) or if brachial pressure remained elevated (control). Subjects randomized to active treatment experienced greater improvement in peak oxygen consumption compared with controls (1.37±3.76 versus −0.65±2.21 mL min −1 kg −1 , P =0.025) though reductions in aortic augmentation index were similar (−7±9% versus −5±6%, P =0.46). Forward stroke volume increased while arterial elastance and left ventricular volumes decreased in all participants, with no between‐group difference. Subjects randomized to active treatment were more likely to receive additional vasoactive therapies including nitrates, aldosterone antagonists and hydralazine, with no increased risk of hypotension or worsening renal function. Conclusions Maximization of goal‐directed medical therapy in heart failure patients may enhance afterload reduction and lead to reverse remodeling, while additional medicine titration based upon aortic pressure data improves exercise capacity in patients with heart failure.

New FindingsWhat is the central question of this study?Patients with heart failure often develop ventilatory abnormalities at rest and during exercise, but the mechanisms underlying these abnormalities remain unclear. This study investigated the influence of inhibiting afferent neural feedback from locomotor muscles on the ventilatory response during exercise in heart failure patients.What is the main finding and its importance?Our results suggest that inhibiting afferent feedback from locomotor muscle via intrathecal opioid administration significantly reduces the ventilatory response to exercise in heart failure patients.Patients with heart failure (HF) develop ventilatory abnormalities at rest and during exercise, but the mechanism(s) underlying these abnormalities remain unclear. We examined whether the inhibition of afferent neural feedback from locomotor muscles during exercise reduces exercise ventilation in HF patients. In a randomized, placebo‐controlled design, nine HF patients (age, 60 ± 2 years; ejection fraction, 27 ± 2%; New York Heart Association class 2 ± 1) and nine control subjects (age, 63 ± 2 years) underwent constant‐work submaximal cycling (65% peak power) with intrathecal fentanyl (impairing the cephalad projection of opioid receptor‐sensitive afferents) or sham injection. The hypercapnic ventilatory response was measured to determine whether cephalad migration of fentanyl occurred. There were no differences in hypercapnic ventilatory response within or between groups in either condition. Despite a lack of change in ventilation, tidal volume or respiratory rate, HF patients had a mild increase in arterial carbon dioxide () and a decrease in oxygen (;P< 0.05 for both) at rest. The control subjects demonstrated no change in,, ventilation, tidal volume or respiratory rate at rest. In response to fentanyl during exercise, HF patients had a reduction in ventilation (63 ± 6versus44 ± 3 l min−1,P< 0.05) due to a lower respiratory rate (30 ± 1versus26 ± 2 breaths min−1,P< 0.05). The reduced ventilation resulted in lower(97.6 ± 2.5versus79.5 ± 3.0 mmHg,P< 0.05) and increased(37.3 ± 0.9versus43.5 ± 1.1 mmHg,P< 0.05), with significant improvement in ventilatory efficiency (reduction in the ventilatory equivalent for carbon dioxide;P< 0.05 for all). The control subjects had no change in ventilation or measures of arterial blood gases. These data suggest that inhibition of afferent feedback from locomotor muscle significantly reduces the ventilatory response to exercise in HF patients.