Myocardial O2 Demand Research Articles

Increased inflammatory proteins in patients with severe obesity is associated with persistent myocardial dysfunction one year after bariatric surgery. The FatWest study

Abstract Background Over half of patients with severe obesity have subclinical cardiac dysfunction and about 40% maintain impaired left ventricular (LV) mechanics one year after bariatric surgery despite impressive weight reduction. Purpose To investigate whether measurement of serum markers of chronic inflammation before bariatric surgery can help identify patients with persistent postoperative cardiac dysfunction. Methods In the prospective FatWest (Bariatric Surgery on the West Coast of Norway) study 75 patients with severe obesity (44±9 years, 72% women, body mass index [BMI] 41.5±4.7 kg/m², 56% with hypertension) underwent echocardiography before and 1 year after Roux-en-Y gastric bypass surgery. We assessed LV mechanics in the radial and longitudinal direction by the midwall shortening (MWS) and global longitudinal strain (GLS). Myocardial oxygen (O2) demand was derived from the LV mass-wall stress-heart rate product. Inflammation was assessed by high-sensitive C-reactive protein, serum amyloid A and calprotectin in biobank samples. Results Preoperatively, patients with low MWS (45% of the group) had increased high-sensitive C-reactive protein, total calprotectin, and several amyloid A isoforms, and patients with high myocardial O2 demand (20%) had high total calprotectin (all p<0.05). In the whole study population, bariatric surgery induced a significant improvement in both BMI (12.6±3.7 kg/m²), GLS (4.74±5.20%), myocardial O2 demand and inflammatory proteins (Figure A, all p<0.001). However, there were no significant improvement in MWS, and 33% of patients still had low MWS at the 1-year control. In logistic regression analyses, after adjustment for sex, BMI and hypertension, increased preoperative serum total calprotectin was independently associated with high myocardial O2 demand both pre- and postoperatively (Nagelkerke R² 0.47 and 0.51, p<0.05). In similar analyses, higher preoperative serum total amyloid A was related to low MWS and high myocardial O2 demand 1 year after surgery (Nagelkerke R² 0.55 and 0.51, p<0.05). A simple preoperative risk score based on sex, hypertension, biplane ejection fraction, and serum total amyloid A above 4.0 mg/ml predicted low 1-year MWS with 79% sensitivity and 75% specificity at a value of 1.75 in Receiver Operating Characteristic (ROC) analysis (AUC 0.80, p<0.001) (Figure B). Low GLS was not predicted by inflammatory biomarkers at any timepoint. Conclusion Increased serum concentration of inflammatory proteins in patients with severe obesity is linked to persistently elevated myocardial O2 demand and impaired LV midwall mechanics 1 year after bariatric surgery.Figure AFigure B

Abstract 10291: Electrocardiographic Markers of Subclinical Myocardial Dysfunction in Patients with Severe Obesity and Normal Ejection Fraction. The FatWest Study

Introduction: Patients with severe obesity are predisposed to left ventricular (LV) myocardial dysfunction and increased myocardial oxygen (O 2 ) demand despite preserved ejection fraction (EF). Hypothesis: To test whether electrocardiography (ECG) may be used to identify patients with severe obesity that have myocardial dysfunction despite normal EF by echocardiography. Methods: In the prospective FatWest (Bariatric Surgery on the West Coast of Norway) study, 116 severely obese patients (41±11 years, 75% women, body mass index [BMI] 41.7±4.6 kg/m 2 , 57% with hypertension, EF 61±5%) underwent 12-lead ECG and echocardiography before a Roux-en-Y gastric bypass surgery. Low LV mechanics was defined as global longitudinal strain (GLS) below the median, and high myocardial O 2 demand as LV mass-wall stress-heart rate product above the median value. ECG markers of atrial (P axis and duration) and ventricular (QRS axis and duration, T axis, QRS-T angle, time to intrinsicoid deflection (ID), and corrected QT (QTc)) de- and repolarization were analyzed. Results: Median GLS was -15.5%, and median myocardial O 2 demand 1.47 x106 g kdyne/cm 2 bpm. Patients with low GLS had longer QRS, time to ID and QTc duration, while those with high myocardial O 2 demand had increased P axis and duration (all p<0.05). In multivariate regression analyses, longer QTc was associated with lower GLS (R 2 0.24) and increased P axis with higher myocardial O 2 demand (R 2 0.21) independent of age, gender, BMI and hypertension (all p<0.05). A QTc >435ms and P axis >42° had 70% specificity in detecting low GLS and high myocardial O 2 demand (Figure). Conclusion: In severely obese patients, ECG measures of atrial activation and delayed ventricular repolarization were independently associated with low LV myocardial function and high myocardial O 2 demand. ECG screening before bariatric surgery may identify patients in whom advanced echocardiography is warranted.

Abstract 16319: Large Weight Loss Improves Left Ventricular Geometry but Not Myocardial Function 6 Months After Bariatric Surgery (the Fatwest Study)

Background: Bariatric surgery causes rapid and large weight loss and improves cardiovascular risk profile, yet the effect on left ventricular (LV) systolic function has been less explored. Methods: In the prospective FatWest (Bariatric Surgery on the West Coast of Norway) study 98 severely obese patients (44±10 years, 72% women, preoperative body mass index [BMI] 41.8±4.8 kg/m 2 , 36% with hypertension) underwent echocardiography before and 5.9 months after gastric bypass surgery. We assessed changes in LV geometry and systolic function by biplane ejection fraction (EF), midwall shortening (MWS) and mitral annular systolic velocity (s′). LV hypertrophy was defined based on LV mass/height 2.7 . Myocardial O 2 demand was derived from the LV mass-wall stress-heart rate product. Results: Patients experienced on average a 10 kg/m 2 reduction in BMI, and a significant drop in heart rate and blood pressure (all p<0.001). LV mass (-12 g) and myocardial O 2 demand improved significantly (all p<0.01). However, LV EF (60 vs. 61%), s’ (8.5 vs. 8.3cm/s) and MWS (16.1 vs. 15.7%) remained unchanged, and 45% of patients had low MWS 6 months after surgery (Figure). In multivariable regression analyses, LV mass reduction was predicted by weight loss and female sex, independent of changes in blood pressure and heart rate (R 2 0.24, p <0.001) while lower myocardial O2 demand was explained by improvement in its three components, particularly lower LV end-systolic wall stress (R 2 0.9, p<0.001). Conclusion: In severely obese patients with normal EF, bariatric surgery induces a significant reduction in BMI, LV mass and myocardial O 2 demand, but no improvement in LV myocardial systolic function 6 months after surgery.

Left ventricular myocardial oxygen demand and subclinical dysfunction in patients with severe obesity referred for bariatric surgery

Background and aimsIncreased myocardial oxygen (O2) demand carries higher cardiovascular risk in hypertension. We hypothesized that myocardial O2 demand is increased in severe obesity and linked to early left ventricular (LV) dysfunction. Methods and resultsBaseline data from 106 severely obese subjects referred for gastric bypass surgery (42 ± 11 years, 74% women, body mass index [BMI] 41.9 ± 4.8 kg/m2, 32% with hypertension) in the prospective FatWest (Bariatric Surgery on the West Coast of Norway) study was used. LV systolic function was assessed by biplane ejection fraction (EF), midwall shortening (MWS) and endocardial global longitudinal strain (GLS), and LV diastolic function by mitral annular early diastolic velocity (e’). Myocardial O2 demand was estimated from the LV mass-wall stress-heart rate product (high if > 1.62 × 106/2.29 × 106 g kdyne/cm2 bpm in women/men). High myocardial O2 demand was found in 33% and associated with higher BMI and high prevalence of low GLS (65%) and low MWS (63%) despite normal EF. In ROC analyses, higher myocardial O2 demand discriminated between patients with low vs. normal MWS and GLS (area under curve 0.71 and 0.63, p < 0.05). In successive multiple regression analyses, higher myocardial O2 demand was associated with lower LV MWS, GLS and average e’, respectively, independent of age, gender, BMI, pulse pressure, diabetes mellitus, and EF (all p < 0.05). ConclusionIn obese patients without known heart disease and with normal EF referred for bariatric surgery, high myocardial O2 demand is associated with lower myocardial function whether assessed by GLS or MWS independent of confounders. Clinicaltrials.gov identifierNCT01533142;

When Less Is More: Why Extubation With Less Than Routine 100% Oxygen May Be a Reasonable Strategy.

When Less Is More: Why Extubation With Less Than Routine 100% Oxygen May Be a Reasonable Strategy.

Abstract 16845: Functional Regulation of Native Coronary Kv1 Channels by Pyridine Nucleotides

Introduction: Recent studies indicate that vasodilation and enhanced blood flow to the heart following increases in myocardial O 2 demand are mediated by voltage-gated Kv1 channels in coronary smooth muscle cells (CVSM). Periods of high O 2 demand alter the intracellular pyridine nucleotide (PN) redox (e.g., elevated NADH:NAD + ), which, in heterologous systems, differentially modulates the gating properties of Kv1 channels by binding to intracellular Kvβ subunits. Hypothesis: Elevated levels of reduced PNs increase Kv1 channel activity in CVSM via the Kvβ complex. Methods: We performed patch clamp electrophysiology on CVSM freshly isolated from the left anterior descending coronary arteries (1 st and 2 nd order) of wild type and Kvβ2-null (Kvβ2 -/- ) mice. In the conventional whole cell configuration, we measured outward K + current density and the voltage-dependence of activation and inactivation (V 0.5, act, V 0.5,inact , respectively) in the absence and presence of extracellular lactate or pyruvate (10 mM), which alter intracellular PN levels. In inside-out membrane patches, we measured the open probability (nPo) of single K + -permeable channels that are sensitive to the Kv1 channel inhibitors 4-aminopyridine (4-AP; 1 mM) and psora-4 (500 nM), in the absence and presence of NADH (1 mM). Results: Treatment of wild type CVSM with lactate to elevate [NADH] I significantly increased whole cell Kv current density and shifted V 0.5, act to more negative membrane potentials (n=4, P&lt;0.05). This response was effectively reversed upon increasing [NAD + ] i by treatment with pyruvate. Recordings performed in the inside-out configuration revealed K + currents that were sensitive to inhibition by psora-4 and 4-AP and had a unitary conductance of 70.2 ± 2.4 pS. Perfusion with a bath solution that contained 1 mM NADH lead to a significant increase (~2-fold) in the nPo of 4-AP-sensitive channels (n=25-30 cells, P&lt;0.05). However, this effect was largely attenuated in membrane patches from Kvβ2 -/- CVSM. Conclusions: Native Kv1 channels in CVSM are functionally regulated by the intracellular NADH:NAD + ratio via their auxiliary Kvβ subunit complex.

Preservation of myocardial contractility during acute hypoxia with OMX-CV, a novel oxygen delivery biotherapeutic.

The heart exhibits the highest basal oxygen (O2) consumption per tissue mass of any organ in the body and is uniquely dependent on aerobic metabolism to sustain contractile function. During acute hypoxic states, the body responds with a compensatory increase in cardiac output that further increases myocardial O2 demand, predisposing the heart to ischemic stress and myocardial dysfunction. Here, we test the utility of a novel engineered protein derived from the heme-based nitric oxide (NO)/oxygen (H-NOX) family of bacterial proteins as an O2 delivery biotherapeutic (Omniox-cardiovascular [OMX-CV]) for the hypoxic myocardium. Because of their unique binding characteristics, H-NOX–based variants effectively deliver O2 to hypoxic tissues, but not those at physiologic O2 tension. Additionally, H-NOX–based variants exhibit tunable binding that is specific for O2 with subphysiologic reactivity towards NO, circumventing a significant toxicity exhibited by hemoglobin (Hb)-based O2 carriers (HBOCs). Juvenile lambs were sedated, mechanically ventilated, and instrumented to measure cardiovascular parameters. Biventricular admittance catheters were inserted to perform pressure-volume (PV) analyses. Systemic hypoxia was induced by ventilation with 10% O2. Following 15 minutes of hypoxia, the lambs were treated with OMX-CV (200 mg/kg IV) or vehicle. Acute hypoxia induced significant increases in heart rate (HR), pulmonary blood flow (PBF), and pulmonary vascular resistance (PVR) (p < 0.05). At 1 hour, vehicle-treated lambs exhibited severe hypoxia and a significant decrease in biventricular contractile function. However, in OMX-CV–treated animals, myocardial oxygenation was improved without negatively impacting systemic or PVR, and both right ventricle (RV) and left ventricle (LV) contractile function were maintained at pre-hypoxic baseline levels. These data suggest that OMX-CV is a promising and safe O2 delivery biotherapeutic for the preservation of myocardial contractility in the setting of acute hypoxia.

Heart-lung interactions during mechanical ventilation: the basics.

The hemodynamic effects of mechanical ventilation can be grouped into three clinically relevant concepts. First, since spontaneous ventilation is exercise. In patients increased work of breathing, initiation of mechanical ventilatory support may improve O2 delivery because the work of breathing is reduced. Second, changes in lung volume alter autonomic tone, pulmonary vascular resistance, and at high lung volumes compress the heart in the cardiac fossa similarly to cardiac tamponade. As lung volume increases so does the pressure difference between airway and pleural pressure. When this pressure difference exceeds pulmonary artery pressure, pulmonary vessels collapse as they pass form the pulmonary arteries into the alveolar space increasing pulmonary vascular resistance. Hyperinflation increases pulmonary vascular resistance impeding right ventricular ejection. Anything that over distends lung units will increase their vascular resistance, and if occurring globally throughout the lung, increase pulmonary vascular resistance. Decreases in end-expiratory lung volume cause alveolar collapse increases pulmonary vasomotor tone by the process of hypoxic pulmonary vasoconstriction. Recruitment maneuvers that restore alveolar oxygenation without over distention will reduce pulmonary artery pressure. Third, positive-pressure ventilation increases intrathoracic pressure. Since diaphragmatic descent increases intra-abdominal pressure, the decrease in the pressure gradient for venous return is less than would otherwise occur if the only change were an increase in right atrial pressure. However, in hypovolemic states, it can induce profound decreases in venous return. Increases in intrathoracic pressure decreases left ventricular afterload and will augment left ventricular ejection. In patients with hypervolemic heart failure, this afterload reducing effect can result in improved left ventricular ejection, increased cardiac output and reduced myocardial O2 demand. This brief review will focus primarily on mechanical ventilation and intrathoracic pressure as they affect right and left ventricular function and cardiac output.

Influence of myocardial oxygen demand on the coronary vascular response to arterial blood gas changes in humans.

It remains unclear if the human coronary vasculature is inherently sensitive to changes in arterial Po2 and Pco2 or if coronary vascular responses are the result of concomitant increases in myocardial O2 consumption/demand ([Formula: see text]). We hypothesized that the coronary vascular response to Po2 and Pco2 would be attenuated in healthy men when [Formula: see text] was attenuated with β1-adrenergic receptor blockade. Healthy men (age: 25 ± 1 yr, n = 11) received intravenous esmolol (β1-adrenergic receptor antagonist) or volume-matched saline in a double-blind, randomized crossover study and were exposed to poikilocapnic hypoxia, isocapnic hypoxia, and hypercapnic hypoxia. Measurements made at baseline and after 5 min of steady state at each gas manipulation included left anterior descending coronary blood velocity (LADV; Doppler echocardiography), heart rate, and arterial blood pressure. LADV values at the end of each hypoxic condition were compared between esmolol and placebo. The rate-pressure product (RPP) and left ventricular mechanical energy (MELV) were calculated as indexes of [Formula: see text]. All gas manipulations augmented RPP, MELV, and LADV, but only RPP and MELV were attenuated (4-18%) after β1-adrenergic receptor blockade ( P < 0.05). Despite attenuated RPP and MELV responses, β1-adrenergic receptor blockade did not attenuate the mean LADV vasodilatory response compared with placebo during poikilocapnic hypoxia (29.4 ± 2.2 vs. 27.3 ± 1.6 cm/s) and isocapnic hypoxia (29.5 ± 1.5 vs. 30.3 ± 2.2 cm/s). Hypercapnic hypoxia elicited a feedforward coronary dilation that was blocked by β1-adrenergic receptor blockade. These results indicate a direct influence of arterial Po2 on coronary vascular regulation that is independent of [Formula: see text]. NEW & NOTEWORTHY In humans, arterial hypoxemia led to an increase in epicardial coronary artery blood velocity. β1-Adrenergic receptor blockade did not diminish the hypoxemic coronary response despite reduced myocardial O2 demand. These data indicate hypoxemia can regulate coronary blood flow independent of myocardial O2 consumption. A plateau in the mean left anterior descending coronary artery blood velocity-rate-pressure product relationship suggested β1-adrenergic receptor-mediated, feedforward epicardial coronary artery dilation. In addition, we observed a synergistic effect of Po2 and Pco2 during hypercapnic hypoxia.

Exaggerated Hemodynamic Responses Upon the Initiation of Thermoregulatory Behavior in ‘At Risk’ Older Adults

Cold or heat exposure presents a challenge to blood pressure that can strain cardiovascular function. The risk of thermal induced cardiovascular morbidity and mortality is heightened in older adults who often present with co‐morbidities such as hypertension, diabetes, and hypercholesterolemia. In young healthy adults the initiation of thermoregulatory behavior is preceded by modest changes in blood pressure, which could strain cardiovascular function. We tested the hypothesis that older adults with existing cardiovascular co‐morbidities demonstrate exaggerated hyper‐ or hypo‐ tension upon the initiation of thermoregulatory behavior.We studied twelve healthy younger adults (Y, 25 ± 4 y, 6 females) and six older adults (O, 67 ± 4 y, 3 females) who each reported taking prescription medications for at least two of the following conditions: hypertension (n=2), type II diabetes (n=2), hypercholesterolemia (n=5). Participants wore shorts and a t‐shirt and underwent a 90 min test in which they voluntarily moved between cool (18.1 ± 1.8°C. RH: 29 ± 5%) and warm (40.2 ± 0.3°C, RH: 20 ± 0%) rooms when they felt ‘too cool’ or ‘too warm’. Blood pressure (Finometer), stroke volume (Model flow), cardiac output, heart rate (ECG), and mean skin and intestinal temperatures were measured continually. Data are reported as a 30 s average immediately prior to moving from cool to warm (C‐W) and warm to cool (W‐C). Data were averaged across behaviors for a given subject and are reported as a change from the pretest baseline.Time before initiating behavior did not differ between groups at C‐W (Y: 9.8 ± 4.3 min, O: 8.4 ± 2.8 min, P=0.47) or W‐C (Y: 14.5 ± 4.3 min, O: 18.9 ± 18.4 min, P=0.22). Changes in mean skin temperature were not different between groups at C‐W (Y: +0.2 ± 0.8°C, O: +0.7 ± 1.8, P=0.22) or W‐C (Y: +2.7 ± 0.6°C, O: +2.9 ± 1.9, P=0.37). Changes in intestinal temperature were also not different at C‐W (Y: 0.0 ± 0.1°C, O: +0.1 ± 0.2, P=0.06), but were higher at W‐C in O (Y: −0.1 ± 0.2°C, O: +0.1 ± 0.3°C, P=0.03). Systolic pressure at C‐W increased (Y: +10 ± 9 mmHg, O: +24 ± 17 mmHg, P=0.02) and at W‐C decreased (Y: −4 ± 13 mmHg, O: −23 ± 19 mmHg, P=0.01) to a greater extent in O. Differences were also apparent for diastolic pressure at C‐W (Y: −2 ± 4 mmHg, O: +17 ± 23 mmHg, P&lt;0.01) and W‐C (Y: +4 ± 13 mmHg, O: −1 ± 6 mmHg, P=0.03). Changes in heart rate were not different between groups at C‐W (Y: −2 ± 3 bpm, O: −2 ± 3 bpm, P=0.45) or W‐C (Y: +6 ± 5 bpm, O: +7 ± 6 bpm, P=0.28). Stroke volume differed between groups at C‐W (Y: −6 ± 7 mL, O: +6 ± 10 mL, P&lt;0.01), but not at W‐C (Y: −4 ± 11 mL, O: −3 ± 10 mL, P=0.43). Cardiac output differed between groups at C‐W (Y: −0.5 ± 0.5 L/min, O: +0.1 ± 0.6 L/min, P&lt;0.01), but not at W‐C (Y: +0.1 ± 0.9 L/min, O: +0.4 ± 1.2 L/min, P=0.28). Rate pressure product, an index of myocardial O2 demand, changed to a greater extent in O at C‐W (Y: +0.5 ± 7 mmHg*bpm, O: +1.2 ± 1.0 mmHg*bpm, P=0.05) and W‐C (Y: +0.3 ± 1.0 mmHg*bpm, O: −0.5 ± 0.8 mmHg*bpm, P=0.05).Despite modest changes in body temperature, the initiation of thermoregulatory behavior in ‘at risk’ older adults is preceded by exaggerated hyper‐ and hypo‐ tensive responses that may strain cardiovascular function.

Limitation of Infarct Size and the Open Artery Hypothesis: A Conversation With Eugene Braunwald, MD.

Eugene Braunwald received an MD from the New York University School of Medicine. He completed an internal medicine residency at Johns Hopkins Hospital and cardiology fellowships at Mount Sinai Hospital, Columbia University, and the National Heart Institute. He served as chief of cardiology and subsequently clinical director of the institute. From 1968 to 1972, he was the founding chair of medicine at the University of California, San Diego. From 1972 to 1996, he served as chair of medicine at the Brigham and Women’s Hospital. In 1975, he was elected to the National Academy of Sciences. He is now the Distinguished Hersey Professor of Medicine at Harvard Medical School and a senior investigator of the TIMI Study Group, which he founded in 1984. Dr Braunwald replies: I became aware of the importance of AMI in 1951 during an elective in cardiology during my senior year at the New York University School of Medicine. At the time, AMI was by far the most common cause of death in adults in the United States. Of the patients who survived to be admitted to hospitals (no one knew how many AMI patients failed to reach hospital emergency departments), about one third died before discharge, either suddenly, presumably from an arrhythmia, or secondary to pump failure. Of the patients who were discharged alive, about one quarter died within a year, most frequently as a consequence of heart failure or recurrent MI. Pathologists had taught that AMI was usually associated with coronary thrombosis. Indeed, during my cardiology elective, Herrick’s classic article describing AMI was required reading. Its title, “Clinical Features of Sudden Obstruction of the Coronary Arteries,” showed how these 2 conditions (coronary occlusion and AMI) were intertwined.1 My direct involvement in the care of several patients who did not survive the acute event left …

Anaesthetic Management of Ischemic Heart Disease Patients in Noncardiac Surgery

Perioperative myocardial infarction is one of the most important predictors of short and long term morbidity and mortality associated with noncardiac surgery. Myocardial infraction occurs whenever myocardial oxygen supply does not match myocardial oxygen demand. Intraoperative ischemia can be precipitated by increase in myocardial oxygen demand caused by tachycardia, hypertension, anaemia, stress, sympathomimatic drugs or discontinuation of beta blocker. Clinical predictors of perioperative cardiac morbidity are acute myocardial infraction or recent myocardial infraction, unstable or severe angina, decompensated heart failure, severe valvular disease, mild angina pectoris, previous myocardial infraction, diabetic mellitus etc. The preoperative history is meant to elicit the severity, progression and functional limitations imposed by ischemic heart disease. Limited exercise tolerance in the absence of significant lung disease is very good evidence of decreased cardiac reserve. The basic challenges during induction and maintenance of anaesthesia in patients with ischemic heart disease are prevent myocardial infraction by increasing myocardial O2 supply and reducing myocardial O2 demand and monitor for ischemia and to treat ischemia if it develops. There are no one best myocardial protective agents or technique. Maintenance of balance between myocardial oxygen supply and demand is more important than the specific technique or drugs selected to produce anaesthesia and muscle relaxation. Potential benefits of a regional anaesthetic include excellent pain control, a decreased incidence of deep vein thrombosis (DVT) in some patients and the opportunity to continue the block into the postoperative period. The postoperative period appears to present the highest risk for cardiac morbidity. It is during this period where 67% of the ischemic events occur. Effective pain management is essential to prevent these adverse outcomes. Successful perioperative evaluation and treatment of cardiac patients undergoing noncardiac surgery requires careful teamwork and communication between patient, anaesthesiologist and surgeon.&#x0D; Ibrahim Cardiac Med J 2014; 4(2): 56-60

Influence of the cold pressor test upon aortic pulse wave reflection in individuals with increased arterial stiffness

Aortic pulse wave reflection is an indicator of LV after load, myocardial O2 demand and a predictor of cardiovascular events and is partly determined by muscular and elastic artery stiffness and pulse wave velocity. Acute stimulation of the sympathetic nervous system increases the vascular resistance of the muscular arteries thereby influencing arterial stiffness. The aim of this study was to examine the influence of acute sympathetic stimulation via the cold pressor test upon aortic pulse wave reflection in individuals with and without increased arterial stiffness. Eleven participants (4 males, 31±12yrs; 172±10cm; 75±15kg) completed a cold pressor test (CPT) wherein the left hand was immersed up to the wrist in 2–4°C water for 3 minutes. Blood pressure (mean arterial pressure; MAP) and pulse wave reflection (radial tonometry) were measured throughout. Stroke volume was calculated (photoplethysmography; NexFin) and heart rate measured (ECG; HR) throughout to provide cardiac output (Q). Aortic pulse wave velocity was measured before the CPT (Mobil‐O‐Graph®; aPWV). Pulse wave reflection was referenced to a heart rate of 75 bpm (augmentation index; Aix75). At baseline heart rate was 66±8 bpm and the change during CPT was variable between participants (Range: −11 to +14 bpm). Prior to CPT, Aix75 was 0±19% (Range −31 to 31%) and MAP was 87±10 mmHg. During the CPT Aix75 increased to 17±13% while MAP increased to 102±7 mmHg (both P ≤ 0.05). The change in Aix75 during CPT correlated poorly with age (R2 = 0.13), baseline MAP (R2 = 0.03), the change in MAP during CPT (R2 = 0.05) and baseline aPWV (R2 = 0.08) (all P &gt; 0.05). However, the increase in Aix75 during the CPT correlated moderately with baseline Aix75 (R2 = 0.75; P = 0.0006) and the change in Q during CPT (R2 = 0.40; P = 0.049). Increases in aortic pulse wave reflection during the cold pressor test were inversely related to baseline aortic pulse wave reflection. This may be indicative of a ceiling effect where individuals with evidence of existing arterial stiffening demonstrate a reduced increase in pulse wave reflection during sympathetic stimulation via cold pressor test. Nevertheless individuals with evidence of increased arterial stiffness still experience acute increases in pulse wave reflection during sympathetic stimulation via the cold pressor test.

Effects of chronic dietary nitrate supplementation on the hemodynamic response to dynamic exercise.

While acute treatment with beetroot juice (BRJ) containing nitrate (NO3 (-)) can lower systolic blood pressure (SBP), afterload, and myocardial O2 demand during submaximal exercise, effects of chronic supplementation with BRJ (containing a relatively low dose of NO3 (-), 400 mg) on cardiac output (CO), SBP, total peripheral resistance (TPR), and the work of the heart in response to dynamic exercise are not known. Thus, in 14 healthy males (22 ± 1 yr), we compared effects of 15 days of both BRJ and nitrate-depleted beetroot juice (NDBRJ) supplementation on plasma concentrations of NOx (NO3 (-)/NO2 (-)), SBP, diastolic blood pressure (DBP), mean arterial pressure (MAP), CO, TPR, and rate pressure product (RPP) at rest and during progressive cycling exercise. Endothelial function was also assessed via flow-mediated dilation (FMD). BRJ supplementation increased plasma NOx from 83.8 ± 13.8 to 167.6 ± 13.2 μM. Compared with NDBRJ, BRJ reduced SBP, DBP, MAP, and TPR at rest and during exercise (P < 0.05). In addition, RPP was decreased during exercise, while CO was increased, but only at rest and the 30% workload (P < 0.05). BRJ enhanced FMD-induced increases in brachial artery diameter (pre: 12.3 ± 1.6%; post: 17.8 ± 1.9%). We conclude that 1) chronic supplementation with BRJ lowers blood pressure and vascular resistance at rest and during exercise and attenuates RPP during exercise and 2) these effects may be due, in part, to enhanced endothelium-induced vasodilation in contracting skeletal muscle. Findings suggest that BRJ can act as a dietary nutraceutical capable of enhancing O2 delivery and reducing work of the heart, such that exercise can be performed at a given workload for a longer period of time before the onset of fatigue.

Coronary blood flow during cold air breathing: mechanistic insights using pharmacological blockade

Recent work from our laboratory has demonstrated that cold air inhalation (CAI) impairs coronary blood flow velocity (CBV) in healthy humans. The first objective of this study was to determine if blockade of oropharyngeal afferents would improve coronary perfusion during CAI. The second objective was to determine if systemic beta‐adrenergic blockade would improve coronary perfusion during CAI. In study 1, ten subjects received upper airway anesthesia with lidocaine then underwent CAI (−15 to − 30°C) for 5 minutes. In study 2, eight subjects received intravenous propranolol prior to CAI. Control experiments were performed on separate days. HR, MAP, and CBV (from Doppler echocardiography) were obtained. Rate pressure product (RPP) was used as an index of myocardial O2 demand and CBV was an index of myocardial O2 supply; changes (Δ) from baseline were calculated. In study 1, lidocaine blocked the gag reflex but did not affect ΔRPP (428 ± 159 vs 496 ± 339) or ΔCBV (0.8 ± 1.2 vs 0.9 ± 0.9 cm/sec) to CAI compared to control. In study 2, intravenous propranolol lowered resting HR and completely blocked the HR increase to isoproterenol. Further, propranolol lowered O2 demand in response to CAI (ΔRPP=169 ± 285 vs 1106 ± 360) compared to control. These data indicate that the detrimental effects of CAI on the coronary circulation are due in part to activation of beta‐adrenergic receptors. Supported by NIH P01 HL096570 and UL1 TR000127.

Muscle metaboreflex-induced coronary vasoconstriction limits ventricular contractility during dynamic exercise in heart failure

Muscle metaboreflex activation (MMA) during dynamic exercise increases cardiac work and myocardial O2 demand via increases in heart rate, ventricular contractility, and afterload. This increase in cardiac work should lead to metabolic coronary vasodilation; however, no change in coronary vascular conductance occurs. This indicates that the MMA-induced increase in sympathetic activity to the heart, which raises heart rate, ventricular contractility, and cardiac output, also elicits coronary vasoconstriction. In heart failure, cardiac output does not increase with MMA presumably due to impaired ability to improve left ventricular contractility. In this setting actual coronary vasoconstriction is observed. We tested whether this coronary vasoconstriction could explain, in part, the reduced ability to increase cardiac performance during MMA. In conscious, chronically instrumented dogs before and after pacing-induced heart failure, MMA responses during mild exercise were observed before and after α1-adrenergic blockade (prazosin 20-50 μg/kg). During MMA, the increases in coronary vascular conductance, coronary blood flow, maximal rate of left ventricular pressure change, and cardiac output were significantly greater after α1-adrenergic blockade. We conclude that in subjects with heart failure, coronary vasoconstriction during MMA limits the ability to increase left ventricular contractility.

Cardioprotection of electroacupuncture against myocardial ischemia-reperfusion injury by modulation of cardiac norepinephrine release

Augmentation of cardiac sympathetic tone during myocardial ischemia has been shown to increase myocardial O(2) demand and infarct size as well as induce arrhythmias. We have previously demonstrated that electroacupuncture (EA) inhibits the visceral sympathoexcitatory cardiovascular reflex. The purpose of this study was to determine the effects of EA on left ventricular (LV) function, O(2) demand, infarct size, arrhythmogenesis, and in vivo cardiac norepinephrine (NE) release in a myocardial ischemia-reperfusion model. Anesthetized rabbits (n = 36) underwent 30 min of left anterior descending coronary artery occlusion followed by 90 min of reperfusion. We evaluated myocardial O(2) demand, infarct size, ventricular arrhythmias, and myocardial NE release using microdialysis under the following experimental conditions: 1) untreated, 2) EA at P5-6 acupoints, 3) sham acupuncture, 4) EA with pretreatment with naloxone (a nonselective opioid receptor antagonist), 5) EA with pretreatment with chelerythrine (a nonselective PKC inhibitor), and 6) EA with pretreatment with both naloxone and chelerythrine. Compared with the untreated and sham acupuncture groups, EA resulted in decreased O(2) demand, myocardial NE concentration, and infarct size. Furthermore, the degree of ST segment elevation and severity of LV dysfunction and ventricular arrhythmias were all significantly decreased (P < 0.05). The cardioprotective effects of EA were partially blocked by pretreatment with naloxone or chelerythrine alone and completely blocked by pretreatment with both naloxone and chelerythrine. These results suggest that the cardioprotective effects of EA against myocardial ischemia-reperfusion are mediated through inhibition of the cardiac sympathetic nervous system as well as opioid and PKC-dependent pathways.

Aging attenuates the coronary blood flow response to cold air breathing and isometric handgrip in healthy humans

The purpose of this echocardiography study was to measure peak coronary blood flow velocity (CBV(peak)) and left ventricular function (via tissue Doppler imaging) during separate and combined bouts of cold air inhalation (-14 ± 3°C) and isometric handgrip (30% maximum voluntary contraction). Thirteen young adults and thirteen older adults volunteered to participate in this study and underwent echocardiographic examination in the left lateral position. Cold air inhalation was 5 min in duration, and isometric handgrip (grip protocol) was 2 min in duration; a combined stimulus (cold + grip protocol) and a cold pressor test (hand in 1°C water) were also performed. Heart rate, blood pressure, O(2) saturation, and inspired air temperature were monitored on a beat-by-beat basis. The rate-pressure product (RPP) was used as an index of myocardial O(2) demand, and CBV(peak) was used as an index of myocardial O(2) supply. The RPP response to the grip protocol was significantly blunted in older subjects (Δ1,964 ± 396 beats·min(-1)·mmHg) compared with young subjects (Δ3,898 ± 452 beats·min(-1)·mmHg), and the change in CBV(peak) was also blunted (Δ6.3 ± 1.2 vs. 11.2 ± 2.0 cm/s). Paired t-tests showed that older subjects had a greater change in the RPP during the cold + grip protocol [Δ2,697 ± 391 beats·min(-1)·mmHg compared with the grip protocol alone (Δ2,115 ± 375 beats·min(-1)·mmHg)]. An accentuated RPP response to the cold + grip protocol (compared with the grip protocol alone) without a concomitant increase in CBV(peak) may suggest a dissociation between the O(2) supply and demand in the coronary circulation. In conclusion, older adults have blunted coronary blood flow responses to isometric exercise.

Altered coronary vascular control during cold stress in healthy older adults

Cardiovascular-related mortality increases in the cold winter months, particularly in older adults. Previously, we reported that determinants of myocardial O(2) demand, such as the rate-pressure product, increase more in older adults compared with young adults during cold stress. The aim of the present study was to determine if aging influences the coronary hemodynamic response to cold stress in humans. Transthoracic Doppler echocardiography was used to noninvasively measure peak coronary blood velocity in the left anterior descending artery before and during acute (20 min) whole body cold stress in 10 young adults (25 ± 1 yr) and 11 older healthy adults (65 ± 2 yr). Coronary vascular resistance (diastolic blood pressure/peak coronary blood velocity), coronary perfusion time fraction (coronary perfusion time/R-R interval), and left ventricular wall stress were calculated. We found that cooling (via a water-perfused suit) increased left ventricular wall stress, a primary determinant of myocardial O(2) consumption, in both young and older adults, although the magnitude of this increase was nearly twofold greater in older adults (change of 9.1 ± 3.5% vs. 17.6 ± 3.2%, P < 0.05, change from baseline in young and older adults and young vs. older adults). Despite the increased myocardial O(2) demand during cooling, coronary vasodilation (decreased coronary vascular resistance) occurred only in young adults (3.22 ± 0.23 to 2.85 ± 0.18 mmHg·cm(-1)·s(-1), P < 0.05) and not older adults (3.97 ± 0.24 to 3.79 ± 0.27 mmHg·cm(-1)·s(-1), P > 0.05). Consistent with a blunted coronary vascular response, absolute coronary perfusion time tended to decrease (P = 0.13) and coronary perfusion time fraction decreased (P < 0.05) during cooling in older adults but not young adults. Collectively, these data suggest that older adults demonstrate an altered coronary hemodynamic response to acute cold stress.

The muscle metaboreflex: reining in the heart?

the muscle metaboreflex, also known as the muscle chemoreflex, is one of the principal mediators of the cardiovascular exercise response. This reflex is thought to be triggered by metabolic by-products of ischemia that stimulate afferent nerve endings in skeletal muscle and leads to an increase in