Adenosine Triphosphate (ATP) – Energy used to fuel all cellular functions is provided by adenosine triphosphate, or ATP. ATP is composed of a structural sugar (D-ribose), a purine ring (adenine), and three phosphoryl groups (triphosphate) attached to the purine moeity by high-energy phosphoryl bonds. The chemical energy holding the third phosphoryl group to the phosphate chain fuels cellular energy. Breaking this high-energy chemical bond releases energy to the cell that is converted into mechanical energy to perform work. The resulting byproducts are adenosine diphosphate (ADP) and heat. To maintain a constant supply of energy, the ADP formed as a byproduct of energy utilization can be recycled to ATP.

Alveoli – small sacs in the lungs where gas exchange occurs. Grape like bunches of tiny air chambers are found at the end of each bronchiole in the lungs. Each chamber contains several cup-shaped cavities called alveoli. The one cell thick wall of the alveoli are the respiratory surface. It is through these walls that oxygen and carbon exchange takes place between blood and air that is breathed into the lungs. There are only about 300 million alveoli in the lungs with a total surface area of 70m2.

Anaerobic Threshold (AT) – AT denotes the point in exercise at which normal breathing cannot supply enough O2 to the blood to offset the metabolic demand of the tissue. Beyond this point, aerobic metabolism is supplemented by anaerobic metabolism, which does not consume O2. In gas exchange, the AT is reflected by a more rapid rise of VCO2 relative to VO2. Exercise above this point is increasingly difficult and cannot be maintained. The Shape test parameters can be measured below AT, which has been a significant limitation to previous gas exchange tests.

Anaerobic metabolism causes an increase in blood lactic acid concentration. This increase is buffered by bicarbonate (HCO3-) causing an increase in CO2 production.

ANP and BNP – proteins excreted by heart tissue indicating presence of Heart Failure. ANP and BNP are often tracked to measure disease progression. Recent studies show that changes in partial pressure of end tidal carbon dioxide (PetCO2) and oxygen efficiency uptake slope (OUES) correlate to these biomarkers. PetCO2 and OUES are Shape testing parameters. There is no level of BNP that perfectly separates patients with and without heart failure. BNP tests have high sensitivity but rather low specificity, meaning that low values are accurate at excluding heart failure as a diagnosis, but high values are not conclusive in identifying heart failure.

BNP (B-type natriuretic peptide or brain natriuretic peptide) is a polypeptide (or protein) secreted by the ventricles of the heart in response to excessive stretching of the heart muscle cells (cardiomyocytes). ANP (atrial natriuretic peptide, also referred to as atrial natriuretic factor [ANF], atrial natriuretic hormone [ANH] or atriopeptin) is a polypeptide hormone secreted by the atria in response to high blood pressure. Both BNP and ANP act to reduce water, sodium and fat loads in the blood, thereby reducing blood pressure. BNP and ANP reduce systemic vascular resistance and central venous pressure, while increasing sodium excretion (natriuresis). As such, the net effect of BNP and ANP is to reduce cardiac output and blood volume. BNP and ANP are biomarkers for chronic heart failure, with values above 500 picograms (pg)/ml of blood considered positive for the disease. Values elevate as heart failure progresses.

Atrial Sensing (As) and Atrial Pacing (Ap) – Terms used in dual chamber pacemaker (i.e., one that paces both the atrium and ventricle) therapy. Atrial sensing refers to the ability of the pacemaker to sense an atrial event, or beat, while atrial pacing refers to the application of an electrical signal to the atrium causing it to beat. Whether the atrium is As or Ap is input by the test administrator during Shape-HF steady state exercise testing. Knowing whether the patient is atrial sensed or atrial paced helps the physician determine which AV intervals should be studied in the test and offsets to be used for final programming
In dual chamber pacing that is programmed to both perform both sensing and pacing, a sensed atrial beat inhibits the atrial pacing channel and triggers ventricular pacing after a programmable AV delay. In patients with pacemakers capable of sensing and pacing both the atrium and ventricle (so-called DDD pacemakers), four different rhythm scenarios are possible, and patients may exhibit more than one scenario. The four rhythm scenarios are:

  • Normal sinus rhythm with no atrial or ventricular pacing. Here, the patient’s native heart rate is faster than the programmed lower rate of the pacemaker such that pacing is not required. In this scenario, pacing of both the atrium and ventricle are inhibited.
  • Atrial sensed; ventricular pacing. The patient’s atrial rate is faster than the lower rate limit and the atrioventricular conduction interval (AVI) is longer than the programmed AVI. In this situation, the patient’s atrium is not paced, but the ventricle is paced at the patient’s sinus rate until the upper rate limit is reached.
  • Atrial paced; ventricular sensed. In this scenario the patient’s atrial rate is slower than the programmed lower rate and the patient’s AVI is shorter than the programmed AVI. Here, the patient is atrial paced at the lower rate limit, but the ventricle is not paced.
  • Atrial and ventricular pacing. Here the sinus rate is slower than the lower rate limit and AVI is longer, or absent, resulting in a need for both atrial and ventricular pacing at the lower rate limit.

Breath-by-Breath – A method for measurement of respiratory gas exchange in a breath during which expired gas volume and simultaneously measured expired gas concentration are collected, integrated and reported.

Capneic Buffering – The physiological process by which bicarbonate (HCO3-) is used to buffer lactic acid in the blood resulting from anaerobic metabolism. The buffering reaction yields CO2 as a byproduct.

Carbon Dioxide Output (VCO2) – The amount of CO2 exhaled from the body into the atmosphere per unit time, expressed in milliliters (mL) or liters (L) per minute.

This is not to be confused with carbon dioxide production (QCO2), which is the amount of carbon dioxide produced by the body’s metabolic and buffering processes. QCO2 is similarly reported in mL or L per minute.

Chronotropic incompetence (CI) – The inability of the sinus node of the heart to react adequately to an increase in exercise or other metabolic stress with an increase in heart rate. Basically, it is the inability to achieve a target increase in heart rate with increasing exercise. An indication of CI can be diagnosed by the Shape calculation of Chronotropic Response Index (CRI).

Chronotropic Response Index (CRI) – CRI is a measure of the heart rate response to dynamic exercise. It is the ratio of percent Heart Rate Reserve (HRR) to percent Metabolic Reserve (%HRR / %Metabolic Reserve). Chronotropically incompetent patients cannot increase heart rate at a sufficient rate to keep pace with exercise, which partially explains exercise intolerance in heart disease.

CRI is a slope value, meaning the result reflects the linear regression of the observed data points over the course of exercise. A normal CRI slope is close to one (stated normal, 0.96). In chronotropically incompetent patients, however, the slope is more shallow, with <0.8 representing the cut off for chronotropic incompetence. In basic terms, this means that chronotropically incompetent patients require more oxygen uptake (and energy expenditure) relative to increasing utilization of heart rate capacity.

Clinical studies have shown that CRI is a significant independent risk factor for all-cause and cardiovascular mortality in individuals with known or suspected coronary artery disease and heart failure, and provides a useful physiological parameter in assessing pharmaceutical and medical device intervention or cardiac rehabilitation.

CPX or CPET – Abbreviations for cardiopulmonary exercise testing.

Dead Space (VD) – In physiology, dead space is air that is inhaled by the body in breathing, but does not partake in gas exchange. Leaks in the Shape system look like dead space to the analyzer, which explains why it is important to guard against system leaks and why the analyzer conducts a leak test before each testing session. Components of the Shape Disposable Patient Interface add to dead space, and this dead space is taken into account in Shape system calculations.

About a third of every resting breath, or about 150 mL, is exhaled exactly as it came into the body. Because of dead space, taking deep breaths more slowly (e.g., ten 500 mL breaths per minute) is more effective than taking shallow breaths quickly (e.g., twenty 250 mL breaths per minute). Although the amount of gas per minute is the same (5 L/min), a large proportion of the shallow breaths is dead space, and does not allow oxygen to get into the blood.

There are several components that go into dead space. These include anatomical dead space (gas in the conducting areas of the respiratory system, such as the mouth and trachea, where the air doesn't come to the alveoli of the lungs), physiological dead space (the anatomical dead space plus the alveolar dead space), and alveolar dead space (the area in the alveoli that does not exchange air because there is not enough blood flowing through the capillaries for exchange to be effective). Alveolar dead space is normally very small (less than 5 mL) in healthy individuals, but can increase dramatically in heart or lung disease.

End-Tidal Partial Pressure of CO2, (PetCO2, ETCO2) –The concentration of carbon dioxide in expired air at the end of expiration (measured in percent or pressure in millimeters of mercury or mmHg). PetCO2 should not to be confused with VCO2, which is the volume (as opposed to percent or pressure) of CO2 produced in one minute. PetCO2 is similar to O2 pulse in that it reflects cardiac output. As cardiac output increases, so does the concentration of expired CO2. A PetCO2 value of <34 mmHg at the conclusion of short-term, submaximal exercise, or a change from rest to exercise of <1 mmHg is indicative of risk. In heart failure, PetCO2 is reduced because blood flow is low relative to ventilation in regional lung units.

End-Tidal Partial Pressure of O2, (PetO2, ETO2) –The concentration (pressure in mmHg) of oxygen at the end of expiration. This contrasts with VO2, which is the volume of O2 consumed in one minute.

Forward Pump Function – Refers to the ability of the heart to contract and eject blood that has returned to the heart from the aorta during its relaxation, or filling, cycle (i.e., diastole) against a given amount of resistance, or after load.

Heart Rate Recovery (HRR) – HRR is defined as the decay in heart rate over the first one minute of exercise recovery and it relates to the degree of sympathetic and parasympathetic neuronal control. The average normal Heart Rate Recovery is 28 beats per minute, and a HRR of less than 12 beats per minute is indicative of patient risk.

This parameter is useful in assessing patients with congestive heart failure, coronary artery disease and angina. It is effectively used in evaluating the physiological response to cardiac rehabilitation and pharmaceutical or medical device intervention.

Heart rate reserve (percent) – The percent or ratio of the actual heart rate at a level of work to the maximum heart rate. (How close an individual is to achieving their max heart rate). The percent heart rate reserve is part of the Chronotropic Response Index (CRI) calculation.
In most Shape testing applications, the percent heart rate reserve is calculated as follows:

[(HRstage – HRrest)/(HRpeak – HRrest)] X 100,

where HRstage is the observed heart rate at any point in exercise, HRpeak is the actual observed HR at the peak level of exercise performed (i.e., not a theoretical value), and HRrest is the observed resting heart rate. In other words, percent heart rate reserve is the difference between the heart rate at any point in exercise and the heart rate at rest divided by the difference between the maximally observed heart rate and the heart rate at rest with the result multiplied by 100 to equal percent. The exception to this formula is in maximal exercise stress testing, where HRpeak is a theoretical value based on the formula 220 minus the patient’s age in years (220 – age in years).

Homeostasis – An ideal or virtual state of equilibrium in which all body systems are working and interacting in an appropriate way to fulfill the needs of the body. When homeostasis is interrupted, the body tries to restore it by adjusting one or more physiological processes.

Inspiratory drive (VT/ti) – A measure of the force of inspiration or the “amount of gasping for air.” Inspiratory drive is calculated by dividing the amount of air ventilated (Tidal Volume, or VT) by inspiratory time (ti), or the amount of time it takes to inhale. As exercise increases, the shorter the time of inspiration, the higher the force of inspiration. Inspiratory drive reflects the transition from normal, deeper and more cyclical breathing to shorter, shallower gasps. In our application, inspiratory drive is one of the parameters used to measure the physiological response to changes in cardiac resynchronization (CRT) therapy settings.

Inspiratory time (ti) – the time it takes to complete one full inspiration from the end of one expiration to the initiation of the next expiration.

Lactic Acid – Lactic acid is a blood marker of anaerobic metabolism. A three-carbon acid that is one of the end products of glucose oxidation during anaerobic energy metabolism that occurs once the anaerobic threshold has been reached.

Metabolic Equivalent (MET) – Metabolic Equivalent is defined as the ratio of a person's working, or exercising, metabolic rate relative to the resting metabolic rate. It basically quantifies the effort required to do a task. METs are part of the metabolic reserve calculation. Shape provides a direct measurement of MET level during exercise. One MET is the caloric consumption of a person while at complete rest, and is variable from one person to another based on body weight. Typically, one MET equals about 3.5 mLO2/kg body weight/minute, or about 1 calorie per 2.2 pounds of body weight per hour. As such, a person weighing 200 pounds (90 kilograms, or kg) exercising at 6 METs would burn considerably more calories than a person weighing 120 pounds (55 kg) doing the same exercise. At rest, the body uses 1 MET to “sustain life”. As activity increase, so does METs. For example in healthy normals, walking at 2 mph equates to about 2 METs, or twice the energy expenditure of rest; walking at 4 mph equals about 5 METs; jogging at 6 mph about 8 METs, and so on. Therefore jogging at 6 mph requires four times the energy expenditure as walking at 2 mph.

Metabolic reserve (percent) – percent metabolic reserve is the difference between the MET level at any point in exercise and MET level achieved at peak exercise. It reflects the level of work during any stage of exercise . The percent metabolic reserve is part of the Chronotropic Response Index (CRI) calculation.
The percent metabolic reserve is calculated as follows:

[(METstage – METrest)/(METpeak – METrest)] X 100,

where METstage is the observed metabolic equivalents (MET) at any point in exercise, METpeak is the actual observed MET at the peak level of exercise performed (i.e., not a theoretical peak value), and METrest is the MET value while the patient is at rest.

Minute Ventilation (VE) – VE is the quantity of gas expired from the lungs in one minute. It is the product of tidal volume times respiratory rate. The normal Minute Volume is 5 - 8 liters per minute.

Oximeter – A device that uses light transmission to estimate the saturation of blood hemoglobin with oxygen. A Pulse Oximeter also measures the heart rate. The Pulse Oximeter used in the Shape system is placed on the patient’s index finger and measures both heart rate and blood oxygen saturation.

Oxygen Pulse (O2 Pulse) – O2 Pulse is an indirect measurement of stroke volume. It is defined as the oxygen uptake per heart beat and is measured by dividing the oxygen uptake in one minute over heart rate (VO2/HR). As stroke volume increase, so does O2 pulse. It is the amount of oxygen extracted by the tissues of the body from the O2 carried by the blood pumped from the heart in each stroke.

Oxygen Uptake (VO2) – The amount of oxygen extracted from the inspired gas in a given period of time, expressed in mL or L per minute.

This can differ from oxygen consumption (QO2), which is the amount of oxygen utilized by the body’s metabolic processes in a given time, which is also expressed in mL or L per minute.

Oxygen uptake efficiency slope, or OUES (VO2/logVE) – OUES measures the amount of oxygen consumed vs. minute ventilation. Basically it shows the amount of ventilation required to deliver a measured amount of oxygen to the body. The higher the value, the more efficient the O2 consumption. It is used to assess the coupling between the heart and lungs and has been identified as a significant independent predictor of patient risk. The average normal oxygen uptake efficiency is reported as 2.12, with a value <1.39 indicating risk.

This value is defined as the linear slope of the amount of oxygen consumed per minute (VO2) versus the log of amount of air expired per minute (logVE). The log value simply allows for a more linear display. This parameter is useful in assessing patients with congestive heart failure, and is also effective in evaluating the physiological response to cardiac rehabilitation and pharmaceutical or medical device intervention.

Peak VO2 (VO2peak) – Amount of oxygen consumed at peak exercise. In traditional cpx tests, this was the target measurement. The VO2peak is often used to classify the severity of HF and mortality risk. Shape uses a standard calculation to predict VO2peak, and measures VO2 at the maximal level of exercise attained during a Shape test for comparative purposes.

VO2max and VO2peak are often used interchangeably, but they are not the same. VO2max is actually defined as the amount of oxygen consumed at maximal exercise, but because of the intensity of exercise required to attain this value, it is very difficult to obtain, especially in patients with heart disease. As such, the value VO2peak is used to reflect the oxygen consumption at the level of exercise determined to represent the patient’s peak exercise effort.

Pneumotach – A device used to measure gas flow. In Shape testing, the pneumotach is attached to a mouthpiece or mask and is used to separate a known volume of gas from the expired air and send it to the analyzer via the sampling lines.

Respiratory exchange ratio (RER) – RER is the ratio of CO2 output divided by O2 uptake (VCO2/VO2). This value should be monitored during a Shape test to ensure there are no leaks in the system and the subject is at rest prior to the start. A resting RER of 0.85 is typical and a sharp jump indicates a leak. Unless a peak exercise test is used, RER values should remain <1.0.

Respiratory Quotient (RQ) – The ratio of the rate of CO2 production to O2 consumption. This ratio reflects the metabolic exchange of the gases in the body’s tissues and is dictated by the percentage of carbohydrate, fat, and amino acids used in energy production by the cells.

Carbohydrate metabolism yields an RQ of 1, whereas proteins and fats yield RQs of 0.8 - 0.9 and 0.7, respectively. A normal mixture of fat and carbohydrate metabolism yields an RQ of around 0.8. Except in malnourishment, protein is seldom used for energy metabolism. This number is seldom used in Shape testing, but is monitored by the system and available for use in studies where patient metabolism is under review.

Retrograde Pump Function – Refers to the filling of the heart during the relaxation phase of the cardiac cycle. Filling pressure and the volume of blood that returns to the heart during diastole are termed preload. Forward pump failure can increase the preload on the heart to undesirable levels, which, in turn, has an adverse retrograde effect on gas exchange in the lung.

Slope – the trend or angle of a line on a graph. Slope is the value used to measure several gas exchange parameters measured in Shape testing, including Oxygen Uptake Efficiency Slope (OUES), Ventilatory Efficiency Slope, CRI and HRR. The smaller the slope value, the more shallow the angle.

During a Shape test, several calculations are made with each breath and plotted on a graph. The graph, therefore, accumulates a multitude of data points by the end of a test (referred to as a scatter plot). For noted parameters, the predictive value is determined by the trend in these data points rather than the actual value of an individual data point. To aid in interpretation of this “scatter,” a trend line is calculated mathematically using a complicated method called least squares regression equation. The angle, or steepness, of this trend line is called its slope. The smaller the slope value, the more shallow the angle. So, for example, a Ventilation Efficiency Slope of a normal person might be 24, while that of a heart failure patient might be 40, meaning the angle of the slope in the patient is greater and, in this case, meaning it takes a greater amount of ventilation to eliminate a given volume of CO2.

Steady State and Steady State Exercise – Steady State is a characteristic of physiological systems in which its functional demands are being met such that its output per unit time becomes constant. Steady State Exercise is a level of exercise intensity at which the patient is in steady state. To reach steady state exercise intensity, the patient must first pass through a period of dynamic exercise to reach the Steady State level. Shape uses a steady state exercise test to monitor physiological response to changes in CRT therapy settings.

Submaximal Exercise – Level of exercise up to, and frequently including, the anaerobic threshold. Standard Shape testing employs submaximal exercise protocols.

Sympathetic/parasympathetic response – This is the nervous system’s subconscious or autonomic control of certain body functions, such as heart rate. Sympathetic response can be thought of as the accelerator and parasympathetic response as the brakes. During exercise, sympathetic response increases heart rate until the increase comes under parasympathetic control to slow the rate of increase. At the conclusion of exercise, sympathetic control is restored.

Tidal Volume (VT) – is the normal lung volume of air inspired or expired in a single breath during regular breathing. Normally, this is about 500 mL.

Ventilation-Perfusion Coupling – For gas exchange to be most efficient there must be a precise match, or coupling, between ventilation (the amount of gas reaching the smallest spaces of the lung, or alveoli) and perfusion (the blood flow to pulmonary capillaries). Increased CO2 level (PetCO2) within the alveoli cause changes in the diameter of the passageways of the lung leading to them. This increased diameter allows carbon dioxide to be eliminated from the body more rapidly. Conversely, capillaries servicing areas of the lung where the O2 concentration is low constrict and shunt blood away to more oxygen rich areas. As a result of these modifications, alveolar ventilation and pulmonary perfusion are synchronized. Poor alveolar ventilation results in low oxygen in the capillaries and high carbon dioxide levels in the alveoli. Consequently, the pulmonary capillaries constrict and the airways dilate, bringing airflow and blood flow into closer physiological match. High oxygen and low carbon dioxide alveolar partial pressures cause constriction of the respiratory passageways and a flushing of blood into the pulmonary capillaries. At all times, these homeostatic mechanisms provide the most appropriate conditions for efficient gas exchange.

Ventilatory Efficiency Slope (VE/VCO2 slope) – Ventilation efficiency is the relationship between the volume of CO2 produced and the amount of air which must be breathed to “blow it off.” This is called the ventilatory equivalent of CO2 and is calculated by dividing volume of air exhaled per minute, or Minute Ventilation (VE), by the volume of carbon dioxide output (VCO2). By plotting multiple ventilatory equivalents measured during an exercise test, the slope of the resulting line can be calculated. Since elevated CO2, is a strong stimulus for ventilation during exercise, VE and VCO2, closely mirror one another. After a drop in early exercise, VE/VCO2 normally does not increase significantly throughout submaximal exercise, and the resulting slope is shallow. However, in the presence of chronic heart failure the slope is shifted upward, and high VE/VCO2 values are characteristic. The risk cutoff for VE/VCO2 has been established in the literature to be ≥35.