Posts Tagged ‘Heart rate’

Innervation of Heart and Heart Rate

Writer and Curator: Larry H Bernstein, MD, FCAP



The heart is a four-chambered 350 gm semi-oval muscular organ composed of syncytial myocardium, innervated by the vagus nerve with a sino-atrial (SA) and a atrial ventricular (AV) node.  The blood circulates through it by way of the pulmonary artery and aorta, carrying blood away from the ventricles, to the lungs and the systemic circulation, respectively, and two veins, the vena cava and pulmonary, carrying blood to the atria from the systemic circulation and lungs, respectively.  The coronary arterial supply is the left anterior and left circumflex artery, and posteriorly, the right coronary artery, supplied by the aorta.  Much of the pathology has been referred to in the introduction, except for the molecular pathology of atherosclerosis, which has been well covered in this journal. The chambers are divided centrally by the interventricular septum, which is not completely closed in the blue-baby syndrome, which was repaired surgically by Helen Taussig and Richard Bing.  The piece that follows is primarily directed to the sympathetic innervation of the heart, variation in heart rate, and exercise or reaction to external threats.

What are the common observable events that stimulate or relax the heart:

  1. Running or a treadmill test
  2. Rowing or arm movement exercise
  3. A whole body workout
  4. Yoga or Ayurveda
  5. Sleep – normal or disruptive

Some things that can cause a disruption of balance in integrated circulation, neural innervation, innate immune and hormonal response are:

  1. Traumatic experience and/or Injuries
  2. Climate and seasonal changes
  3. Age
  4. Emotions

The basis for the physiological distress has long been the primary basis for acupuncture, holistic and transcendental medicine, and stress management.

I shall here examine the experimental work that supports such an approach – in principle.

Seattle Heart Watch: Initial Clinical, Circulatory and Electrocardiographic Responses to Maximal Exercise

Robert A Bruce, G0 Gey, Jr., Mn Cooper, Ld Fisher, Dr Peterson
Amer J Cardiol 1974; 33(4): 459-469.

A network of 15 maximal exercise testing facilities in four teaching hospitals, 10 private offices and clinics and an industrial medical department was organized in July 1971 to study prospectively the antecedents of myocardial infarction and sudden cardiac death. Within 18 months 2,332 men were tested: 1,275 healthy “normal” subjects, 97 with prior myocardial infarction, 306 with angina pectoris, 193 with hypertension and 461 with various mutually exclusive combinations of these diagnoses; among these clinical groups were five patients who had had a prior episode of ventricular fibrillation.
Historical, physical and laboratory data were recorded on self-teaching printed forms, with normal, borderline and abnormal responses arranged in three columns. Classification with respect to “unlikely,” “questionable” or “likely” risk of future cardiac events was assessed from the highest tally of items in these columns.
Analysis showed computer-averaged S-T segment responses were more consistent and reliable predictors than visual interpretations. Cardiac manifestations in healthy men varled with age and risk assessment, and in patients with cardiovascular disease varied with diagnosis and natural history of disease. Many significant differences provided insights into mechanisms of impaired cardiac function in relation to type of clinical disease. Testing was responsible for one post-exertional cardiac arrest. Recovery was effected promptly by defibrillation; there was no mortality.

Normal and Abnormal Heart Rate Responses to Exercise

  1. Kirk Hammond and Victor F. Froelicher
    Prog Cardiovasc Dis 1985; XXVII(4) (January/February), pp 27l-296

Of the many factors ultimately important in determining the cardiac output, the heart rate is certainly the easiest to measure. By analysis of the heart rate response to exercise in a variety of disease states we felt that the interrelationships of inotropic state, stroke volume, autonomic dysfunction, and myocardial disease could be clarified. This paper reviews the normal and abnormal heart rate responses to exercise.

The normal heart rate is determined by the frequency of depolarization of specialized cells within the sino-atrial node (S-A node). The S-A node, the vestigal sinus venosus, lies in the posterior portion of the heart near the demarcation between the right atrium and the superior vena cava. In about 80% of humans it receives its primary source of blood from a branch of the right coronary artery. Unlike other myocardial cells, the specialized cells of the S-A node have a slow sodium channel and a low resting potential which give these cells their special property. The slowly rising diastolic depolarization (stage four) leads to a rhythmic slow rising action potential.

The autonomic nervous system plays a key role in the regulation of heart rate (Fig 1). The sympathetic nervous system input to the heart originates in a nucleus in the medulla oblongata. Stimulation of this area with implanted electrodes results in increased heart rate and systemic vascular resistance due to increased sympathetic output. Axons from these nuclei descend to the sympathetic trunk via the intermediolateral columns of the spinal cord. From their synapses in cervical ganglia, postganglionic fibers directly innervate the atrial and ventricular musculature, the S-A node, and the A-V node. The effector neurotransmitter is norepinephrine and the receptors are of the beta adrenergic type. There is evidence from competitive binding studies that the postganglionic fibers are predominantly associated with type I beta receptors. The parasympathetic influence to the S-A node and the myocardium originates from nuclei very near the origin of the sympathetic nerves. From the motor nuclei of the vagus and the nucleus solitarius come fibers that form part of the vagus nerve. These fibers terminate at ganglia in the wall of the heart. The postganglionic cholinergic fibers end mostly near the S-A node and the A-V node; there is little evidence for the distribution of parasympathetic nerves to the ventricular myocardium although cholinergic muscarinic receptors have been characterized. In normal conditions there exists a well balanced autonomic tone influencing the S-A node.

There is a complex interrelation among many systems to determine the autonomic tone at the S-A node (Fig 2). [Arterial mechanoreceptors of the carotid sinus and aortic arch respond to changes in arterial pressure and result in appropriate adjustment in the sympathetic and vagal outflow to the heart and resistance and capacitance vessels. (Reprinted with permission from Shepherd JT, Van Houlte PM: The Human Cardiovascular System, Facts and Concepts. New York, Raven Press, 1979).]

There are cortical inputs to the medullary centers; for example, fear results in tachycardia by this pathway. Visceral afferent inputs increase parasympathetic tone resulting in bradycardia. Several reflexes are present for homeostasis. For example, the baroreflex is important in sensing changes in blood pressure and increasing or decreasing the heart rate via autonomic influences at the S-A node to maintain appropriate cardiac output.

Arterial mechanoreceptors of the carotid sinus and aortic arch respond to changes in arterial pressure and result in appropriate adjustment in the sympathetic and vagal outflow to the heart and resistance and capacitance vessels. (Reprinted with permission from Shepherd JT, Van Houlte PM: The Human Cardiovascular System, Facts and Concepts. New York, Raven Press, 1979).

Although the importance of autonomic influence is well accepted in the usual cardioacceleration to exercise, the role of the recovery or deceleration of heart rate following exercise may not be influenced by autonomic input. Six men were studied after peak treadmill exercise. To assess the contribution of autonomic factors in heart rate recovery, the men were given atropine, propranolol, or both agents. It was found that exponential cardio-deceleration occurred under each experimental condition. They concluded that heart rate recovery after exercise is regulated by changes in venous return mediated through atrial stretch receptors of pacemaker tissue. This study implies that deceleration depends primarily on factors intrinsic to the intact circulation that are independent of autonomic control.

The control of heart rate is complex; autonomic tone, central and peripheral reflexes, hormonal influences, and factors intrinsic to the heart are all important. Although easily measured, the heart rate reflects an integrated physiologic response.

The physiologic response to exercise depends on the type of exercise performed; the two major types are isometric and isotonic. Creating muscle tension with no movement against resistance is a pure form of isometric exercise; this results in increased muscle mass and strength. Isotonic exercise is the repetitive, rhythmic movement of large muscle masses against little resistance, known also as dynamic or aerobic exercise. Although most activities involve degrees of both, running is predominantly dynamic, and weight lifting is predominantly isometric.

Bezucha and colleagues investigated the cardiovascular responses to isometric (static) exercise (leg extension) and compared these to those observed during static-dynamic exercise (one arm cranking) and dynamic exercise (leg cycling) in normal men. Heart rate responses to these three tasks were markedly different with static exercise (holding a 30% of maximum voluntary contraction for 3 minutes) resulting in a mean heart rate of 110 + 6 compared with 164 + 4 beats/min in bicycle exercise at 80% of Vo max. Cardiac outputs were raised in all three activities in a proportional manner: 6.8 + 0.7 for static, 10.8 f 0.7 for arm cranking, and 31.9 + 1.0 L/min for bicycling. Stroke volume did not significantly change in the static or combined static-dynamic exercises. The increases in cardiac output were primarily the result of increases in heart rate. This study demonstrates the predominant pressor response and modest cardio-acceleration of isometric exercise.

Longhurst and coworkers, examined the response to acute and chronic exercise in two groups of athletes who typify the two major types of exercise: long distance runners (dynamic) and weight lifters (isometric). The runners responded to isometric exercise with lower double products than the weight lifters. The end-diastolic volume index (evaluated by echocardiography) in the runners was greater than control subjects both at rest and with exercise. In contrast, the weight lifters’ responses were similar to weight matched controls. Not only is the type of exercise an important determinant of acute physiologic response, but chronic static exercise results in physiologic responses that are no different from the responses of sedentary men.

Dynamic exercise, also called isotonic or aerobic, involves the rapid movement of large muscle masses that results in the need for the body to respond with increased ventilation to increase oxygen consumption. Such exercise is called aerobic since it must be performed by using oxygen. The heart must increase its output and performs flow work rather than pressure work. The response to dynamic muscular exercise consists of a complex series of cardiovascular adjustments designed to:

(1) see that active muscles receive a blood supply appropriate to their metabolic needs;

(2) dissipate the heat generated by active muscles; and,

(3) maintain the blood supply to the brain and the heart.

The regulation of the circulation during exercise involves the four following adaptations?

  • Local
  • Nervous adaptations
  • Humoral adaptations
  • Mechanical adaptations

The relationship of pressure, flow, and resistance in rigid tubes is defined by Poiseuille’s law. This law states that resistance is proportional to pressure divided by flow. Peripheral resistance increases in the tissues that do not function in the performance of the ongoing exercise and decreases in active muscle. The result is a decrease in systemic vascular resistance. While pressure only increases mildly, flow can increase by as much as five times during dynamic exercise. Since flow increases much more than pressure, the result is a decrease in systemic resistance. Another mechanical adaptation occurs when the increasing venous return dilates the left ventricle and cardiac function is enhanced via the Frank-Starling mechanism.

There is a highly predictable relationship between total body oxygen consumption and both the cardiovascular and respiratory responses to exercise (Fig 4). [ (A) The linear relationship between heart rate and oxygen uptake. The data was collected from 86 adult male and female subjects. (B) The linear relationship between cardiac output and oxygen uptake. C The data was collected from 23 adult male and female subjects. (C) The linear relationship between minute ventilation and oxygen uptake. ] The data was collected from 225 subjects.  (Reprinted with permission.) Both parameters increase linearly with increasing oxygen consumption until maximal oxygen consumption is approached.

In summary, the type of exercise is an important determinant of both acute and chronic cardiovascular responses. Isometric exercise can be viewed as a pressure load and dynamic exercise as a volume load to the left ventricle. The acute physiological adjustments to dynamic exercise include peripheral vasodilation in exercising muscle, neural mediated increases in sympathetic tone to the heart and the periphery, the release of catecholamines from the adrenal medulla, and changes in venous return due to mechanical and humoral factors. A linear relationship exists between the consumption of oxygen and cardiac output and minute ventilation such that the work performed is highly correlated with the amount of blood pumped and the oxygen consumed.

An increase in heart rate is a major factor contributing to the exercise-induced increased cardiac output. Bowditch demonstrated that the time interval between beats is a determinant of the force of myocardial contraction. This has been called the frequency-force relationship (Fig 5). [The frequency force relationship is demonstrated by a sudden increase in beat frequency in papillary muscle fixed for isometric contraction. A slow increase in isometric tension results from the change in rate implying in increased contractile state. Each vertical line represents an isometric contraction. (Reprinted with permission of W.B. Saunders.)] The increased tension that accompanies an increased heart rate is the result of increased contractility. Although the mechanism of this phenomenon is not known, it may have to do with calcium availability to contractile elements. Thus an increase in heart rate results in an increase in the force of contraction.

Variations in and Significance of Systolic Pressure During Maximal Exercise (Treadmill) Testing: Relation to Severity of Coronary Artery Disease and Cardiac Mortality

John B. Irving, Robert A. Bruce,, Timothy A. Derouen
Amer J Cardiol 1977; 39: 841-848.

Variations in clinical noninvasive systolic pressure at the point of symptom-limited exercise on a treadmill were examined in six groups of subjects: 5,459 men and 749 women classified into three categories each. Among the men, 2,532 were asymptomatic healthy, 592 were hypertensive and 1,586 had clinical manifestations of coronary heart disease (that is, typical angina pectoris, prior myocardial Infarction or sudden cardiac arrest with resuscitation). Among the women, 244, 158 and 347 were in the corresponding clinical categories. None had had cardiac surgery; all had follow-up status ascertained by periodic mail questionnaires.
Reported deaths were reviewed and classified by three cardiologists; 140 deaths were attributed to coronary heart disease, 118 of them in the men classified as having coronary heart disease. The majority of maximal systolic blood pressure readings were reported to the nearest centimeter rather than millimeter of pressure. Retesting of 156 persons from 1 to 32 months later showed that pressure values agreed within 10 percent in two thirds, the overall mean difference was only 8.6 mm Hg and the correlation at maximal exercise was superior to that of the resting observations just before exercise. Hypertensive patients had a significantly greater body weight than normotensive persons. Among men, the lowest maximal systolic pressure was observed in the group with coronary heart disease; among women, the lowest mean pressure was found in the healthy group. Patients with coronary heart disease were slightly older, and only the women showed a significant correlation in maximal pressure with age. Only 5 percent of the variation in maximal systolic pressure in the patients with coronary heart disease was due to a shortened duration of exercise. Maximal systolic pressures correlated fairly well (r = 0.46 to 0.68 for the various groups) with resting systolic pressure, and this relation was independent of the diagnosis of cardiovascular disease in both men and women. Relations between pressure and the number of stenotic coronary arteries and Impaired ejection fraction at rest were examined in 22 men without and 162 men with coronary artery disease. Lower maximal systolic pressures were often associated with two or three vessel disease or reduced ejection fraction, or both.

The prognostic value of maximal systolic pressure for subsequent death due to coronary heart disease was examined in the men with coronary heart disease. The annual rate of sudden cardiac death decreased from 97.9 per 1,000 men to 25.3 and 6.6 per 1,000 men as the range of maximal systolic pressure increased from less than 140 to 140 to 199 and to 200 mm Hg or more, respectively. Cardiomegaly, Q waves in the resting electrocardiogram and persistent postexertional S-T depression were more common in men with the lowest systolic pressure at maximal exercise.

Circulatory Adjustments to Dynamic Exercise and Effect of Physical Training in Normal Subjects and in Patients With Coronary Artery Disease

Jan Praetorius Clausen
Prog Cardiov Dis 1976; XVIII(6): 459-496

The present paper focuses upon the importance of peripheral circulatory alterations during adjustments to exercise and training. Although training results in central circulatory adaptations and may also improve left ventricular function, the prime importance of such adaptations as regards the circulatory and metabolic response to training will be questioned. The thesis that increased maximal exercise capacity can at least in part be attributed to local alterations in the trained muscles will be presented and analyzed. While it is accepted that maximal oxygen uptake is limited by the blood oxygen transport capacity, it will be postulated that the primary event normally responsible for an enhanced oxygen supply after training is an increased ability to reduce resistance to blood flow in exercising muscles rather than improved performance of the central pump.

adjustment to exercise is limited to factors pertinent to physical training of patients with CAD. More detailed accounts of the normal response to exercise can be found in recent books or reviews.

  1. Astrand, P-O, Rodahl K: Textbook of Work Physiology. New York, McGraw-Hill, 1970
  2. Ekblom B, Hermansen L: Cardiac outputs in athletes. J Appl Physiol 25:619, 1968
  3. Christensen EH: Beitrlge zur Physiologie schwerer kijrperlicher Arbeit. Arbeits physiol 4:470, 1931
  4. Saltin B, Blomqvist G, Mitchell JH, et al: Response to exercise after bed rest and after training. Circulation 38 (Suppl 7): 1, 1968
  5. Clausen JP, Klausen K, Blomqvist G, et al. Central and peripheral circulatory changes after training of the arms or legs. Am J Physiol 225:675, 1973

In connection with patients with CAD, only one type of muscular work is of interest; namely, rhythmic or dynamic exercise, in which a considerable part of the skeletal muscle mass is active. This applies to naturally occurring physical activity. Only these types of activity will be referred to and only at work intensities that can be continued for 3-5 min or more.

Dynamic muscular exercise is characterized by a high metabolic rate in the muscle cells with the skeletal muscle functioning in a manner similar to the myocardium, with regularly alternating contraction and relaxation phases. The mechanical energy expended is grossly proportional to the force and the frequency of contraction, and it is derived from the breakdown of adenosine triphosphate (ATP) and creatine phosphate (CP). Only a limited number of a muscle’s fibers, and thus, of its maximal contractile power, can be used in dynamic work continuing for several minutes. During maximal exercise on a bicycle ergometer with a pedaling frequency of 60 rpm, about 15%-2% of the maximal isometric strength of the quadriceps muscle is mobilized. This is thought related to the fact that skeletal muscle, in contrast to myocardium, is composed of several types of fibers with different enzymatic characteristics.29 Some fibers are similar to cardiac muscle being rich in oxidative intramitochondrial enzymes connected to the citric acid cycle, the fatty acid cycle, and the respiratory chain. These are the classical “red” muscle fibers. At the other end of a continuous spectrum is the typical “white” muscle fiber, with a high content of enzymes necessary for anaerobic glycolysis, but containing few mitochondria. Due to their great capability for aerobic metabolism, red fibers sustain rhythmic contractions for long periods of time, whereas the anaerobic white fibers require longer restitution phases even after short periods of activity.

Oxygen extraction per milliliter of blood perfusing the muscle may increase three- to fourfold, and the enhanced muscle blood flow (MBF) is responsible for the remainder of the augmented oxygen uptake. In human muscle, maximal MBF is in the order of 70-100 ml X 100 g-r X min--1 against a resting value of 2-5 ml X 100 g-r X min--1. The increase in MBF is locally controlled by release of vasodilator metabolites and thereby closely geared to the metabolic demands. Muscle blood flow per unit weight of muscle is closely related to the relative work load; i.e., percentage of maximal work load. The metabolites responsible for the exercise-induced vasodilation and hyperemia in muscle are not yet conclusively identified. The finding that both MBF and ATP-CP depletion are related to the relative work load supports the speculation that split products from high energy phosphates may be involved.

During strenuous exercise, VO2  can attain individually varying maximal values, typically ranging from 2.0 to 6.0 1 02/min. The maximal oxygen consumption (VO2 max) is a highly reproducible measure of a given subject’s capability to perform this type of exercise, and it constitutes a useful physiologic reference standard. The conditions required to obtain VO2 max, and its physiologic implications have recently been reviewed in detail by Rowe and by Hermansen. The VO2 max  for a given type of work is normally achieved at a work intensity that can be sustained for at least 3 min, but will cause complete exhaustion within 5-10 min.  At this intensity of exercise, the cardiovascular functional capacity with respect to increase in cardiac output (Q), widening of systemic arteriovenous oxygen difference (AVDO2), and elevation of heart rate (HR) will be challenged maximally for the given type of exercise. However, the relative contribution of Q and AVDO2.

The above description of the normal central and peripheral circulatory adjustment to exercise can be recapitulated as follows:

During dynamic exercise, Q increases in direct proportion to the augmentation of 30,. The increase in Q is directed to exercising skeletal muscles, to the myocardium and-if exercise is continued for more than approximately 5 min-also to the skin. Blood flow to most “nonexercising” tissues (SBF, RBF,
and noncontracting muscles) is reduced due to a general sympathetic vasoconstriction. At submaximal levels, muscle blood flow per unit tissue,
the degree of peripheral vasoconstriction, the acceleration of HR, and in consequence, the increase in myocardial blood flow and oxygen consumption are all functions of the relative V02 ; i.e., the actual VO2 expressed as a percentage of the highest achievable V02 for the given type of exercise.

Most patients with CAD who have been included in exercise and training studies have had healed myocardial infarction and/or stable angina pectoris and have been between 35 and 65 years of age. Both the aging process and myocardial lesions contribute to the modification of the circulatory response to exercise in this group, as compared to healthy young people. In advanced age-especially after 60 years-the circulation tends to become hypokinetic; i.e., Q/VO2 is reduced.  The decline of Q in l/min is almost the same during submaximal exercise as at rest, and thus the increase in Q with VO2 is essentially the same in older as in younger subjects. Stroke volume is lower at a given VO2 , while arterial blood pressures are higher; Q, HR, and VO2 max decline with aging.

Although patients with angina pectoris often exhibit a more profound impairment of left ventricular function and of working capacity than patients with CAD without angina, there seems not to be any specific differences in their central or peripheral circulatory response to exercise. Accordingly, the abnormalities in hemodynamic adaptations in a patient with angina pectoris are present also at workloads that do not provoke angina pectoris.

From the point of view of an exercise physiologist, the patient with angina pectoris is peculiar in that his capacity for dynamic work is not limited by his total body VO2 max, but by VO2 max in myocardial regions supplied by narrowed coronary arteries. If pain is prevented by prophylactic administration of nitroglycerin, a patient with angina pectoris can exercise longer at a given work load or achieve higher workloads and thus obtain a higher VO2 max.

The circulatory adjustment to exercise in patients with CAD typically differs from that of normal subjects in that the maximal values for Q (and thus for VO2), for HR, and for blood pressures are lower. During submaximal exercise, the relation between Q and VO2 tends to be reduced. Moreover, most of the patients with CAD exhibit signs of left ventricular failure during exercise, including a decrease in SV at higher workloads, reduced myocardial contractility, and increased LVEDp. Nonetheless, the peripheral circulatory regulation in patients with CAD corresponds in principle to that seen in healthy subjects of the same age.

Training changes the different local flows during exercise in such a way that, within the framework of an unchanged or reduced Q, its regional distribution at a given submaximal work load deviates less from that seen at rest: the perfusion of nonworking tissues is relatively greater and the flow to active muscles less elevated. However, this is only valid for exercise performed with trained muscles.

Although the precise mechanism mediating exercise hyperemia is unknown, it seems acceptable that enhanced content of oxidative enzymes enables a reduction in MBF at a given submaximal VO2 . After training, due to the increased capacity for oxidative phosphorylation, ATP and CP in active muscles stabilize at a higher steady state level. At the same time glycolysis occurs at a slower rate, pH is relatively increased, and the concentration of multiple intermediate metabolic products may be lower. In consequence, the intra- and intercellular biochemical milieu-concentrations of electrolytes and osmolality included-is less disturbed as compared to the conditions at rest. Whatever substance or combinations of chemical alterations cause the vasodilation, their extent of change is probably reduced at a given respiratory rate in trained muscle tissue, and the vasodilation is thus diminished.

Training improves exercise tolerance in most patients with angina pectoris. The main part of this effect can be related to the training-induced reduction in HR and SBP that decreases myocardial O2 requirements at a given total body O2 uptake. However, at the same time, higher values for the product of HR and SBP are tolerated before pain is provoked after training, suggesting that training has additional economizing effects on myocardial function or directly improves myocardial O2 supply. As judged from the results obtained in exercise tests, training and nitroglycerin seem almost equally potent in alleviating or preventing angina pectoris on exertion. Beta receptor blockade may be somewhat less efficient, whereas aorto-coronary bypass surgery, when practicable, may be the most efficient treatment of exertional angina available today.

Physical training is efficient in improving exercise capacity in about two thirds of all patients with angina pectoris. Patients with angina pectoris provoked only by exercise will often respond favorably to training, even if their exercise capacity is low.  In contrast, patients who suffer from angina at rest, especially nocturnal attacks, may be less likely to increase their exercise tolerance by training. Accordingly, Hellerstein reports that in patients with more severe coronary arteriosclerosis as assessed from coronary arteriograms and left ventricular function, physical fitness fails to improve from training.

Unfortunately, it appears that the patients who cannot be expected to respond favorably to training are also less likely to improve from other modes of treatment. According to Balcon, only younger patients with normal left ventricular function are prone to achieve substantial improvement in physical working capacity by vein graft surgery. Furthermore, the mortality from the operation is higher in patients with abnormal ventricular function. Thus, the appearance of an apparently efficient surgical intervention has not simplified the selection of treatment.

Characteristics of the Ventilatory Exercise Stimulus

F.M. Bennett and W.E. Fordyce
Respiration Physiology 1985; 59, 55-63

Simple mathematical models were used to quantitatively examine a number of hypotheses concerning the nature of the exercise stimulus. The modelling demonstrated the following for an exercise intensity of 5 times the resting metabolic rate.

(1) During the steady state, a deviation in the coupling between VE and metabolic rate by + 25 % of the value necessary for isocapnia, results in a deviation of Paco2 of + 2 torr from isocapnia.

(2) In the transient phase, a mismatch between VE and Q (and thus CO2 flow) of 50% results in a change of Paco2 of only 1 torr.

(3)When resting Paco2 is changed by 10 torr and it is assumed that the coupling between VE and Paco2 does not change, Paco2 deviates from isocapnia by less than 2 torr.

It is concluded that –

(1) to experimentally test hypotheses of the exercise stimulus requires resolution of small changes in Paco2;

(2)  good regulation of Paco2 does not necessarily imply precise coupling between VE and Vco2;

(3) the ventilatory exercise stimulus need not be a precise function of metabolic rate;

(4) in the steady state, the normal CO2 controller will be very effective in minimizing changes in Paco2 due to a mismatch between ventilation and metabolic rate.

Cardiorespiratory and Metabolic Responses to Positive, Negative and
Minimum-Load Dynamic Leg Exercise

Carl Magnus Hesser, Dag Linnarsson And Hilding Bjurstedt
Respiration Physiology 1977; 30, 5 I-67

Cardiorespiratory and metabolic responses to steady-state dynamic leg exercise were studied in seven male subjects who performed positive and negative work on a modified Krogh cycle ergometer at loads of 0. 16,33,49.98, and 147 W with a pedaling rate of60 rpm.
In positive work, O2 uptake increased with the ergometric load in a parabolic fashion. Net O2 uptake averaged 220 ml*min– 1 at 0 W (loadless pedaling), and was 75 ml* min– 1 lower at the point of physiological minimum load which occurred in negative work at approximately 9 W. The O2 cost of loadless pedaling is for one-third attributed to the work of overcoming elastic and viscous resistance, the remaining part being due mainly to the work of antagonistic muscle contraction in the moving legs. Although at a given Vo2 work rate was much higher in negative than in positive work, corresponding values for VE were similar, suggesting that the mechanical tension in working muscles is of little or no importance in the control of ventilation in steady-state exercise.
Heart rate increased linearly with Vo2 in both positive and negative work, with a steeper slope in negative work. Evidence is presented that none of the current definitions of muscular efficiency yields the true efficiency of muscular contraction in cycle ergometry, net efficiency calculation resulting in too low estimates, and work and delta efficiency calculations in overestimated values in the low-intensity work range, and in underestimated values in the high-intensity range.

The effect of exercise on left ventricular ejection time in patients with hypertension or angina pectoris

James R. Bowlby
Amer Heart J 1979; 97(3): 348-350

Using the method and regression equation of Lewis and associates, the present study confirms their findings in normal men up to the age of 65 years. Despite the significantly higher myocardial oxygen consumption, as measured by the double product, the hypertensive patients responded in a similar fashion. The patients with angina pectoris, however, showed a significantly prolonged post-exercise ejection time.

Cardiac Effects of Prolonged and Intense Exercise Training in Patients With Coronary Artery Disease

Ali A. Ehsani, Wade H. Martin Iii, Gregory W. Heath, Edward F. Coyle
Amer J Cardiol 1982; 50: 246-254

The effects of intense and prolonged exercise training on the heart were studied with echocardiography in eight men with coronary artery disease with a mean age (standard error of the mean) of 52 + 3 years. Training consisted of endurance exercise 3 times/week at 50 to 60 percent of the measured maximal oxygen uptake for 3 months followed by exercise 4 to 5 days/week at 70 to 60 percent of maximal oxygen uptake for 9 months. Maximal oxygen uptake capacity increased by 42 percent (26 + 1 versus 37 + 2 ml/kg per min; p <0.001). Heart rate at rest and submaximal heart rate and systolic blood pressure at a given work rate were significantly lower after training. Systolic blood pressure at the time of maximal exercise increased (145 + 9 before versus 166 + 6 mm Hg after training; probability [p] <0.01). Left ventricular end-diastolic diameter was increased after 12 months of training (from 47 + 1 to 51 + 1 mm; p <0.01. Left ventricular fractional shortening and mean velocity of circumferential shortening decreased progressively in response to graded iisometric handgrip exercise before training but not after training. At comparable levels of blood pressure during static exercise, mean velocity of circumferential shortening was significantly higher after training (0.76 + 0.04 versus 0.96 + 0.07 diameter/set, p <0.01). No improvement in echocardio-graphic or exercise variables was observed over a 12 month period in another group of five patients who did not exercise. Thus the data suggest that prolonged and vigorous exercise training in selected patients with coronary artery disease can elicit cardiac adaptations.

Physical activity and resting pulse rate in older adults: Findings from a randomized controlled trial

Bríain O’Hartaigh, Marco Pahor, Thomas W. Buford, John A. Dodson, et al.
Am Heart J 2014;168:597-604

Background Elevated resting pulse rate (RPR) is a well-recognized risk factor for adverse outcomes. Epidemiological evidence supports the beneficial effects of regular exercise for lowering RPR, but studies are mainly confined to persons younger than 65 years. We set out to evaluate the utility of a physical activity (PA) intervention for slowing RPR among older adults.
Methods A total of 424 seniors (ages 70-89 years) were randomized to a moderate intensity PA intervention or an education-based “successful aging” health program. Resting pulse rate was assessed at baseline, 6 months, and 12 months. Longitudinal differences in RPR were evaluated between treatment groups using generalized estimating equation models, reporting unstandardized β coefficients with robust SEs.
Results Increased frequency and duration of aerobic training were observed for the PA group at 6 and 12 months as compared with the successful aging group (P = 0.001). In both groups, RPR remained unchanged over the course of the 12-month study period (P = .67). No significant improvement was observed (β [SE] = 0.58 [0.88]; P = .51) for RPR when treatment groups were compared using the generalized estimating equation method. Comparable results were found after omitting participants with a pacemaker, cardiac arrhythmia, or who were receiving β-blockers.
Conclusions Twelve months of moderate intensity aerobic training did not improve RPR among older adults. Additional studies are needed to determine whether PA of longer duration and/or greater intensity can slow RPR in older persons.

Autonomic regulation and maze-learning performance in older and younger dults

Karen J. Mathewson, J Dywan, PJ Snyder, WJ Tays, SJ Segalowitz
Biological Psychology 88 (2011) 20– 27

There is growing evidence that centrally modulated autonomic regulation can influence performance on complex cognitive tasks but the specificity of these influences and the effects of age-related decline in these systems have not been determined. We recorded pre-task levels of respiratory sinus arrhythmia (RSA; an index of phasic vagal cardiac control) and rate pressure produce (RPP; an index of cardiac workload) to determine their relationship to performance on a cumulative maze learning task. Maze performance has been shown to reflect executive error monitoring capacity and non-executive visuomotor processing speed. Error monitoring was predicted by RSA in both older and younger adults but by RPP only in the older group. Non-executive processes were unrelated to either measure. These data suggest that vagal regulation is more closely associated with executive than nonexecutive aspects of maze performance and that, in later life, pre-task levels of cardiac workload also influence executive control.

Sympathovagal Imbalance Contributes to Prehypertension Status and Cardiovascular Risks Attributed by Insulin Resistance, Inflammation, Dyslipidemia and Oxidative Stress in First Degree Relatives of Type 2 Diabetics

Gopal Krushna Pal, C Adithan, P Hariharan Ananthanarayanan, Pravati Pal, et al.
PLoS OME 2013; 8(11), e78072 http://dx.doi.org:/10.1371/journal.pone.0078072

Background: Though cardiovascular (CV) risks are reported in first-degree relatives (FDR) of type 2 diabetics, the pathophysiological mechanisms contributing to these risks are not known. We investigated the association of sympathovagal imbalance (SVI) with CV risks in these subjects.
Subjects and Methods: Body mass index (BMI), basal heart rate (BHR), blood pressure (BP), rate-pressure product (RPP), spectral indices of heart rate variability (HRV), autonomic function tests, insulin resistance (HOMA-IR), lipid profile, inflammatory markers, oxidative stress (OS) marker, rennin, thyroid profile and serum electrolytes were measured and analyzed in subjects of study group (FDR of type 2 diabetics, n = 72) and control group (subjects with no family history of diabetes, n = 104).
Results: BMI, BP, BHR, HOMA-IR, lipid profile, inflammatory and OS markers, renin, LF-HF (ratio of low-frequency to high frequency power of HRV, a sensitive marker of SVI) were significantly increased (p,0.0001) in study group compared to the control group. SVI in study group was due to concomitant sympathetic activation and vagal inhibition. There was significant correlation and independent contribution of markers of insulin resistance, dyslipidemia, inflammation and OS to LF-HF ratio. Multiple-regression analysis demonstrated an independent contribution of LF-HF ratio to prehypertension status (standardized beta 0.415, p,0.001) and bivariate logistic-regression showed significant prediction (OR 2.40, CI 1.128–5.326, p = 0.002) of LF-HF ratio of HRV to increased RPP, the marker of CV risk, in study group.
Conclusion: SVI in FDR of type 2 diabetics occurs due to sympathetic activation and vagal withdrawal. The SVI contributes to prehypertension status and CV risks caused by insulin resistance, dyslipidemia, inflammation and oxidative stress in FDR of type 2 diabetics.

Exercise prescription for patients with type 2 diabetes and pre-diabetes: A position statement from Exercise and Sport Science Australia

Matthew D. Hordern, DW Dunstan, JB Prins, MK Baker, et al.
Journal of Science and Medicine in Sport 15 (2012) 25–31

Type 2 diabetes mellitus (T2DM) and pre-diabetic conditions such as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are rapidly increasing in prevalence. There is compelling evidence that T2DM is more likely to develop in individuals who are insufficiently active. Exercise training, often in combination with other lifestyle strategies, has beneficial effects on preventing the onset of T2DM and improving glycaemic control in those with pre-diabetes. In addition, exercise training improves cardiovascular risk profile, body composition and cardiorespiratory fitness, all strongly related to better health outcomes. Based on the evidence, it is recommended that patients with T2DM or pre-diabetes accumulate a minimum of 210 min per week of moderate-intensity exercise or 125 min per week of vigorous intensity exercise with no more than two consecutive days without training. Vigorous intensity exercise is more time efficient and may also result in greater benefits in appropriate individuals with consideration of complications and contraindications. It is further recommended that two or more resistance training sessions per week (2–4 sets of 8–10 repetitions) should be included in the total 210 or 125 min of moderate or vigorous exercise, respectively. It is also recommended that, due to the high prevalence and incidence of comorbid conditions in patients with T2DM, exercise training programs should be written and delivered by individuals with appropriate qualifications and experience to recognise and accommodate comorbidities and complications.

Estimation of the Ejection Fraction in Patients with Myocardial Infarction Obtained from the Combined Index of Systolic and Diastolic Left Ventricular Function: A New Method

Jorge A. Lax, Alejandra M. Bermann, Tomás F. Cianciulli, Luis A. Morita, et al.
J Am Soc Echocardiogr 2000;13:116-23.

The index of myocardial performance combining systolic and diastolic time intervals (Index) is a useful method, already explained in past studies, that offers new values that have not been widely known among clinical cardiologists. The aim of this study is to obtain from this Index a measurement of the ejection fraction (EF), which is a very well-known value.
The study involved 97 patients with myocardial infarction, 55 of whom were studied retrospectively (group A, aged 46-62 years, 50 men) to obtain and test the formula EF = 60 – (34 × Index). The second group (group B, aged 47-63 years, 40 men) included 42 patients who were evaluated prospectively. The EF obtained was compared with that reached through the use of radionuclide angiography (EF-RNA).
The Index was obtained through the use of the formula (a – b)/b, where a is the interval between cessation and onset of the mitral inflow, and b is the ejection time. In group A the EF obtained by the Index (EF-Index) was 37.5% ± .8%, and the EF-RNA was 37.7% ± 11% (r = 0.76). In group B the EF-Index was 41.6% ± 7%, and the EF-RNA was 41.2% ± 10% (r = 0.75).
Conclusion: Through the new formula described here it is possible to obtain a reliable measurement of the EF in patients with myocardial infarction, a well known and extremely useful value, especially for those patients with poor acoustic windows.

HCN channels: new roles in sinoatrial node function

Christian Wahl-Schott, Stefanie Fenske and Martin Biel
Current Opinion in Pharmacology 2014, 15:83–90

Hyperpolarization-activated cyclic nucleotide gated (HCN) channels pass a cationic current (Ih/If) that crucially contributes to the slow diastolic depolarization (SDD) of sinoatrial pacemaker cells and, hence, is a key determinant of cardiac automaticity and the generation of the heart beat. There is growing evidence, that HCN channel functions in the sinoatrial node (SAN) are not restricted to impulse formation but are also required for impulse propagation. In addition, HCN channels are involved in coordination and maintenance of sinoatrial network activity and, hence, are crucial for stabilizing cardiac rhythmicity. In the present review we will outline these new concepts.

In this review we will focus on HCN channel functions in the sinoatrial node beyond the established concepts described above. We will outline recent advances involving the characterization of the HCN1-deficient mouse line (HCN1-/- mouse) which have provided evidence that HCN channels are required for impulse propagation and the precision of the heart beat [19**]. Furthermore, we show how these properties can be generalized across the other HCN channel subtypes in the sinoatrial node.

19** Fenske S, Krause SC, Hassan SI, Becirovic E, Auer F, Bernard R, Kupatt C, Lange P, Ziegler T, Wotjak CT et al.: Sick sinus syndrome in HCN1-deficient Mice. Circulation 2013. Epub 2013 Nov 11.
First demonstration of a functional relevance of HCN1 channels in the murine sinoatrial node. The authors demonstrate that mice lacking the pacemaker channel HCN1 display congenital sinoatrial node dysfunction characterized by bradycardia, sinus dysrhythmia, prolonged sinoatrial node recovery time, increased sinoatrial conduction time and recurrent sinus pauses. As a consequence of sinoatrial node dysfunction HCN1-deficient mice display a severely reduced cardiac output.

Recent studies indicate that the role of cardiac HCN channels extends well beyond generation of pacemaker potentials. In addition to being merely ‘pacemaker channels’, HCN channels are important for sinoatrial impulse propagation, cardiac excitability and for the precision of the heartbeat. Furthermore, cardiac HCN channels are involved in the repolarization process of heart ventricles [56**,57]. It will be important to consider the full spectrum of these diverse cardiac functions when exploring agents acting on HCN channels for a specific clinical purpose such as reduction of heart rate.

56.** Fenske S, Mader R, Scharr A, Paparizos C, Cao-Ehlker X, et al.: HCN3 contributes to the ventricular action potential waveform in the murine heart. Circ Res 2011, 109:1015-1023.
First study demonstrating a functional role of HCN3 channels in the heart. Using HCN3-deficient mouse line the authors show that HCN3 together with other members of the HCN channel family confers a depolarizing background current that regulates ventricular resting potential and counteracts the action of hyperpolarizing potassium currents in late repolarization.
57. Fenske S, Krause S, Biel M, Wahl-Schott C: The role of HCN channels in ventricular repolarization. Trends Cardiovasc Med 2011, 21:216-220.

Roles of HCN1 channels for sinoatrial impulse conduction (source-sink relation) The primary impulse initiating the heart beat is generated in the leading pacemaker cell(s) of the sinoatrial node. Once the leading pacemaker cell(s) reaches the threshold for L-type Ca2+ channels an action potential is generated. Since pacemaker cells are interconnected via gap junctions, the impulse is conducted through the sinoatrial network and to the atrium. During impulse propagation the source cell (the cell which first reached AP threshold and is firing the action potential) charges the neighboring cell (sink), in which the membrane potential is below threshold (Figure 1) [24*]. Impulse propagation depends on the source-sink relation [24*, 25–29]. HCN1 deletion increases the sinoatrial conduction time suggesting the existence of a source sink mismatch in the HCN1-deficient mouse [19**].

Role of HCN1 channels for impulse formation and impulse conduction in the sinoatrial node. Schematic pacemaker potential in sinoatrial node cells of wild type (a) and HCN1-/- mice.
(b) HCN channels contribute to the slow diastolic depolarization. In the absence of HCN1 the slope of SDD isdecreased and the time to threshold for an action potential increased. HCN channels decrease the maximal diastolic potential (MDP). In the absence of HCN1 the MDP is increased. This results in an increased distance and time to threshold for an action potential and a decrease in impulse propagation.  [SDD: slow diastolic depolarization; MDD: maximal diastolic depolarization; Vthr: threshold potential for the generation of an action potential.]
(c) Direction of intracellular and extracellular current flow during propagation of an action potential from depolarized (source) to resting cells (sink).
(d)Source sink relationship in propagation. Charge from excited cells (source) flows into unexcited cell (sink) and provides the charge to depolarize them to activation threshold. Arrows and dotted lines indicate changes observed in HCN1-/- mice of parameter indicated leading to source sink mismatch and prolonged sinoatrial conduction. Modified from [24*].

24.* Spector P: Principles of cardiac electric propagation and their implications for re-entrant arrhythmias. Circ Arrhythm Electrophysiol 2013, 6:655-661.
The authors provide an excellent review of the principles of impulse propagation in relation to arrhythmia.

HCN1 channels increase the temporal and spatial precision of impulse formation in sinoatrial node

HCN1 channels increase the temporal and spatial precision of impulse formation in sinoatrial node

HCN1 channels increase the temporal and spatial precision of impulse formation in sinoatrial node.
(a) Schematic of the sinoatrial node. Atrial cells invaginate into the central sinoatrial node. Putative localization of HCN1 channels at contact interface between strands of atrial myocytes which extend into the central SAN and sinoatrial node pacemaker cells. Green: autonomous innervation. HCN1 channels dampen network noise generated by neighboring pacemaker cells in the sinoatrial network, by invading hyperpolarization of atrial cells and by autonomous regulation. SAN: sinoatrial node, RA: right atrium, CT: crista terminalis.
(b) Model of sinoatrial node function (for detail see text). Note that individual cells display different phases and slightly different periods.

Pharmacological inhibition of cardiac HCN channels

HCN channels have emerged as interesting targets for the development of drugs that lower the heart rate. Ivabradine is the first and currently the only clinically approved compound that specifically targets HCN channels. The therapeutic indication of ivabradine is the symptomatic treatment of chronic stable angina pectoris in patients with coronary artery disease with a normal sinus rhythm (for details see [48], the international trial on the treatment of angina with ivabradine vs. atenolol (INITIATIVE) trial (n = 939) [49] and the antianginal efficacy and safety of the association of the Ih/If current inhibitor ivabradine with a beta-blocker (ASSOCIATE) study (n = 889) [50]).

The Role of HCN Channels in Ventricular Repolarization

Stefanie Fenske, Stefanie Krause, Martin Biel, and Christian Wahl-Schott
Trends Cardiovasc Med 2011; 21:216-220
PII S1050-1738(12)00143-0

Hyperpolarization-activated cyclic nucleotide gated (HCN) channels pass a cationic current (Ih/If) that crucially contributes to the slow diastolic depolarization (SDD) of sinoatrial pacemaker cells and, hence, is a key determinant of cardiac automaticity and the generation of the heartbeat. However, there is growing evidence that HCN channels are not restricted to the spontaneously active cells of the sinoatrial node and the conduction system but are also present in ventricular cardiomyocytes that produce an action potential lacking SDD. This observation raises the question of the principal function(s) of HCN channels in working myocardium. Our recent analysis of an HCN3-deficient (HCN3–/–) mouse line has shed new light on this central question.

We propose that HCN channels contribute to the ventricular action potential waveform, specifically during late repolarization. In this review, we outline this new concept.

In the late 1970s, the hyperpolarization activated current (Ih/If) was discovered and characterized in sinoatrial node cells (Brown and Difrancesco 1980). This current displays several unique biophysical properties: activation upon hyperpolarization and deactivation by depolarization, with a small but substantial degree of activation at resting potentials typically observed in sinoatrial node pacemaker cells (–60 to –50 mV) and ventricular cells (–85 to –75 mV); shift of the activation curve to more positive potentials by cAMP;  block by millimolar concentrations of external Cs+; and permeability for Na+ and K+ions with a reversal potential near –35 mV.

  • HCN3 Is a Component of Ventricular Ih
  • HCN Channels Prolong Action Potentials During Late Repolarization
  • HCN3 Forms Background Channels That Do Not Deactivate During the Action Potential
  • HCN channels need to be open at the resting membrane potential;
    (2) HCN channels remain open during the entire time course of the action potential—de novo opening of HCN channels during the AP does not occur because these channels are activated by hyperpolarization and depolarization decreases open probability; and
    (3) a driving force is needed to sustain an HCN-mediated current during the AP. A detailed analysis of the functional properties of heterologously expressed HCN3 channels revealed that these three prerequisites are met.

Neurophysiology of HCN channels: From cellular functions to multiple regulations

Chao He, Fang Chen, Bo Li, Zhian Hu
Progress in Neurobiology 112 (2014) 1–23

Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels are encoded by HCN1-4 gene family and have four subtypes. These channels are activated upon hyperpolarization of membrane potential and conduct an inward, excitatory current Ih in the nervous system. Ih acts as pacemaker current to initiate rhythmic firing, dampen dendritic excitability and regulate presynaptic neurotransmitter release. This review summarizes recent insights into the cellular functions of Ih and associated behavior such as learning and memory, sleep and arousal. HCN channels are excellent targets of various cellular signals to finely regulate neuronal responses to external stimuli. Numerous mechanisms, including transcriptional control, trafficking, as well as channel assembly and modification, underlie HCN channel regulation. In the next section, we discuss how the intracellular signals, especially recent findings concerning protein kinases and interacting proteins such as cGKII, Ca2+/CaMKII and TRIP8b, regulate function and expression of HCN channels, and subsequently provide an overview of the effects of neurotransmitters on HCN channels and their corresponding intracellular mechanisms. We also discuss the dysregulation of HCN channels in pathological conditions. Finally, insight into future directions in this exciting area of ion channel research is provided.

The hyperpolarization-activated current, Ih, was first observed in sino-atrial node tissue in 1976 and later was identified in rod photoreceptors and hippocampal pyramidal neurons (Noma and Irisawa, 1976). Due to its unique properties, particularly the activation upon hyperpolarization of the membrane potential, Ih has been also termed If (f for funny) or Iq (q for queer). The hyperpolarization-activated cyclic nucleotide-gated (HCN) cation ion channels underlying Ih were discovered in the late 1990s and subsequently, the genes encoding these channels were identified, which enable the expression of HCN channels in heterologous systems.

HCN channels belong to the superfamily of voltage-gated pore loop channels with four pore-forming subunits (HCN1-4) encoded by the HCN1-4 gene family in mammals (Robinson and Siegelbaum, 2003). Each subunit has six transmembrane helices (S1–S6), with the positively charged voltage sensor (S4) and the pore region carrying the GYG motif between S5 and S6, which forms the ion selectivity filter (Macri et al., 2012). Following S6 is the 80-residue C-linker comprising six a-helices (A0–F0) and the cyclic nucleotide binding domain (CNBD). The CNBD consists of three a-helices (A–C) and a b-roll between the A- and B-helices (Fig. 1) (Biel et al., 2009; Wahl-Schott and Biel, 2009; Wicks et al., 2011). Together, the C-linker and CBND can be referred to as the ‘‘cAMP-sensing domain’’ (CSD) because they are of functional importance for the cAMP-induced positive shift of the voltage-dependent activation of HCN channels. The crystal structure of CSD has been elucidated at an atomic resolution, but a high-resolution structure of the transmembrane core remains unsolved.

Structure of HCN channels

Structure of HCN channels

Structure of HCN channels. Left: one subunit is composed of six transmembrane segments (S1–S6), with the positive charged voltage sensor (S4) and the pore region carrying the GYG motif between S5 and S6. The C-terminal of HCN channels is composed of the C-linker and the cyclic nucleotide-binding domain (CNBD) which mediates their responses to cAMP. The C-linker consists of six a-helices: A0 to F0 . The CNBD follows the C-linker domain and consists of a-helices A–C with a b-roll between the A- and B-helices. Right: the four subunits assemble in homomeric or heteromeric tetramer configurations in vivo.

Regulatory mechanisms of Ih function by the small molecules, protein kinases and interacting proteins.

Regulatory mechanisms of Ih function by the small molecules, protein kinases and interacting proteins.

Regulatory mechanisms of Ih function by the small molecules, protein kinases and interacting proteins. Black arrows indicate known sites of HCN channels interaction with small molecules, protein kinases and interacting proteins. Broken lines indicate the speculated interaction sites. Filamin A interacts with HCN1 via a region of 22 amino acids located downstream from the CNBD. Tamalin and Mint2 bind to the CNBD-downstream sequence of HCN2. The binding of the PDZ domain of S-SCAM occurs at the cyclic nucleotide-binding domain (CNBD) and the CNBD downstream sequence of the carboxy-terminal tail. CNBD, cyclic nucleotide binding domain; SNL, C-terminal tripeptide of HCN1, HCN2 and HCN4.

modulation of HCN channels by neurotransmitters and associated intracellular signal pathways

modulation of HCN channels by neurotransmitters and associated intracellular signal pathways

The modulation of HCN channels by neurotransmitters and associated intracellular signal pathways. Glutamate (Glu) activates N-methyl-D-aspartate receptors (NMDARs) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) which results in the Ca2+ influx and subsequently activates calcium calmodulin kinase (CaMKII). CaMKII increases channels surface expression through the interacting protein TRIP8b (1a-4) or reduces the HCN1 gene transcription via Neuronal Restrictive Silencing Factor (NRSF) in pathological conditions. Glu, norepinephrine (NE, in rats), 5-hydroxytryptamine (5-HT) and triphosphate (ATP) bind to specific G-coupled receptors and modulate the activity of HCN channels via the PLC-PKC or p38-MAPK signaling pathways. Activation of PKC suppresses the activation of HCN channels, whereas p38-MAPK causes a positive shift of HCN channels voltage-dependent activation. Adenosine, NE (in monkey), 5-HT, dopamine (DA) and Ach (acetylcholine) bind to Gs- or Gi coupled receptors. Gs or Gi oppositely control the activity of adenylate cyclase (AC), which catalyzes the ATP to cAMP. cAMP could shift the HCN channels voltage-dependent activation to positive direction and accelerate the kinetics of channels activation. Nitric oxide (NO) interacts with soluble guanylyl cyclase (GC) and thus increases the intracellular concentration of cGMP, which induces a positive shift of HCN channels voltage-dependent activation. Sharp and blunted arrows represent the positive and negative regulation, respectively. Broken lines indicate the speculated signal pathway.

Ultimately, the study of the HCN channels will provide an overall picture underlying the real-time in vivo regulation of the function and expression of HCN channels to fulfill complex functions in different contexts.

Oxygen uptake kinetics during high-intensity arm and leg exercise

Katrien Koppo, Jacques Bouckaert, Andrew M. Jones
Respiratory Physiology & Neurobiology 133 (2002) 241-250
PII: S1569 – 9048 ( 02 ) 00184 – 2

The purpose of the present study was to examine the oxygen uptake kinetics during heavy arm exercise using appropriate modelling techniques, and to compare the responses to those observed during heavy leg exercise at the same relative intensity. We hypothesized that any differences in the response might be related to differences in muscle fiber composition that are known to exist between the upper and lower body musculature. To test this, ten subjects completed several bouts of constant-load cycling and arm cranking exercise at 90% of the mode specific ˙VO2 peak. There was no difference in plasma [lactate] at the end of arm and leg exercise. The time constant of the fast component response was significantly longer in arm exercise compared to leg exercise (mean ­+ S.D., 489 +12 vs. 219 + 5 sec; P < 0.01), while the fast component gain was significantly greater in arm exercise (12.19 + 1.0 vs. 9.29 + 0.5 ml min-1 W-1; P < 0.01). The ˙VO2 slow component emerged later in arm exercise (1269 + 27 vs. 959 + 20 sec; P < 0.01) and, in relative terms, increased more per unit time (5.5 vs. 4.4% min-1; P < 0.01). These differences between arm crank and leg cycle exercise are consistent with a greater and/or earlier recruitment of type II muscle fibers during arm crank exercise.

Probability and magnitude of response to cardiac resynchronization therapy according to QRS duration and gender in nonischemic cardiomyopathy and LBBB

Niraj Varma, Mahesh Manne, Dat Nguyen, …, Patrick Tchou
Heart Rhythm 2014; 11: 1139–1147

BACKGROUND QRS morphology and QRS duration (QRSd) determine cardiac resynchronization therapy (CRT) candidate selection but criteria require refinement.
OBJECTIVE To assess CRT effect according to QRSd, treated by dichotomization vs a continuous function, and modulation by gender.
METHODS Patients selected were those with New York Heart Association classIII/IV heart failure and with left bundle branch block and nonischemic cardiomyopathy (totest “pure” CRT effect) with pre-and post- implant echocardiographic evaluations. Positive response was defined as increased left ventricular ejection fraction (LVEF) post-CRT.
RESULTS In 212 patients (LVEF 19% +  7.1%; QRSd 160 + 23 ms; 105 (49.5%) women), CRT increased LVEF to 30% + 15% (P < .001) during a median follow-up of 2 years. Positive response occurred in 150 of 212 (71%) patients. Genders did not differ for QRSd, pharmacotherapy, and comorbidities, but response to CRT among women was greater: incidence 84% (88of105) in women vs 58% (62of107) in men (P < .001); increase in LVEF 15%+ 14% vs 7.2% + 13%, respectively (P < .001). Overall, the response rate was 58% when QRSd <150 ms and 76% when QRSd > 150 ms (P <.009). This probability differed between genders: 86% in women vs 36% in men (P < .001) when QRSd <150 ms and 83% vs 69%, respectively, when QRSd >150 ms (P < .05). Thus, female response rates remained high whether QRSd was < 150 ms >150 ms (86% vs 83%; P = .77) but differed in men (36% vs 69%; P < .001). With QRSd as a continuum, the CRT-response relationship was nonlinear and significantly different between genders. Female superiority at shorter QRSd inverted with prolongation > 180 ms.
CONCLUSION The QRSd-CRT response relationship in patients with heart failure and with left bundle branch block and non-ischemic cardiomyopathy is better  described by a sex-specific continuous function and not by dichotomization by 150ms, which excludes a large proportion of women with potentially favorable outcome.

Comparison of eterminants Myocardial Oxygen Consumption During Arm and Leg Exercise in Normal Persons

Gary J. Balady, et al.  Am J Cardiol 1985; 57: 1385-87.

The effects of arm exercise on myocardiai oxygen consumption are not well understood; they may differ from the effects of leg exercise. Previous studies have shown that the ischemic threshold is higher in patients performing arm exercise and leg exercise at the same heart rate-blood pressure product. The contribution of other determinants of myocardiai oxygen consumption-left ventricular (LV) peak meridional systolic wail stress and contractility-to these observed differences were studied.
Thirty healthy subjects exercised to the same peak rate-pressure product during dynamic upper- and lower-extremity exercise. Peak workload was lower
during arm exercise (100 + 16 W) leg exercise (170 + 21 W, p < 0.001). LV wail stress did not differ during either form of exercise (197 + 44 vs 204 + 33 dynes/cm2 X 103, arm vs leg, respectively). This was also true of contractility as assessed by the velocity of circumferential fiber shortening (2.6 + 0.6 vs 2.5 + 0.4 circ/s, arm vs leg, respectively) and the preejection period/LV ejection time ratio (0.33 + 0.11 vs 0.31 + 0.07, arm vs leg, respectively). Normal subjects exercising to a similar rate-pressure product showed the same levels at LV wail stress and contractility for arm and leg exercise despite the lower rkioad performed with arm exercise.

Anti-hypertensive effect of radiofrequency renal denervation in spontaneously hypertensive rats

Takeshi Machino, N Murakoshi, A Sato, …, T Hoshi, T Kimura, K Aonuma
Life Sciences 110 (2014) 86–92 http://dx.doi.org/10.1016/j.lfs.2014.06.015

Aims: We aimed to investigate the anti-hypertensive effect of radiofrequency (RF) renal denervation (RDN) in an animal model of hypertension.           Materials and methods: RF energy was delivered to bilateral renal arteries through a 2 Fr catheter with opening abdomen in 8 spontaneously hypertensive rats (SHRs) and 8 Wistar–Kyoto rats (WKYs). Sham operation was performed in other 8 SHRs and 8 WKYs. Blood pressure (BP), heart rate (HR), and urinary norepinephrine excretion were followed up for 3 months. Plasma and renal tissue concentrations of norepinephrine and plasma renin activity were measured 3 months after the procedure. The RDN was confirmed by a decrease in renal tissue norepinephrine.
Key findings: RF-RDN restrained a spontaneous rise in systolic BP (46 ± 12% increase from 158 ± 8 to 230 ± 14 mmHg vs. 21 ± 18% increase from 165 ± 9 to 197 ± 20 mmHg, p= 0.01) and diastolic BP (55 ± 27% increase from 117 ± 9 to 179 ± 23 mmHg vs. 28 ± 13% increase from 120 ± 7 to 154 ± 13 mm Hg, p= 0.04) in SHRs; however, WKYs were not affected. Although there were no changes in HR and systemic norepinephrine, the renal tissue norepinephrine was decreased by RF-RDN in both SHR (302±41 vs. 159±44 ng/g kidney, p b 0.01) and WKY (203 ± 33 vs. 145 ± 26 ng/g kidney, p= 0.01). Plasma renin activity was reduced by the RF-RDN only in SHR (35.3 ± 9.5 vs. 21.4 ±  8.6 ng/mL/h, p < 0.01).
Significance: RF-RDN demonstrated an anti-hypertensive effect with a reduction of renal tissue norepinephrine and plasma renin activity in SHR.

Effectiveness of Renal Denervation Therapy for Resistant Hypertension: A Systematic Review and Meta-Analysis

Mark I. Davis, KB Filion, D Zhang, MJ Eisenberg, …, EL Schiffrin, D Joyal
J Am Coll  Cardiol 2013; 62(3): 231-241.

Objectives This study sought to determine the current effectiveness and safety of sympathetic renal denervation (RDN) for resistant hypertension.               Background RDN is a novel approach that has been evaluated in multiple small studies.
Methods We performed a systematic review and meta-analysis of published studies evaluating the effect of RDN in patients with resistant hypertension. Studies were stratified according to controlled versus uncontrolled design and analyzed using random-effects meta-analysis models.                                    Results We identified 2 randomized controlled trials, 1 observational study with a control group, and 9 observational studies without a control group. In controlled studies, there was a reduction in mean systolic and diastolic blood pressure (BP) at 6 months of –28.9 mm Hg (95% confidence interval [CI]: –37.2 to –20.6 mm Hg) and –11.0 mm Hg (95% CI: –16.4 to –5.7 mm Hg), respectively, compared with medically treated patients (for both, p < 0.0001). In uncontrolled studies, there was a reduction in mean systolic and diastolic BP at 6 months of –25.0 mm Hg (95% CI: –29.9 to –20.1 mm Hg) and –10.0 mm Hg (95% CI: –12.5 to –7.5 mm Hg), respectively, compared with pre-RDN values (for both, p < 0.00001). There was no difference in the effect of RDN according to the 5 catheters employed. Reported procedural complications included 1 renal artery dissection and 4 femoral pseudoaneurysms.
Conclusions RDN resulted in a substantial reduction in mean BP at 6 months in patients with resistant hypertension. The decrease in BP was similar irrespective of study design and type of catheter employed. Large randomized controlled trials with long-term follow-up are needed to confirm the sustained efficacy and safety of RDN.

Effects of renal denervation on the development of post-myocardial infarction heart failure and cardiac autonomic nervous system in rats

Jialu Hu, Yan Yan, Qina Zhou, Meng Ji, Conway Niu, Yuemei Hou, Junbo Ge
Intl J Cardiol 172 (2014) e414–e416 http://dx.doi.org/10.1016/j.ijcard.2013.12.254

Prior studies indicated that radiofrequency renal denervation (RD) had beneficial effects on post-myocardial infarction (MI) heart failure (HF) in rats. In this study we aimed to assess its effects on cardiac autonomic nervous system (CANS) which might be one of the most important mechanisms of RD’s therapeutic effect on post-MI HF and determine the best timing for RD.

One hundred Wistar rats were randomly assigned into five experimental groups: MI group (n = 20), RD group (n = 20), MI-1d + RD group (RD performed one day post-MI, n = 20), MI-4w + RD group (RD performed four weeks post-MI, n = 20), and N group (control group, n = 20).MI was produced through ligation of the anterior descending artery. RD was performed through stripping of the renal nerves. The experimental design and implementation were conducted in accordance with animal welfare guidelines.

Eight weeks post-MI, significant improvements were observed in both MI-1d + RD and MI-4w + RD groups compared to the MI group, that include

(1) improved left ventricular (LV) function and hemodynamics with increased water and sodium excretion;
(2) decreased plasma and renal tissue norepinephrine levels while tissue norepinephrine content increased in myocardium;
(3) increased β1-receptor in myocardium and improved heart rate variability;  (4) decreased plasma renin, angiotensin II, aldosterone, BNP and endothelin levels.

More therapeutic effects were found in the MI-1d + RD group than the MI-4w + RD group.

Firstly, our study showed that RD attenuated the remodeling of CANS and modulated its activities. RD leads to preservation of β1 receptors content along with the β1 mRNA expression in noninfarcted cardiac tissue in this HF model (Fig. 1). This correlated with an improvement in heart function and cardiac remodeling. HRV is a sensitive marker for the CANS. RD led to a slower HR and higher SDNN in both intervention groups.

Secondly, we found that RD blocked both peripheral and central RAAS and sympathetic nervous system (SNS) at the same time. And this may answer the question how RD exerted effect on CANS. In our study RD restores renin, angiotensin II, and aldosterone to near normal levels. This not only explains the increase in sodium and water excretion, but also confirms that RD blocks renal RAAS via blockage of the efferent renal sympathetic nerves which is consistent with our previous study.

Thirdly, early RD, performed one day post-MI, resulted in greater excretion of urinary sodium, lower circulating BNP and ET-1 levels compared to late interventions (four weeks post-MI). This suggests that RD performed in the acute phase of MI may not only reverse cardiac remodeling but also has a preventive effect against the development of HF, as what was observed with β-blockers. RD alleviated cardiac preload and afterload by increasing water and sodium retention, blocking cardiac sympathetic activation and decreasing a variety of vasomotor factors which may lead to alleviated acute and chronic ischemia of the heart.

RD improves hemodynamics, decreases neuro-hormonal activations, modulates cardiac autonomic activities, and attenuates LV remodeling in HF. Early intervention appears to have greater beneficial effects on cardiac functional recovery and reverse remodeling after myocardial injury. Circulating neuro-hormones may be effective indicators to evaluate the therapeutic effect of RD on HF. Our data suggested that RD is a safe, non-pharmaceutical treatment of HF after cardiac injury, with unique benefits in stabilizing cardiac autonomic activity and remodeling post-MI.

The cardiac pacemaker current

Mirko Baruscotti, Andrea Barbuti, Annalisa Bucchi
Journal of Molecular and Cellular Cardiology 48 (2010) 55–64

In mammals cardiac rate is determined by the duration of the diastolic depolarization of sinoatrial node (SAN) cells which is mainly determined by the pacemaker If current. f-channels are encoded by four members of the hyperpolarization-activated cyclic nucleotide-gated gene (HCN1–4) family. HCN4 is the most abundant isoform in the SAN, and its relevance to pacemaking has been further supported by the discovery of four loss-of-function mutations in patients with mild or severe forms of cardiac rate disturbances. Due to its selective contribution to pacemaking, the If current is also the pharmacological target of a selective heart rate-reducing agent (ivabradine) currently used in the clinical practice. Albeit to a minor extent, the If current is also present in other spontaneously active myocytes of the cardiac conduction system (atrioventricular node and Purkinje fibres). In working atrial and ventricular myocytes f-channels are expressed at a very low level and do not play any physiological role; however in certain pathological conditions over-expression of HCN proteins may represent an arrhythmogenic mechanism. In this review some of the most recent findings on f/HCN channels contribution to pacemaking are described.

Cardiac pacemaking originates in the sinoatrial node (SAN) as a consequence of spontaneous firing of rhythmic action potentials generated by specialized myocytes. Although the electrical behavior of a typical SAN cell differs in several aspects from that of a working myocyte, the functional hallmark can be precisely identified in the events that take place during the diastolic interval. During this phase atrial and ventricular myocytes rest in a standby-like condition at a stable voltage (∼−80 mV); a quite different situation characterizes SAN cells, where the cell potential slowly creeps up from the
maximum diastolic potential of about −60 mV to the threshold for the ignition of a new action potential. Since this time interval sets the pace of the heart, this phase is named “pacemaker depolarization”. Given the large spectrum of heart rates observed in mammals the duration of this phase can vary substantially, however the voltage range encompassed is extremely constant and roughly extends from −60 to−40 mV . To sustain this phase several ionic currents and pumps enter in action at variable times and voltages, and this complexity allows for a highly flexible system since the chronotropic fine tuning operated by neuro-hormonal regulators can target different effectors.

In this review we will focus on the If current which is responsiblefor initiating the diastolic depolarization of SAN cells. Due to its fundamental role and its unusual characteristics of being activated in hyperpolarization, this current was named “pacemaker current” or “funny” (If) current. The unique property of a reverse voltage dependence, together with the inward nature of the current at diastolic potentials, makes this current apt to initiate and support the diastolic depolarization. In addition, the direct modulation of the current operated by the second messenger cAMP, represents one of the main pathways by which the autonomic nervous system controls cardiac chronotropism. Two recent clinical findings further confirm the role of f-channels in setting the cardiac rate: one is the evidence of a causative link between the presence of loss-of-function mutations found in these channels and the arrhythmic state of individuals carrying the mutations, and the other is the specific heart rate reduction observed in patients treated with ivabradine, a drug that at therapeutic doses selectively reduces the If current (see specific sections in this review).

Although originally discovered in the heart, the If current is also abundantly present in a large fraction of neuronal elements, where it contributes to rhythmic firing, synaptic integration, and dendritic integration.

Molecular and functional properties of SAN myocytes

Molecular and functional properties of SAN myocytes

Molecular and functional properties of SAN myocytes. (A) Spontaneous action potentials (left) and If current traces (right) recorded from typical rabbit SANmyocytes; currents were elicited by hyperpolarizing voltage steps in the range−45 to −75 mV. (B) Immunofluorescence analysis of rabbit SAN tissue slice labelled with anti-connexin 43 (Cx43, red) and anti-HCN4 (green) antibodies. HCN4 is strongly expressed in the central region of the SAN, while the opposite staining is observed for Cx43; crista terminalis (CT), interatrial septum (IS). (C) HCN4 labelling of single myocytes isolated from CT, SAN and IS (top), and  representative current traces recorded at−125mV frommyocytes isolated from the same regions (bottom). Both If current density and HCN4 labelling are more abundant in the central nodal area. (Panels B and C from [61] with permission).

[61] Brioschi C, Micheloni S, Tellez JO, Pisoni G, Longhi R, Moroni P, et al. Distribution of the pacemaker HCN4 channel mRNA and protein in the rabbit sinoatrial node. J Mol Cell Cardiol 2009;47:221–7.

The search of new therapeutic tools consisting of gene- and/or cell-based intervention aimed to restore compromised cardiac functions has prompted researchers to exploit the use of HCN channels to alter cellular electrical activity in order to generate, in normally quiescent substrates, stable rhythmic activity similar to that of native pacemaker myocytes. The specific features of pacemaker channels and in particular the fact that they are activated only at diastolic potentials and do not contribute to other phases of the action potentials, make them particularly suitable for such purpose. Early in vitro studies demonstrated that virus-mediated over-expression of HCN2 channels induced a significant increase in the rate of spontaneously beating neonatal ventricular myocytes by causing an If-mediated increase of the diastolic depolarization slope. This approach was later confirmed in vivo by showing that direct injection of the HCN2-adenovirus in the left atrium or into the ventricular conduction system of dogs, was able to induce ectopic regular spontaneous activity after AV block. Similarly, adenovirus-mediated over-expression of HCN1 or HCN4 was sufficient to induce a regular rhythm in quiescent cardiomyocyte. Alternative cell-based strategies, aimed to avoid the use of viruses, have been developed by engineering cells in order to express high levels of HCN channels. Engineered human mesenchymal stem cells (hMSCs) expressing either HCN2 or HCN4 have been shown in vitro to properly connect to neonatal cardiomyocytes and to increase their intrinsic spontaneous rhythm. HCN2-expressing hMSCs have also been successfully transplanted in canine left ventricular wall where they were able to induce stable ectopic beats.

Currently, ivabradine is marketed for treatment of chronic stable angina in patients with normal sinus rhythm who have a contraindication or intolerance to β-blockers; clinical studies of patients with chronic stable angina have shown that ivabradine acts as a pure heart rate-reducing agent and has anti-ischemic and anti-anginal properties equivalent to β-blockers and Ca2+ channel blockers and presents a good safety and tolerability profile even during long-term treatment. Mild visual symptoms (phosphenes) were occasionally reported, but were generally well tolerated. Additional information comes from results from a recent large clinical trial (BEAUTIFUL) which indicate that ivabradine treatment of patients with stable coronary artery disease (CAD) and heart rate ≥70 bpm can reduce the incidence of some CAD outcomes such as hospitalization for myocardial infarction and coronary revascularization.

The beat goes on: Cardiac pacemaking in extreme conditions

Christopher M.Wilson, Georgina K. Cox, Anthony P. Farrell
Comparative Biochemistry and Physiology, Part A xxx (2014) xxx–xxx

In order for an animal to survive, the heart beat must go on in all environmental conditions, or at least restart its beat. This review is about maintaining a rhythmic heartbeat under the extreme conditions of anoxia (or very severe hypoxia) and high temperatures. It starts by considering the primitive versions of the protein channels that are responsible for initiating the heartbeat, HCN channels, divulging recent findings from the ancestral craniate, the Pacific hagfish (Eptatretus stoutii). It then explores how a heartbeat can maintain a rhythm, albeit slower, for hours without any oxygen, and sometimes without autonomic innervation. It closes with a discussion of recent work on fishes, where the cardiac rhythm can become arrhythmic when a fish experiences extreme heat.

Sympathetic renal denervation: Hypertension beyond SYMPLICITY

Israel M. Barbash, Ron Waksman
Cardiovascular Revascularization Medicine 14 (2013) 229–235

Despite a wide range of drug treatment for hypertension, resistant hypertension rates remain high. The Symplicity™ Renal Denervation System (Medtronic, Santa Rosa, CA), which creates renal nerve denervation, has shown initial success in lowering blood pressure among patients with resistant  hypertension. Given the enormous market for this treatment approach, an estimated two dozen other companies are pursuing technologies with alternative approaches. Despite this fact, very little has been published on preclinical and clinical experience with these new devices. The current review summarizes the most prominent technologies in the pipeline and provides insight into the mechanism of action, preclinical, and clinical experience with these new devices

A large body of evidence has established the central role of the kidneys in hypertension, both as an affector and effector of the central sympathetic system [9]. Renal efferent sympathetic activity initiates processes towards fluid retention, such as the release of renin and increased tubular sodium reabsorption. Moreover, afferent sympathetic activity increases central sympathetic drive, which plays a major role in sustaining hypertension. In fact, historic studies of surgical sympathectomy in patients with resistant hypertension or malignant hypertension uncontrolled by pharmacotherapy were shown to be effective in reducing blood pressure, albeit with severe side effects. Thus, with the introduction of more effective medications, this procedure was abandoned. Renal sympathetic nerves run alongside the renal artery adventitia to enter the hilus of the kidney. Thereafter, they divide into smaller nerve bundles following the anatomic course of the renal blood vessels, penetrating the cortical and juxtamedullary areas inside the kidneys. Based on these anatomic features, it was postulated that creating local nerve injury along the renal arteries may achieve effective denervation.

A key issue in accomplishing effective RDN is to target the sympathetic nerve bundles lying in the adventitia of the renal arteries. Because the vast majority of devices currently under development are percutaneous, RDN is performed from within the vessel lumen. Thus, one of the most important features of such a device is the ability to minimize the damage to the renal artery wall.

Ultrasound energy consists of high-frequency sound waves emitted by a transducer within the catheter. This high energy can pass through surrounding fluids and can generate frictional heating in tissues resulting in a temperature increase that is sufficient to cause injury to the surrounding tissue, specifically the renal nerves. Based on these principles, several systems were developed and are currently being evaluated. ReCor Medical’s (Ronkonkoma, NY) PARADISE™ Percutaneous Renal Denervation System is based on delivery of high ultrasonic energy to induce nerve tissue injury. The PARADISE system is composed of two components: a 6 F-compatible balloon catheter with a cylindrical ultrasound transducer that emits ultrasound energy circumferentially (Fig. 2A)[ Ultrasound based renal denervation systems: (A) Percutaneous Renal Denervation System (PARADISE™); (B) TIVUS system]  and a portable generator which controls automated balloon inflation and deflation, and energy delivery. Energy is delivered in 3 different locations along the artery with 50 s inflation and delivery of ultrasound energy at each site. This device received CE mark in February 2012. For RDN, the PARADISE balloon catheter is positioned inside the renal artery and the generator automatically inflates the balloon, delivers the ultrasonic energy, and deflates the balloon. Endothelial thermal damage is prevented by cooled fluid in the balloon.

Radiofrequency based renal denervation systems

Radiofrequency based renal denervation systems: (A) Symplicity Renal Denervation System; (B) EnligHTN Renal Denervation System; (C) V2 bipolar balloon catheter; (D) OneShot Balloon catheter

Sample Entropy and Traditional Measures of Heart Rate Dynamics Reveal Different Modes of Cardiovascular Control During Low Intensity Exercise

Matthias Weippert, Martin Behrens, Annika Rieger and Kristin Behrens
Entropy 2014, 16, 5698-5711; http://dx.doi.org:/10.3390/e16115698

Biological time series like the normal heartbeat-to-heartbeat fluctuation demonstrate complex dynamics. Based on their potential to give additional information beyond traditional heart rate variability (HRV) indices, nonlinear parameters have been applied for investigating short and long term effects of exercise on heart rate (HR) control. However, despite their diagnosticity and their clinical significance, the physiological background of their behavior is not very well established. It is assumed that complexity and regularity measures are fundamentally different from traditional HRV indices and show no correlation to these measures. However, many researchers found at least modest correlations for some nonlinear measures and traditional HRV indices under different conditions. It has also been shown that complexity of short-term HRV is under control of the autonomic nervous system. Currently, there are only few studies available that compared the cardiovascular response pattern to different exercise modes at similar HR. Lindquist et al. found a stronger increase of systolic (SBP) and diastolic arterial blood pressure (DBP) during isometric handgrip compared to cycling at comparable HR of 90 bpm.

Nonlinear parameters of heart rate variability (HRV) have proven their prognostic value in clinical settings, but their physiological background is not very well established. We assessed the effects of low intensity isometric (ISO) and dynamic (DYN) exercise of the lower limbs on heart rate matched intensity on traditional and entropy measures of HRV. Due to changes of afferent feedback under DYN and ISO a distinct autonomic response, mirrored by HRV measures, was hypothesized. Five-minute inter-beat interval measurements of 43 healthy males (26.0 ± 3.1 years) were performed during rest, DYN and ISO in a randomized order. Blood pressures and rate pressure product were higher during ISO vs. DYN (p < 0.001). HRV indicators SDNN as well as low and high frequency power were significantly higher during ISO (p < 0.001 for all measures). Compared to DYN, sample entropy (SampEn) was lower during ISO (p < 0.001). Concluding, contraction mode itself is a significant modulator of the autonomic cardiovascular response to exercise. Compared to DYN, ISO evokes a stronger blood pressure response and an enhanced interplay between both autonomic branches. Non-linear HRV measures indicate a more regular behavior under ISO. Results support the view of the reciprocal antagonism being only one of many modes of autonomic heart rate control. Under different conditions; the identical “end product” heart rate might be achieved by other modes such as sympathovagal co-activation as well.

ANOVA revealed a significant effect of experimental condition on all cardiovascular measures and autonomic indices. Average HR raised moderately from 65 ± 9 bpm at baseline to 85 ± 9 bpm during both types of exercise. HR during the first exercise perfectly matched HR of the subsequent exercise; average difference was only 0.3 ± 1.5 bpm (range: −2.6 to 4.3 bpm). Accordingly, HR and average R-R interval did not differ between DYN and ISO. The traditional vagal modulation HRV measure RMSSD was also not affected by the exercise mode, whereas SDNN was. Natural log-transformed HRV spectral indices HFP and LFP, the normalized powers LF n. u. and HF n. u. as well SampEn (Figure 1) were significantly different between DYN and ISO. Interestingly, SampEn did not differ between REST and DYN. There was no difference of the LF/HF ratio between REST and ISO, whereas comparison of REST vs. DYN showed a statistical trend (p = 0.077). Further, there was a small effect of condition on the HF peak frequency (F(2; 84) = 4.959, p < 0.01, η² = 0.106). While HF peak significantly shifted from 0.22 ± 0.07 Hz during REST to 0.26 ± 0.09 Hz during DYN (p < 0.05), no difference was found between REST and ISO (0.23 ± 0. 07 Hz). Post-hoc pair wise comparison between DYN and ISO showed a statistical trend for the HF peak shift (p = 0.063). SBP and RPP were moderately, DBP and MAP largely affected by the type of exercise. In comparison to DYN, myocardial oxygen consumption, reflected by RPP, was about 5% higher under ISO. Correlation analysis revealed only modest associations between traditional HRV indices and entropy measures during the different experimental conditions. Consistent correlation coefficients across all conditions were found for SampEn and R-R length only.

Mean ± SD of sample entropy during REST, ISO, and DYN; N = 43.

Mean ± SD of sample entropy during REST, ISO, and DYN; N = 43.
*** = significantly different from rest on a p-level < 0.001;
§§§ = significantly different from the respective exercise condition on a p-level < 0.001.

Role of neurotensin and opioid receptors in the cardiorespiratory effects of [Ile9]PK20, a novel antinociceptive chimeric peptide

Katarzyna Kaczynska, M Szereda-Przestaszewska, P Kleczkowska, AW Lipkowski European Journal of Pharmaceutical Sciences 63 (2014) 8–13 http://dx.doi.org/10.1016/j.ejps.2014.06.018

Ile9PK20 is a novel hybrid of opioid–neurotensin peptides synthesized from the C-terminal hexapeptide of neurotensin and endomorphin-2 pharmacophore. This chimeric compound shows potent central and peripheral antinociceptive activity in experimental animals, however nothing is known about its influence on the respiratory and cardiovascular parameters.

The present study was designed to determine the cardiorespiratory effects exerted by an intravenous injection (i.v.) of [Ile9]PK20. Share of the vagal afferentation and the contribution of NTS1 neurotensin and opioid receptors were tested.

Intravenous injection of the hybrid at a dose of 100 lg/kg in the intact, anaesthetized rats provoked an increase in tidal volume preceded by a prompt short-lived decrease. Immediately after the end of injection brief acceleration of the respiratory rhythm appeared, and was ensued by the slowing down of breathing. Changes in respiration were concomitant with a bi-phasic response of the blood pressure: an immediate increase was followed by a sustained hypotension. Midcervical vagotomy eliminated the increase in tidal volume and respiratory rate responses. Antagonist of opioid receptors – naloxone hydrochloride eliminated only [Ile9]PK20-evoked decline in tidal volume response. Blockade of NTS1 receptors with an intravenous dose of SR 142,948, lessened the remaining cardiorespiratory effects. This study depicts that [Ile9]PK20 acting through neurotensin NTS1 receptors augments the tidal component of the breathing pattern and activates respiratory timing response through the vagal pathway. Blood pressure effects occur outside vagal afferentation and might result from activation of the central and peripheral vascular NTS1 receptors. In summary the respiratory effects of the hybrid appeared not to be profound, but they were accompanied with unfavorable prolonged hypotension.

Integrative regulation of human brain blood flow

Christopher K.Willie, Yu-Chieh Tzeng, Joseph A. Fisher and Philip N. Ainslie
J Physiol 2014; 592(5): pp 841–859

Herein, we review mechanisms regulating cerebral blood flow (CBF), with specific focus on humans. We revisit important concepts from the older literature and describe the interaction of various mechanisms of cerebrovascular control. We amalgamate this broad scope of information into a brief review, rather than detailing any one mechanism or area of research. The relationship between regulatory mechanisms is emphasized, but the following three broad categories of control are explicated:

  • the effect of blood gases and neuronal metabolism on CBF;
  • buffering of CBF with changes in blood pressure, termed cerebral autoregulation; and
  • the role of the autonomic nervous system in CBF regulation.

With respect to these control mechanisms, we provide evidence against several canonized paradigms of CBF control. Specifically, we corroborate the following four key theses:

(1) that cerebral autoregulation does not maintain constant perfusion through a mean arterial pressure range of 60–150 mmHg;
(2) that there is important stimulatory synergism and regulatory interdependence of arterial blood gases and blood pressure on CBF regulation;

(3) that cerebral autoregulation and cerebrovascular sensitivity to changes in arterial blood gases are not modulated solely at the pial arterioles; and
(4) that neurogenic control of the cerebral vasculature is an important player in autoregulatory function and, crucially, acts to buffer surges in perfusion pressure.
Finally, we summarize the state of our knowledge with respect to these areas, outline important gaps in the literature and suggest avenues for future research.

Integrative physiological and computational approaches to understand autonomic control of cerebral autoregulation

Can Ozan Tan and J. Andrew Taylor
Exp Physiol 99.1 (2014) pp 3–15 http://dx.doi.org:/10.1113/expphysiol.2013.072355

New Findings

  1. What is the topic of this review?

This review focuses on the autonomic control of the cerebral vasculature in health and disease from an integrative physiological and computational perspective.

  1. What advances does it highlight?

This review highlights recent studies exploring autonomic effectors of cerebral autoregulation as well as recent advances in experimental and analytical approaches to understand cerebral autoregulation.

The brain requires steady delivery of oxygen and glucose, without which neurodegeneration occurs within minutes. Thus, the ability of the cerebral vasculature to maintain relatively steady blood flow in the face of changing systemic pressure, i.e. cerebral autoregulation, is critical to neurophysiological health. Although the study of autoregulation dates to the early 20th century, only the recent availability of cerebral blood flow measures with high temporal resolution has allowed rapid, beat-by-beat measurements to explore the characteristics and mechanisms of autoregulation. These explorations have been further enhanced by the ability to apply sophisticated computational approaches that exploit the large amounts of data that can be acquired. These advances have led to unique insights. For example, recent studies have revealed characteristic time scales wherein cerebral autoregulation is most active, as well as specific regions wherein autonomic mechanisms are prepotent. However, given that effective cerebral autoregulation against pressure fluctuations results in relatively unchanging flow despite changing pressure, estimating the pressure–flow relationship can be limited by the error inherent in computational models of autoregulatory function. This review focuses on the autonomic neural control of the cerebral vasculature in health and disease from an integrative physiological perspective. It also provides a critical overview of the current analytical approaches to understand cerebral autoregulation.

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Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

Author: Larry H. Bernstein, MD, FCAP


Curator: Aviva Lev-Ari, PhD, RN

This is the second of a two part discussion of viscosity, hemostasis, and vascular risk

This is Part II of a series on blood flow and shear stress effects on hemostasis and vascular disease.

See Part I on viscosity, triglycerides and LDL, and thrombotic risk.


Hemostatic Factors in Thrombophilia

Objectives.—To review the state of the art relating to elevated hemostatic factor levels as a potential risk factor for thrombosis, as reflected by the medical literature and the consensus opinion of recognized experts in the field, and to make recommendations for the use of specific measurements of hemostatic factor levels in the assessment of thrombotic risk in individual patients.

Data Sources.—Review of the medical literature, primarily from the last 10 years.

Data Extraction and Synthesis.—After an initial assessment of the literature, key points were identified. Experts were assigned to do an in-depth review of the literature and to prepare a summary of their findings and recommendations.

A draft manuscript was prepared and circulated to every participant in the College of American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia prior to the conference. Each of the key points and associated recommendations was then presented for discussion at the conference. Recommendations were accepted if a consensus of the 27 experts attending the conference was reached. The results of the discussion were used to revise the manuscript into its final form.

Consensus was reached on 8 recommendations concerning the use of hemostatic factor levels in the assessment of thrombotic risk in individual patients.

The underlying premise for measuring elevated coagulation factor levels is that if the average level of the factor is increased in the patient long-term, then the patient may be at increased risk of thrombosis long-term. Both risk of thrombosis and certain factors increase with age (eg, fibrinogen, factor VII, factor VIII, factor IX, and von Willebrand factor). Are these effects linked or do we need age specific ranges? Do acquired effects like other diseases or medications affect factor levels, and do the same risk thresholds apply in these instances? How do we assure that the level we are measuring is a true indication of the patient’s average baseline level and not a transient change? Fibrinogen, factor VIII, and von Willebrand factor are all strong acute-phase reactants.

Risk of bleeding associated with coagulation factor levels increases with roughly log decreases in factor levels. Compared to normal (100%), 60% to 90% decreases in a coagulation factor may be associated with excess bleeding with major trauma, 95% to 98% decreases with minor trauma, and .99% decrease with spontaneous hemorrhage. In contrast, the difference between low risk and high risk for thrombosis may be separated by as little as 15% above normal.

It may be possible to define relative cutoffs for specific factors, for example, 50% above the mean level determined locally in healthy subjects for a certain factor. Before coagulation factor levels can be routinely used to assess individual risk, work must be done to better standardize and calibrate the assays used.

Detailed discussion of the rationale for each of these recommendations is presented in the article. This is an evolving area of research. While routine use of factor level measurements is not recommended, improvements in assay methodology and further clinical studies may change these recommendations in the future.

Chandler WL, Rodgers GM, Sprouse JT, Thompson AR.  Elevated Hemostatic Factor Levels as Potential Risk Factors for Thrombosis.  Arch Pathol Lab Med. 2002;126:1405–1414

Model System for Hemostatic Behavior

This study explores the behavior of a model system in response to perturbations in

  • tissue factor
  • thrombomodulin surface densities
  • tissue factor site dimensions
  • wall shear rate.

The classic time course is characterized by

  • initiation and
  • amplification of thrombin generation
  • the existence of threshold-like responses

This author defines a new parameter, the „effective prothrombotic zone‟,  and its dependence on model parameters. It was found that prothrombotic effects may extend significantly beyond the dimensions of the spatially discrete site of tissue factor expression in both axial and radial directions. Furthermore, he takes advantage of the finite element modeling approach to explore the behavior of systems containing multiple spatially distinct sites of TF expression in a physiologic model. The computational model is applied to assess individualized thrombotic risk from clinical data of plasma coagulation factor levels. He proposes a systems-based parameter with deep venous thrombosis using computational methods in combination with biochemical panels to predict hypercoagulability for high risk populations.


The Vascular Surface

The ‘resting’ endothelium synthesizes and presents a number of antithrombogenic molecules including

  • heparan sulfate proteoglycans
  • ecto-adenosine diphosphatase
  • prostacyclin
  • nitric oxide
  • thrombomodulin.

In response to various stimuli

  • inflammatory mediators
  • hypoxia
  • oxidative stress
  • fluid shear stress

the cell surface becomes ‘activated’ and serves to organize membrane-associated enzyme complexes of coagulation.

Fluid Phase Models of Coagulation

Leipold et al. developed a model of the tissue factor pathway as a design aid for the development of exogenous serine protease inhibitors. In contrast, Guo et al. focused on the reactions of the contact, or intrinsic pathway, to study parameters relevant to material-induced thrombosis, including procoagulant surface area.

Alternative approaches to modeling the coagulation cascade have been pursued including the use of stochastic activity networks to represent the intrinsic, extrinsic, and common pathways through fibrin formation and a kinetic Monte Carlo simulation of TF-initiated thrombin generation. Generally, fluid phase models of the kinetics of coagulation are both computationally and experimentally less complex. As such, the computational models are able to incorporate a large number of species and their reactions, and empirical data is often available for regression analysis and model validation. The range of complexity and motivations for these models is wide, and the models have been used to describe various phenomena including the ‘all-or-none’ threshold behavior of thrombin generation. However, the role of blood flow in coagulation is well recognized in promoting the delivery of substrates to the vessel wall and in regulating the thrombin response by removing activated clotting factors.

Flow Based Models of Coagulation

In 1990, Basmadjian presented a mathematical analysis of the effect of flow and mass transport on a single reactive event at the vessel wall and consequently laid the foundation for the first flow-based models of coagulation. It was proposed that for vessels greater than 0.1 mm in diameter, reactive events at the vessel wall could be adequately described by the assumption of a concentration boundary layer very close to the reactive surface, within which the majority of concentration changes took place. The height of the boundary layer and the mass transfer coefficient that described transport to and from the vessel wall were shown to stabilize on a time scale much shorter than the time scale over which concentration changes were empirically observed. Thus, the vascular space could be divided into two compartments, a boundary volume and a bulk volume, and furthermore, changes within the bulk phase could be considered negligible, thereby reducing the previously intractable problem to a pseudo-one compartment model described by a system of ordinary differential equations.

Basmadjian et al. subsequently published a limited model of six reactions, including two positive feedback reactions and two inhibitory reactions, of the common pathway of coagulation triggered by exogenous factor IXa under flow. As a consequence of the definition of the mass transfer coefficient, the kinetic parameters were dependent on the boundary layer height. Furthermore, the model did not explicitly account for intrinsic tenase or prothrombinase formation, but rather derived a rate expression for reaction in the presence of a cofactor. The major finding of the study was the predicted effect of increased mass transport to enhance thrombin generation by decreasing the induction time up to a critical mass transfer rate, beyond which transport significantly decreased peak thrombin levels thereby reducing overall thrombin production.

Kuharsky and Fogelson formulated a more comprehensive, pseudo-one compartment model of tissue factor-initiated coagulation under flow, which included the description of 59 distinct fluid- and surface-bound species. In contrast to the Baldwin-Basmadjian model, which defined a mass transfer coefficient as a rate of transport to the vessel surface, the Kuharsky-Fogelson model defined the mass transfer coefficient as a rate of transport into the boundary volume, thus eliminating the dependence of kinetic parameters on transport parameters. The computational study focused on the threshold response of thrombin generation to the availability of membrane binding sites. Additionally, the model suggested that adhered platelets may play a role in blocking the activity of the TF/ VIIa complex. Fogelson and Tania later expanded the model to include the protein C and TFPI pathways.

Modeling surface-associated reactions under flow uses finite element method (FEM), which is a technique for solving partial differential equations by dividing the vascular space into a finite number of discrete elements. Hall et al. used FEM to simulate factor X activation over a surface presenting TF in a parallel plate flow reactor. The steady state model was defined by the convection-diffusion equation and Michaelis-Menten reaction kinetics at the surface. The computational results were compared to experimental data for the generation of factor Xa by cultured rat vascular smooth muscle cells expressing TF.

Based on discrepancies between numerical and experimental studies, the catalytic activity of the TF/ VIIa complex may be shear-dependent. Towards the overall objective of developing an antithrombogenic biomaterial, Tummala and Hall studied the kinetics of factor Xa inhibition by surface-immobilized recombinant TFPI under unsteady flow conditions. Similarly, Byun et al. investigated the association and dissociation kinetics of ATIII inactivation of thrombin accelerated by surface-immobilized heparin under steady flow conditions. To date, finite element models that detail surface-bound reactions under flow have been restricted to no more than a single reaction catalyzed by a single surface-immobilized species.


Models of Coagulation Incorporating Spatial Parameter

Major findings include the roles of these specific coagulation pathways in the

  • initiation
  • amplification
  • termination phases of coagulation.

Coagulation near the activating surface was determined by TF/VIIa catalyzed factor Xa production, which was rapidly inhibited close to the wall. In contrast, factor IXa diffused farther from the surface, and thus factor Xa generation and clot formation away from the reactive wall was dependent on intrinsic tenase (IXa/ VIIIa) activity. Additionally, the concentration wave of thrombin propagated away from the activation zone at a rate which was dependent on the efficiency of inhibitory mechanisms.

Experimental and ‘virtual’ addition of plasma-phase thrombomodulin resulted in dose-dependent termination of thrombin generation and provided evidence of spatial localization of clot formation by TM with final clot lengths of 0.2-2 mm under diffusive conditions.

These studies provide an interesting analysis of the roles of specific factors in relation to space due to diffusive effects, but neglect the essential role of blood flow in the transport analysis. Additionally, the spatial dynamics of clot localization by thrombomodulin would likely be affected by restricting the inhibitor to its physiologic site on the vessel surface.

Finite Element Modeling

Finite element method (FEM) is a numerical technique for solving partial differential equations. Originally proposed in the 1940s to approach structural analysis problems in civil engineering, FEM now finds application in a wide variety of disciplines. The computational method relies on mesh discretization of a continuous domain which subdivides the space into a finite number of ‘elements’. The physics of each element are defined by its own set of physical properties and boundary conditions, and the simultaneous solution of the equations describing the individual elements approximate the behavior of the overall domain.

Sumanas W. Jordan, PhD Thesis. A Mathematical Model of Tissue Factor-Induced Blood Coagulation: Discrete Sites of Initiation and Regulation under Conditions of Flow.

Doctor of Philosophy in Biomedical Engineering. Emory University, Georgia Institute of Technology. May 2010.  Under supervision of: Dr. Elliot L. Chaikof, Departments of Surgery and Biomedical Engineering.

Blood Coagulation (Thrombin) and Protein C Pat...

Blood Coagulation (Thrombin) and Protein C Pathways (Blood_Coagulation_and_Protein_C_Pathways.jpg) (Photo credit: Wikipedia)

Coagulation cascade

Coagulation cascade (Photo credit: Wikipedia)


Cardiovascular Physiology: Modeling, Estimation and Signal Processing

With cardiovascular diseases being among the main causes of death in the world, quantitative modeling, assessment and monitoring of cardiovascular dynamics, and functioning play a critical role in bringing important breakthroughs to cardiovascular care. Quantification of cardiovascular physiology and its control mechanisms from physiological recordings, by use of mathematical models and algorithms, has been proved to be of important value in understanding the causes of cardiovascular diseases and assisting the diagnostic and prognostic process. This E-Book is derived from the Frontiers in Computational Physiology and Medicine Research Topic entitled “Engineering Approaches to Study Cardiovascular Physiology: Modeling, Estimation and Signal Processing.”

There are two review articles. The first review article by Chen et al. (2012) presents a unified point process probabilistic framework to assess heart beat dynamics and autonomic cardiovascular control. Using clinical recordings of healthy subjects during Propofol anesthesia, the authors demonstrate the effectiveness of their approach by applying the proposed paradigm to estimate

  • instantaneous heart rate (HR),
  • heart rate variability (HRV),
  • respiratory sinus arrhythmia (RSA)
  • baroreflex sensitivity (BRS).

The second review article, contributed by Zhang et al. (2011), provides a comprehensive overview of tube-load model parameter estimation for monitoring arterial hemodynamics.

The remaining eight original research articles can be mainly classified into two categories. The two articles from the first category emphasize modeling and estimation methods. In particular, the paper “Modeling the autonomic and metabolic effects of obstructive sleep apnea: a simulation study” by Cheng and Khoo (2012), combines computational modeling and simulations to study the autonomic and metabolic effects of obstructive sleep apnea (OSA).

The second paper, “Estimation of cardiac output and peripheral resistance using square-wave-approximated aortic flow signal” by Fazeli and Hahn (2012), presents a model-based approach to estimate cardiac output (CO) and total peripheral resistance (TPR), and validates the proposed approach via in vivo experimental data from animal subjects.

The six articles in the second category focus on application of signal processing techniques and statistical tools to analyze cardiovascular or physiological signals in practical applications. the paper “Modulation of the sympatho-vagal balance during sleep: frequency domain study of heart rate variability and respiration” by Cabiddu et al. (2012), uses spectral and cross-spectral analysis of heartbeat and respiration signals to assess autonomic cardiac regulation and cardiopulmonary coupling variations during different sleep stages in healthy subjects.

The paper “increased non-gaussianity of heart rate variability predicts cardiac mortality after an acute myocardial infarction” by Hayano et al. (2011) uses a new non-gaussian index to assess the HRV of cardiac mortality using 670 post-acute myocardial infarction (AMI) patients. the paper “non-gaussianity of low frequency heart rate variability and sympathetic activation: lack of increases in multiple system atrophy and parkinson disease” by Kiyono et al. (2012), applies a non-gaussian index to assess HRV in patients with multiple system atrophy (MSA) and parkinson diseases and reports the relation between the non-gaussian intermittency of the heartbeat and increased sympathetic activity. The paper “Information domain approach to the investigation of cardio-vascular, cardio-pulmonary, and vasculo-pulmonary causal couplings” by Faes et al. (2011), proposes an information domain approach to evaluate nonlinear causality among heartbeat, arterial pressure, and respiration measures during tilt testing and paced breathing protocols. The paper “integrated central-autonomic multifractal complexity in the heart rate variability of healthy humans” by Lin and Sharif (2012), uses a relative multifractal complexity measure to assess HRV in healthy humans and discusses the related implications in central autonomic interactions. Lastly, the paper “Time scales of autonomic information flow in near-term fetal sheep” by Frasch et al. (2012), analyzes the autonomic information flow (AIF) with kullback–leibler entropy in fetal sheep as a function of vagal and sympathetic modulation of fetal HRV during atropine and propranolol blockade.

In summary, this Research Topic attempts to give a general panorama of the possible state-of-the-art modeling methodologies, practical tools in signal processing and estimation, as well as several important clinical applications, which can altogether help deepen our understanding about heart physiology and pathology and further lead to new scientific findings. We hope that the readership of Frontiers will appreciate this collected volume and enjoy reading the presented contributions. Finally, we are grateful to all contributed authors, reviewers, and editorial staffs who had all put tremendous effort to make this E-Book a reality.

Cabiddu, R., Cerutti, S., Viardot, G., Werner, S., and Bianchi, A. M. (2012). Modulation of the sympatho-vagal balance during sleep: frequency domain study of heart rate variability and respiration. Front. Physio. 3:45. doi: 10.3389/fphys.2012.00045

Chen, Z., Purdon, P. L., Brown, E. N., and Barbieri, R. (2012). A unified point process probabilistic framework to assess heartbeat dynamics and autonomic cardiovascular control. Front. Physio. 3:4. doi: 10.3389/fphys.2012.00004

Cheng, L., and Khoo, M. C. K. (2012). Modeling the autonomic and metabolic effects of obstructive sleep apnea: a simulation study. Front. Physio. 2:111. doi: 10.3389/fphys.2011.00111

Faes, L., Nollo, G., and Porta, A. (2011). Information domain approach to the investigation of cardio-vascular, cardio-pulmonary, and vasculo-pulmonary causal couplings. Front. Physio. 2:80. doi: 10.3389/fphys.2011.00080

Fazeli, N., and Hahn, J.-O. (2012). Estimation of cardiac output and peripheral resistance using square-wave-approximated aortic flow signal. Front. Physio. 3:298. doi: 10.3389/fphys.2012.00298

Frasch, M. G., Frank, B., Last, M., and Müller, T. (2012). Time scales of autonomic information flow in near-term fetal sheep. Front. Physio. 3:378. doi: 10.3389/fphys.2012.00378

Hayano, J., Kiyono, K., Struzik, Z. R., Yamamoto, Y., Watanabe, E., Stein, P. K., et al. (2011). Increased non-gaussianity of heart rate variability predicts cardiac mortality after an acute myocardial infarction. Front. Physio. 2:65. doi: 10.3389/fphys.2011.00065

Kiyono, K., Hayano, J., Kwak, S., Watanabe, E., and Yamamoto, Y. (2012). Non-Gaussianity of low frequency heart rate variability and sympathetic activation: lack of increases in multiple system atrophy and Parkinson disease. Front. Physio. 3:34. doi: 10.3389/fphys.2012.00034

Lin, D. C., and Sharif, A. (2012). Integrated central-autonomic multifractal complexity in the heart rate variability of healthy humans. Front. Physio. 2:123. doi: 10.3389/fphys.2011.00123

Zhang, G., Hahn, J., and Mukkamala, R. (2011). Tube-load model parameter estimation for monitoring arterial hemodynamics. Front. Physio. 2:72. doi: 10.3389/fphys.2011.00072

Citation: Chen Z and Barbieri R (2012) Editorial: engineering approaches to study cardiovascular physiology: modeling, estimation, and signal processing. Front. Physio. 3:425. doi: 10.3389/fphys.2012.00425

fluctuations of cerebral blood flow and metabolic demand following hypoxia in neonatal brain

Most of the research investigating the pathogenesis of perinatal brain injury following hypoxia-ischemia has focused on excitotoxicity, oxidative stress and an inflammatory response, with the response of the developing cerebrovasculature receiving less attention. This is surprising as the presentation of devastating and permanent injury such as germinal matrix-intraventricular haemorrhage (GM-IVH) and perinatal stroke are of vascular origin, and the origin of periventricular leukomalacia (PVL) may also arise from poor perfusion of the white matter. This highlights that cerebrovasculature injury following hypoxia could primarily be responsible for the injury seen in the brain of many infants diagnosed with hypoxic-ischemic encephalopathy (HIE).

The highly dynamic nature of the cerebral blood vessels in the fetus, and the fluctuations of cerebral blood flow and metabolic demand that occur following hypoxia suggest that the response of blood vessels could explain both regional protection and vulnerability in the developing brain.

This review discusses the current concepts on the pathogenesis of perinatal brain injury, the development of the fetal cerebrovasculature and the blood brain barrier (BBB), and key mediators involved with the response of cerebral blood vessels to hypoxia.

Baburamani AA, Ek CJ, Walker DW and Castillo-Melendez M. Vulnerability of the developing brain to hypoxic-ischemic damage: contribution of the cerebral vasculature to injury and repair? Front. Physio. 2012;  3:424. doi: 10.3389/fphys.2012.00424

remodeling of coronary and cerebral arteries and arterioles 

Effects of hypertension on arteries and arterioles often manifest first as a thickened wall, with associated changes in passive material properties (e.g., stiffness) or function (e.g., cellular phenotype, synthesis and removal rates, and vasomotor responsiveness). Less is known, however, regarding the relative evolution of such changes in vessels from different vascular beds.

We used an aortic coarctation model of hypertension in the mini-pig to elucidate spatiotemporal changes in geometry and wall composition (including layer-specific thicknesses as well as presence of collagen, elastin, smooth muscle, endothelial, macrophage, and hematopoietic cells) in three different arterial beds, specifically aortic, cerebral, and coronary, and vasodilator function in two different arteriolar beds, the cerebral and coronary.

Marked geometric and structural changes occurred in the thoracic aorta and left anterior descending coronary artery within 2 weeks of the establishment of hypertension and continued to increase over the 8-week study period. In contrast, no significant changes were observed in the middle cerebral arteries from the same animals. Consistent with these differential findings at the arterial level, we also found a diminished nitric oxide-mediated dilation to adenosine at 8 weeks of hypertension in coronary arterioles, but not cerebral arterioles.

These findings, coupled with the observation that temporal changes in wall constituents and the presence of macrophages differed significantly between the thoracic aorta and coronary arteries, confirm a strong differential progressive remodeling within different vascular beds.

These results suggest a spatiotemporal progression of vascular remodeling, beginning first in large elastic arteries and delayed in distal vessels.

Hayenga HN, Hu J-J, Meyer CA, Wilson E, Hein TW, Kuo L and Humphrey JD  Differential progressive remodeling of coronary and cerebral arteries and arterioles in an aortic coarctation model of hypertension. Front. Physio. 2012; 3:420. doi: 10.3389/fphys.2012.00420

C-reactive protein oxidant-mediated release of pro-thrombotic  factor

Inflammation and the generation of reactive oxygen species (ROS) have been implicated in the initiation and progression of atherosclerosis. Although C-reactive protein (CRP) has traditionally been considered to be a biomarker of inflammation, recent in vitro and in vivo studies have provided evidence that CRP, itself, exerts pro-thrombotic effects on vascular cells and may thus play a critical role in the development of atherothrombosis. Of particular importance is that CRP interacts with Fcγ receptors on cells of the vascular wall giving rise to the release of pro-thrombotic factors. The present review focuses on distinct sources of CRP-mediated ROS generation as well as the pivotal role of ROS in CRP-induced tissue factor expression. These studies provide considerable insight into the role of the oxidative mechanisms in CRP-mediated stimulation of pro-thrombotic factors and activation of platelets. Collectively, the available data provide strong support for ROS playing an important intermediary role in the relationship between CRP and atherothrombosis.

Zhang Z, Yang Y, Hill MA and Wu J.  Does C-reactive protein contribute to atherothrombosis via oxidant-mediated release of pro-thrombotic factors and activation of platelets? Front. Physio.  2012; 3:433. doi: 10.3389/fphys.2012.00433

CRP association with Peripheral Vascular Disease

To determine whether the increase in plasma levels of C-Reactive Protein (CRP), a non-specifi c reactant in the acute-phase of systemic infl ammation, is associated with clinical severity of peripheral arterial disease (PAD).

This is a cross-sectional study at a referral hospital center of institutional practice in Madrid, Spain.  These investigators took a stratifi ed random sampling of 3370 patients with symptomatic PAD from the outpatient vascular laboratory database in 2007 in the order of their clinical severity:

  • the fi rst group of patients with mild chronological clinical severity who did not require surgical revascularization,
  • the second group consisted of patients with moderate clinical severity who had only undergone only one surgical revascularization procedure and
  • the third group consisted of patients who were severely affected and had undergone two or more surgical revascularization procedures of the lower extremities in different areas or needed late re-interventions.

The Neyman affi xation was used to calculate the sample size with a fi xed relative error of 0.1.

A homogeneity analysis between groups and a unifactorial analysis of comparison of medians for CRP was done.

The groups were homogeneous for

  • age
  • smoking status
  • Arterial Hypertension
  • diabetes mellitus
  • dyslipemia
  • homocysteinemia and
  • specifi c markers of infl ammation.

In the unifactorial analysis of multiple comparisons of medians according to Scheffé, it was observed that

the median values of CRP plasma levels were increased in association with higher clinical severity of PAD

  • 3.81 mg/L [2.14–5.48] vs.
  • 8.33 [4.38–9.19] vs.
  • 12.83 [9.5–14.16]; p  0.05

as a unique factor of tested ones.

Plasma levels of CRP are associated with not only the presence of atherosclerosis but also with its chronological clinical severity.

De Haro J, Acin F, Medina FJ, Lopez-Quintana A, and  March JR.  Relationship Between the Plasma Concentration of C-Reactive Protein and Severity of Peripheral Arterial Disease.
Clinical Medicine: Cardiology 2009;3: 1–7

Hemostasis induced by hyperhomocysteinemia

Elevated concentration of homocysteine (Hcy) in human tissues, defined as hyperhomocysteinemia has been correlated with some diseases, such as

  • cardiovascular
  • neurodegenerative
  • kidney disorders

L-Homocysteine (Hcy) is an endogenous amino acid, containing a free thiol group, which in healthy cells is involved in methionine and cysteine synthesis/resynthesis. Indirectly, Hcy participates in methyl, folate, and cellular thiol metabolism. Approximately 80% of total plasma Hcy is protein-bound, and only a small amount exists as a free reduced Hcy (about 0.1 μM). The majority of the unbound fraction of Hcy is oxidized, and forms dimers (homocystine) or mixed disulphides consisting of cysteine and Hcy.

Two main pathways of Hcy biotoxicity are discussed:

  1. Hcy-dependent oxidative stress – generated during oxidation of the free thiol group of Hcy. Hcy binds via a disulphide bridge with

—     plasma proteins

—     or with other low-molecular plasma  thiols

—     or with a second Hcy molecule.

Accumulation of oxidized biomolecules alters the biological functions of many cellular pathways.

  1. Hcy-induced protein structure modifications, named homocysteinylation.

Two main types of homocysteinylation exist: S-homocysteinylation and N-homocysteinylation; both considered as posttranslational protein modifications.

a)      S-homocysteinylation occurs when Hcy reacts, by its free thiol group, with another free thiol derived from a cysteine residue in a protein molecule.

These changes can alter the thiol-dependent redox status of proteins.

b)      N-homocysteinylation takes place after acylation of the free ε-amino lysine groups of proteins by the most reactive form of Hcy — its cyclic thioester (Hcy thiolactone — HTL), representing up to 0.29% of total plasma Hcy.

Homocysteine occurs in human blood plasma in several forms, including the most reactive one, the homocysteine thiolactone (HTL) — a cyclic thioester, which represents up to 0.29% of total plasma Hcy. In human blood, N-homocysteinylated (N-Hcy-protein) and S-homocysteinylated proteins (S-Hcy-protein) such as NHcy-hemoglobin, N-(Hcy-S-S-Cys)-albumin, and S-Hcyalbumin are known. Other pathways of Hcy biotoxicity might be apoptosis and excitotoxicity mediated through glutamate receptors. The relationship between homocysteine and risk appears to hold for total plasma concentrations of homocysteine between 10 and 30 μM.

Different forms of homocysteine present in human blood.

*Total level of homocysteine — the term “total homocysteine” describes the pool of homocysteine released by reduction of all disulphide bonds in the sample (Perla-Kajan et al., 2007; Zimny, 2008; Manolescu et al., 2010, modified).

The form of Hcy The concentration in human blood
Homocysteine thiolactone (HTL) 0–35 nM
Protein N-linked homocysteine:
N-Hcy-hemoglobin, N-(Hcy-S-S-Cys)-albumin
about 15.5 μM: 12.7 μM, 2.8 μM
Protein S-linked homocysteine — S-Hcy-albumin about 7.3 μM*
Homocystine (Hcy-S-S-Hcy) and combined with cysteine to from mixed disulphides (Hcy-S-S-Cys) about 2 μM*
Free reduced Hcy about 0.1 μM*

As early as in the 1960s it was noted that the risk of atherosclerosis is markedly increased in patients with homocystinuria, an inherited disease resulting from homozygous CBS deficiency and characterized by episodes of

—     thromboembolism

—     mental retardation

—     lens dislocation

—     hepatic steatosis

—     osteoporosis.

—     very high concentrations of plasma homocysteine and methionine.

Patients with homocystinuria have very severe hyperhomocysteinemia, with plasma homocysteine concentration reaching even 400 μM, and represent a very small proportion of the population (approximately 1 in 200,000 individuals). Heterozygous lack of CBS, CBS mutations and polymorphism of the methylenetetrahydrofolate reductase gene are considered to be the most probable causes of hyperhomocysteinemia.

The effects of hyperhomocysteinemia include the complex process of hemostasis, which regulates the properties of blood flow. Interactions of homocysteine and its different derivatives, including homocysteine thiolactone, with the major components of hemostasis are:

  • endothelial cells
  • platelets
  • fibrinogen
  • plasminogen

Elevated plasma Hcy (>15 μM; Hcy) is associated with an increased risk of cardiovascular diseases

  • thrombosis
  • thrombosis related diseases
  • ischemic brain stroke (independent of other, conventional risk factors of this disease)

Every increase of 2.5 μM in plasma Hcy may be associated with an increase of stroke risk of about 20%.  Total plasma Hcy level above 20 μM are associated with a nine-fold increase of the myocardial infarction and stroke risk, in comparison to the concentrations below 9 μM. The increase of Hcy concentration has been also found in other human pathologies, including neurodegenerative diseases

Modifications of hemostatic proteins (N-homocysteinylation or S-homocysteinylation) induced by Hcy or its thiolactone seem to be the main cause of homocysteine biotoxicity in hemostatic abnormalities.

Hcy and HTL may act as oxidants, but various polyphenolic antioxidants are able to inhibit the oxidative damage induced by Hcy or HTL. Therefore, we have to consider the role of phenolic antioxidants in hyperhomocysteinemia –induced changes in hemostasis.

The synthesis of homocysteine thiolactone is associated with the activation of the amino acid by aminoacyl-tRNA synthetase (AARS). Hcy may also undergo erroneous activation, e.g. by methionyl-t-RNA synthetase (MetRS). In the first step of conversion of Hcy to HTL, MetRS misactivates Hcy giving rise to homocysteinyl-adenylate. In the next phase, the homocysteine side chain thiol group reacts with the activated carboxyl group and HTL is produced. The level of HTL synthesis in cultured cells depends on Hcy and Met levels.

Hyperhomocysteinemia and Changes in Fibrinolysis and Coagulation Process

The fibrinolytic activity of blood is regulated by specific inhibitors; the inhibition of fibrinolysis takes place at the level of plasminogen activation (by PA-inhibitors: plasminogen activator inhibitor type-1, -2; PAI-1 or PAI-2) or at the level of plasmin activity (mainly by α2-antiplasmin). Hyperhomocysteinemia disturbs hemostasis and shifts the hemostatic mechanisms in favor of thrombosis. The recent reports indicate that the prothrombotic state observed in hyperhomocysteinemia may arise not only due to endothelium dysfunction or blood platelet and coagulation activation, but also due to impaired fibrinolysis. Hcy-modified fibrinogen is more resistant to the fibrinolytic action. Oral methionine load increases total Hcy, but may diminish the fibrinolytic activity of the euglobulin plasma fraction. Homocysteine-lowering therapies may increase fibrinolytic activity, thereby, prevent atherothrombotic events in patients with cardiovascular diseases after the first myocardial infarction.

Homocysteine — Fibronectin Interaction and its Consequences

Fibronectin (Fn) plays key roles in

  • cell adhesion
  • migration
  • embryogenesis
  • differentiation
  • hemostasis
  • thrombosis
  • wound healing
  • tissue remodeling

Interaction of FN with fibrin, mediated by factor XIII transglutaminase, is thought to be important for cell adhesion or cell migration into fibrin clots. After tissue injury, a blood clot formation serves the dual role of restoring vascular integrity and serving as a temporary scaffold for the wound healing process. Fibrin and plasma FN, the major protein components of blood clots, are essential to perform these functions. In the blood clotting process, after fibrin deposition, plasma FN-fibrin matrix is covalently crosslinked, and it then promotes fibroblast adhesion, spreading, and migration into the clot.

Homocysteine binds to several human plasma proteins, including fibronectin. If homocysteine binds to fibronectin via a disulphide linkage, this binding results in a functional change, namely, the inhibition of fibrin binding by fibronectin. This inhibition may lead to a prolonged recovery from a thrombotic event and contribute to vascular occlusion.

Grape seeds are one of the richest plant sources of phenolic substances, and grape seed extract reduces the toxic effect of Hcys and HTL on fibrinolysis. The grape seed extract (12.5–50 μg/ml) supported plasminogen to plasmin conversion inhibited by Hcys or HTL. In vitro experiments showed in the presence of grape seed extract (at the highest tested concentration — 50 μg/ml) the increase of about 78% (for human plasminogen-treated with Hcys) and 56% (for human plasma-treated with Hcys). Thus, in the in vitro model system, that the grape seed extract (12.5–50 μg/ml) diminished the reduction of thiol groups and of lysine ε-amino groups in plasma proteins treated with Hcys (0.1 mM) or HTL (1 μM). In the presence of the grape seed extract at the concentration of 50 μg/ml, the level of reduction of thiol groups reached about 45% (for plasma treated with Hcys) and about 15% (for plasma treated with HTL).

In the presence of the grape seed extract at the concentration of 50 μg/ml, the level of reduction of thiol groups reached about 45% (for plasma treated with Hcys) and about 15% (for plasma treated with HTL).Very similar protective effects of the grape seed extract were observed in the measurements of lysine ε-amino groups in plasma proteins treated with Hcys or HTL. These results indicated that the extract from berries of Aronia melanocarpa (a rich source of phenolic substances) reduces the toxic effects of Hcy and HTL on the hemostatic properties of fibrinogen and plasma. These findings indicate a possible protective action of the A. melanocarpa extract in hyperhomocysteinemia-induced cardiovascular disorders. Moreover, the extract from berries of A. melanocarpa, due to its antioxidant action, significantly attenuated the oxidative stress (assessed by measuring of the total antioxidant status — TAS) in plasma in a model of hyperhomocysteinemia.

Proposed model for the protective role of phenolic antioxidants on selected elements of hemostasis during hyperhomocysteinemia.

various antioxidants (present in human diet), including phenolic compounds, may reduce the toxic effects of Hcy or its derivatives on hemostasis. These findings give hope for the develop development of dietary supplements, which will be capable of preventing thrombosis which occurs under pathological conditions, observed also in hyperhomocysteinemia, such as plasma procoagulant activity and oxidative stress.

Malinowska J,  Kolodziejczyk J and Olas B. The disturbance of hemostasis induced by hyper-homocysteinemia; the role of antioxidants. Acta Biochimica Polonica 2012; 59(2): 185–194.

Lipoprotein (a)

Lipoprotein (a) (Lp(a)), for the first time described in 1963 by Berg belongs to the lipoproteins with the strongest atherogenic effect. Its importance for the development of various atherosclerotic vasculopathies (coronary heart disease, ischemic stroke, peripheral vasculopathy, abdominal aneurysm) was recognized considerably later.

Lipoprotein(a) (Lp(a)), an established risk marker of cardiovascular diseases, is independent from other risk markers. The main difference of Lp(a) compared to low density lipoprotein (LDL) is the apo(a) residue, covalently bound to apoB is covalently by a disulfide-bridge. Apo(a) synthesis is performed in the liver, probably followed by extracellular assembly to the apoB location of the LDL.


ApoB-100_______LDL¬¬___ S-S –    9

Apo(a) has been detected bound to triglyceride-rich lipoproteins (Very Low Density Lipoproteins; VLDL). Corresponding to the structural similarity to LDL, both particles are very similar to each other with regard to their composition. It is a glycoprotein which underlies a large genetic polymorphism caused by a variation of the kringle-IV-type-2 repeats of the protein, characterized by a structural homology to plasminogen. Apo(a)’s structural homology to plasminogen, shares the gene localization on chromosome 6. The kringle repeats present a particularly characteristic structure, which have a high similarity to kringle IV (K IV) of plasminogen. Apo(a) also has a kringle V structure of plasminogen and also a protease domain, which cannot be activated, as opposed to the one of plasminogen. At least 30 genetically determined apo(a) isoforms were identified in man.


  • Non covalent binding of kringle -4 types 7 and 8 of apo (a) to apo B
  • Disulfide bond at Cys4326 of ApoB (near its receptor binding domain ) and the only free cysteine group in K –IV type 9 (Cys4057) of apo(a )
  • Binding to fibrin and cell membranes
  • Enhancement by small isoforms ; high concentrations compared to plasminogen and homocysteine
  • Binding to different lysine rich components of the coagulation system (e. g. TFPI)
  • Intense homology to plasminogen but no protease activity
ApoB-100_______LDL¬¬___ S-S – 9

The synthesis of Lp(a), which thus occurs as part of an assembly, is a two-step process.

  • In a first step, which can be competitively inhibited by lysine analogues, the free sulfhydryl groups of apo(a) and apoB are brought close together.
  • The binding of apo(a) then occurs near the apoB domain which binds to the LDL receptor, resulting in a reduced affinity of Lp(a) to the LDL-receptor.

Particles that show a reduced affinity to the LDL receptor are not able to form stable compounds with apo(a). Thus the largest part of apo(a) is present as apo(a) bound to LDL. Only a small, quantitatively variable part of apo(a) remains as free apo(a) and probably plays an important role in the metabolism and physiological function of Lp(a).

The Lp(a) plasma concentration in the population is highly skewed and determined to more than 90 % by genetic factors. In healthy subjects the Lp(a)-concentration is correlated with its synthesis.

It is assumed that the kidney has a specific function in Lp(a) catabolizm, since nephrotic syndrome and terminal kidney failure are associated with an elevation of the Lp(a) plasma concentration. One consequence of the poor knowledge of the metabolic path of Lp(a) is the fact that so far pharmaceutical science has failed to develop drugs that are able to reduce elevated Lp(a) plasma concentrations to a desirable level.

Plasma concentrations of Lp(a) are affected by different diseases (e.g. diseases of liver and kidney), hormonal factors (e.g. sexual steroids, glucocorticoids, thyroid hormones), individual and environmental factors (e.g. age, cigarette smoking) as well as pharmaceuticals (e.g. derivatives of nicotinic acid) and therapeutic procedures (lipid apheresis). This review describes the physiological regulation of Lp(a) as well as factors influencing its plasma concentration.

Apart from its significance as an important agent in the development of atherosclerosis, Lp(a) has even more physiological functions, e.g. in

  • wound healing
  • angiogenesis
  • hemostasis

However, in the meaning of a pleiotropic mechanism the favorable action mechanisms are opposed by pathogenic mechanisms, whereby the importance of Lp(a) in atherogenesis is stressed.

Lp(a) in Atherosclerosis

In transgenic, hyperlipidemic and Lp(a) expressing Watanabe rabbits, Lp(a) leads to enhanced atherosclerosis. Under the influence of Lp(a), the binding of Lp(a) to glycoproteins, e.g. laminin, results – via its apo(a)-part – both in

  • an increased invasion of inflammatory cells and in
  • an activation of smooth vascular muscle cells

with subsequent calcifications in the vascular wall.

The inhibition of transforming growth factor-β1 (TGF-β1) activation is another mechanism via which Lp(a) contributes to the development of atherosclerotic vasculopathies. TGF-β1 is subject to proteolytic activation by plasmin and its active form leads to an inhibition of the proliferation and migration of smooth muscle cells, which play a central role in the formation and progression of atherosclerotic vascular diseases.

In man, Lp(a) is an important risk marker which is independent of other risk markers. Its importance, partly also under consideration of the molecular weight and other genetic polymorphisms, could be demonstrated by a high number of epidemiological and clinical studies investigating the formation and progression of atherosclerosis, myocardial infarction, and stroke.

Lp(a) in Hemostasis

Lp(a) is able to competitively inhibit the binding of plasminogen to fibrinogen and fibrin, and to inhibit the fibrin-dependent activation of plasminogen to plasmin via the tissue plasminogen activator, whereby apo(a) isoforms of low molecular weight have a higher affinity to fibrin than apo(a) isoforms of higher molecular weight. Like other compounds containing sulfhydryl groups, homocysteine enhances the binding of Lp(a) to fibrin.

Pleiotropic effect of Lp(a).

Prothrombotic :

  • Binding to fibrin
  • Competitive inhibition of plasminogen
  • Stimulation of plasminogen activator inhibitor I and II (PAI -I, PAI -II)
  • Inactivation of tissue factor pathway inhibitor (TFPI)

Antithrombotic :

  • Inhibition of platelet activating factor acetylhydrolase (PAF -AH)
  • Inhibition of platelet activating factor
  • Inhibition of collagen dependent platelet aggregation
  • Inhibition of secretion of serotonin und thromboxane

Lp(a) in Angiogenesis

Lp(a) is also important for the process of angiogenesis and the sprouting of new vessels.

  • angiogenesis starts with the remodelling of matrix proteins and
  • activation of matrix metalloproteinases (MMP).

The latter ones are usually synthesised as

  • inactive zymogens and
  • require activation by proteases,

Recall that Apo(a) is not activated by proteases. The angiogenesis is also accomplished by plasminogen. Lp(a) and apo(a) and its fragments has an antiangiogenetic and metastasis inhibiting effect related to the structural homology with plasminogen without the protease activity.

Siekmeier R, Scharnagl H, Kostner GM, T. Grammer T, Stojakovic T and März W.  Variation of Lp(a) Plasma Concentrations in Health and Disease.  The Open Clinical Chemistry Journal, 2010; 3: 72-89.


In 1985, Brown and Goldstein were awarded the Nobel Prize for medicine for their work on the regulation of cholesterol metabolism. On the basis of numerous studies, they were able to demonstrate that circulating low-density lipoprotein (LDL) is absorbed into the cell through receptor linked endocytosis. The absorption of LDL into the cell is specific and is mediated by a LDL receptor. In patients with familial hypercholesterolemia, this receptor is changed, and the LDL particles can no longer be recognized. Their absorption can thus no longer be mediated, leading to an accumulation of LDL in blood.

Furthermore, an excess supply of cholesterol also blocks the 3-hydrox-3 methylglutaryl-Co enzyme A (HMG CoA), reductase enzyme, which otherwise inhibits the cholesterol synthesis rate. Brown and Goldstein also determined the structure of the LDL receptor. They discovered structural defects in this receptor in many patients with familial hypercholesterolemia. Thus, familial hypercholesterolemia was the first metabolic disease that could be tracked back to the mutation of a receptor gene.

Dyslipoproteinemia in combination with diabetes mellitus causes a cumulative insult to the vasculature resulting in more severe disease which occurs at an earlier age in large and small vessels as well as capillaries. The most common clinical conditions resulting from this combination are myocardial infarction and lower extremity vascular disease. Ceriello et al. show an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial function, suggesting oxidative stress as common mediator of such effect. The combination produces greater morbidity and mortality than either alone.

As an antiatherogenic factor, HDL cholesterol correlates inversely to the extent of postprandial lipemia. A high concentration of HDL is a sign that triglyceride-rich particles are quickly decomposed in the postprandial phase of lipemia. Conversely, with a low HDL concentration this decomposition is delayed. Thus, excessively high triglyceride concentrations are accompanied by very low HDL counts. This combination has also been associated with an increased risk of pancreatitis.

The importance of lipoprotein (a) (Lp(a)) as an atherogenic substance has also been recognized in recent years. Lp(a) is very similar to LDL. But it also contains Apo(a), which is very similar to plasminogen, enabling Lp(a) to bind to fibrin clots. Binding of plasminogen is prevented and fibrinolysis obstructed. Thrombi are integrated into the walls of the arteries and become plaque components.

Another strong risk factor for accelerated atherogenesis, which must be mentioned here, are the widespread high homocysteine levels found in dialysis patients. This risk factor is independent of classic risk factors such as high cholesterol and LDL levels, smoking, hypertension, and obesity, and much more predictive of coronary events in dialysis patients than are these better-known factors. Homocysteine is a sulfur aminoacid produced in the metabolism of methionine. Under normal conditions, about 50 percent of homocysteine is remethylated to methionine and the remaining via the transsulfuration pathway.

Defining hyperhomocysteinemia as levels greater than the 90th percentile of controls and elevated Lp(a) level as greater than 30mg/dL, the frequency of the combination increased with declining renal function. Fifty-eight percent of patients with a GFR less than 10mL/min had both hyperhomocysteinemia and elevated Lp(a) levels, and even in patients with mild renal impairment, 20 percent of patients had both risk factors present.

The prognosis of patients suffering from severe hyperlipidemia, sometimes combined with elevated lipoprotein (a) levels, and coronary heart disease refractory to diet and lipid-lowering drugs is poor. For such patients, regular treatment with low-density lipoprotein (LDL) apheresis is the therapeutic option. Today, there are five different LDL-apheresis systems available: cascade filtration or lipid filtration, immunoadsorption, heparin-induced LDL precipitation, dextran sulfate LDL adsorption, and the LDL hemoperfusion. The requirement that the original level of cholesterol is to be reduced by at least 60 percent is fulfilled by all these systems.

There is a strong correlation between hyperlipidemia and atherosclerosis. Besides the elimination of other risk factors, in severe hyperlipidemia therapeutic strategies should focus on a drastic reduction of serum lipoproteins. Despite maximum conventional therapy with a combination of different kinds of lipid-lowering drugs, sometimes the goal of therapy cannot be reached. Hence, in such patients, treatment with LDL-apheresis is indicated. Technical and clinical aspects of these five different LDL-apheresis methods are depicted. There were no significant differences with respect to or concerning all cholesterols, or triglycerides observed.

High plasma levels of Lp(a) are associated with an increased risk for atherosclerotic coronary heart       disease
(CHD) by a mechanism yet to be determined. Because of its structural properties, Lp(a) can have both atherogenic and thrombogenic potentials. The means for correcting the high plasma levels of Lp(a) are still limited in effectiveness. All drug therapies tried thus far have failed. The most effective therapeutic methods in lowering Lp(a) are the LDL-apheresismethods. Since 1993, special immunoadsorption polyclonal antibody columns (Pocard, Moscow, Russia) containing sepharose bound anti-Lp(a) have been available for the treatment of patients with elevated Lp(a) serum concentrations.

With respect to elevated lipoprotein (a) levels, however, the immunoadsorption method seems to be most effective. The different published data clearly demonstrate that treatment with LDL-apheresis in patients suffering from severe hyperlipidemia refractory to maximum conservative therapy is effective and safe in long-term application.

LDL-apheresis decreases not only LDL mass but also improves the patient’s life expectancy. LDL-apheresis performed with different techniques decreases the susceptibility of LDL to oxidation. This decrease may be related to a temporary mass imbalance between freshly produced and older LDL particles. Furthermore, the baseline fatty acid pattern influences pretreatment and postreatment susceptibility to oxidation.

Bambauer R, Bambauer C, Lehmann B, Latza R, and Ralf Schiel R. LDL-Apheresis: Technical and Clinical Aspects. The Scientific World Journal 2012; Article ID 314283, pp 1-19. doi:10.1100/2012/314283

Summary:  This discussion is a two part sequence that first establishes the known strong relationship between blood flow viscosity, shear stress, and plasma triglycerides (VLDL) as risk factors for hemostatic disorders leading to thromboembolic disease, and the association with atherosclerotic disease affecting the heart, the brain (via carotid blood flow), peripheral circulation,the kidneys, and retinopathy as well.

The second part discusses the modeling of hemostasis and takes into account the effects of plasma proteins involved with red cell and endothelial interaction, which is related to part I.  The current laboratory assessment of thrombophilias is taken from a consensus document of the American Society for Clinical Pathology.  The problems encountered are sufficient for the most common problems of coagulation testing and monitoring, but don’t address the large number of patients who are at risk for complications of accelerated vasoconstrictive systemic disease that precede serious hemostatic problems.  Special attention is given to Lp(a) and to homocysteine.  Lp(a) is a protein that has both prothrombotic and antithrombotic characteristics, and is a homologue of plasminogen and is composed of an apo(a) bound to LDL.  Unlike plasminogen, it has no protease activity.   Homocysteine elevation is a known risk factor for downstream myocardial infarct.  Homocysteine is a mirror into sulfur metabolism, so an increase is an independent predictor of risk, not fully discussed here.  The modification of risk is discussed by diet modification.  In the most serious cases of lipoprotein disorders, often including Lp(a) the long term use of LDL-apheresis is described.

see Relevent article that appears in NEJM from American College of Cardiology

Apolipoprotein(a) Genetic Sequence Variants Associated With Systemic Atherosclerosis and Coronary Atherosclerotic Burden but Not With Venous Thromboembolism

Helgadottir A, Gretarsdottir S, Thorleifsson G, et al

J Am Coll Cardiol. 2012;60:722-729

Study Summary

The LPA gene codes for apolipoprotein(a), which, when linked with low-density lipoprotein particles, forms lipoprotein(a) [Lp(a)] — a well-studied molecule associated with coronary artery disease (CAD). The Lp(a) molecule has both atherogenic and thrombogenic effects in vitro , but the extent to which these translate to differences in how atherothrombotic disease presents is unknown.

LPA contains many single-nucleotide polymorphisms, and 2 have been identified by previous groups as being strongly associated with levels of Lp(a) and, as a consequence, strongly associated with CAD. However, because atherosclerosis is thought to be a systemic disease, it is unclear to what extent Lp(a) leads to atherosclerosis in other arterial beds (eg, carotid, abdominal aorta, and lower extremity), as well as to other thrombotic disorders (eg, ischemic/cardioembolic stroke and venous thromboembolism). Such distinctions are important, because therapies that might lower Lp(a) could potentially reduce forms of atherosclerosis beyond the coronary tree.

To answer this question, Helgadottir and colleagues compiled clinical and genetic data on the LPA gene from thousands of previous participants in genetic research studies from across the world. They did not have access to Lp(a) levels, but by knowing the genotypes for 2 LPA variants, they inferred the levels of Lp(a) on the basis of prior associations between these variants and Lp(a) levels. [1] Their studies included not only individuals of white European descent but also a significant proportion of black persons, in order to widen the generalizability of their results.

Their main findings are that LPA variants (and, by proxy, Lp(a) levels) are associated with CAD,  peripheral arterial disease, abdominal aortic aneurysm, number of CAD vessels, age at onset of CAD diagnosis, and large-artery atherosclerosis-type stroke. They did not find an association with cardioembolic or small-vessel disease-type stroke; intracranial aneurysm; venous thrombosis; carotid intima thickness; or, in a small subset of individuals, myocardial infarction.


The main conclusion to draw from this work is that Lp(a) is probably a strong causal factor in not only CAD, but also the development of atherosclerosis in other arterial trees. Although there is no evidence from this study that Lp(a) levels contribute to venous thrombosis, the investigators do not exclude a role for Lp(a) in arterial thrombosis.

Large-artery atherosclerosis stroke is thought to involve some element of arterial thrombosis or thromboembolism, [2] and genetic substudies of randomized trials of aspirin demonstrate that individuals with LPA variants predicted to have elevated levels of Lp(a) benefit the most from antiplatelet therapy. [3] Together, these data suggest that Lp(a) probably has clinically relevant effects on the development of atherosclerosis and arterial thrombosis.

Of  note, the investigators found no association between Lp(a) and carotid intima thickness, suggesting that either intima thickness is a poor surrogate for the clinical manifestations of atherosclerosis or that Lp(a) affects a distinct step in the atherosclerotic disease process that is not demonstrable in the carotid arteries.

Although Lp(a) testing is available, these studies do not provide any evidence that testing for Lp(a) is of clinical benefit, or that screening for atherosclerosis should go beyond well-described clinical risk factors, such as low-density lipoprotein cholesterol levels, high-density lipoprotein levels, hypertension, diabetes, smoking, and family history. Until evidence demonstrates that adding information on Lp(a) levels to routine clinical practice improves the ability of physicians to identify those at highest risk for atherosclerosis, Lp(a) testing should remain a research tool. Nevertheless, these findings do suggest that therapies to lower Lp(a) may have benefits that extend to forms of atherothrombosis beyond the coronary tree.

The finding of this study is interesting:

[1] It consistent with Dr. William LaFramboise..   examination specifically at APO B100, which is part of Lp(a) with some 14 candidate predictors for a more accurate exclusion of patients who don’t need intervention.          Apo B100 was not one of 5 top candidates.

William LaFramboise • Our study (http://www.ncbi.nlm.nih.gov/pubmed/23216991) comprised discovery research using targeted immunochemical screening of retrospective patient samples using both Luminex and Aushon platforms as opposed to shotgun proteomics. Hence the costs constrained sample numbers. Nevertheless, our ability to predict outcome substantially exceeded available methods:

The Framingham CHD scores were statistically different between groups (P <0.001, unpaired Student’s t test) but they classified only 16% of the subjects without significant CAD (10 of 63) at a 95% sensitivity for patients with CAD. In contrast, our algorithm incorporating serum values for OPN, RES, CRP, MMP7 and IFNγ identified 63% of the subjects without significant CAD (40 of 63) at 95% sensitivity for patients with CAD. Thus, our multiplex serum protein classifier correctly identified four times as many patients as the Framingham index.

This study is consistent with the concept of CAD, PVD, and atheromatous disease is a systemic vascular disease, but the point that is made is that it appears to have no relationship to venous thrombosis. The importance for predicting thrombotic events is considered serious.   The venous flow does not have the turbulence of large arteries, so the conclusion is no surprise.  The flow in capillary beds is a linear cell passage with minimal viscosity or turbulence.  The finding of no association with carotid artery disease  is interpreted to mean that the Lp(a) might be an earlier finding than carotid intimal thickness.  It is reassuring to find a recommendation for antiplatelet therapy for individuals with LPA variants based on randomized trials of aspirin substudies.

If that is the conclusion from the studies, and based on the strong association between the prothrombotic (pleiotropic) effect and the association with hyperhomocysteinemia, my own impression is that the recommendation is short-sighted.

[2]  Lp(a) is able to competitively inhibit the binding of plasminogen to fibrinogen and fibrin, and to inhibit the fibrin-dependent activation of plasminogen to plasmin via the tissue plasminogen activator, whereby apo(a) isoforms of low molecular weight have a higher affinity to fibrin than apo(a) isoforms of higher molecular weight. Like other compounds containing sulfhydryl groups, homocysteine enhances the binding of Lp(a) to fibrin.

Prothrombotic :

  • Binding to fibrin
  • Competitive inhibition of plasminogen
  • Stimulation of plasminogen activator inhibitor I and II (PAI -I, PAI -II)
  • Inactivation of tissue factor pathway inhibitor (TFPI)

Source for Lp(a)

Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles


References on Triglycerides and blood viscosity

Lowe GD, Lee AJ, Rumley A, et al. Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study. Br J Haematol 1997; 96:168-173.

Sloop GD. A unifying theory of atherogenesis. Med Hypotheses. 1996; 47:321-5.
Smith WC, Lowe GD, et al. Rheological determinants of blood pressure in a Scottish adult population. J Hypertens 1992; 10:467-72.

Letcher RL, Chien S, et al. Direct relationship between blood pressure and blood viscosity in normal and hypertensive subjects. Role of fibrinogen and concentration. Am J Med 1981; 70:1195-1202.

Devereux RB, Case DB, Alderman MH, et al. Possible role of increased blood viscosity in the hemodynamics of systemic hypertension. Am J Cardiol 2000; 85:1265-1268.

Levenson J, Simon AC, Cambien FA, Beretti C. Cigarette smoking and hypertension. Factors independently associated with blood hyperviscosity and arterial rigidity. Arteriosclerosis 1987; 7:572-577.

Sloop GD, Garber DW. The effects of low-density lipoprotein and high-density lipoprotein on blood viscosity correlate with their association with risk of atherosclerosis in humans. Clin Sci 1997; 92:473-479.

Lowe GD. Blood viscosity, lipoproteins, and cardiovascular risk. Circulation 1992; 85:2329-2331.

Rosenson RS, Shott S, Tangney CC. Hypertriglyceridemia is associated with an elevated blood viscosity: triglycerides and blood viscosity. Atherosclerosis 2002; 161:433-9.

Stamos TD, Rosenson RS. Low high density lipoprotein levels are associated with an elevated blood viscosity. Atherosclerosis 1999; 146:161-5.

Hoieggen A, Fossum E, Moan A, Enger E, Kjeldsen SE. Whole-blood viscosity and the insulin-resistance syndrome. J Hypertens 1998; 16:203-10.

de Simone G, Devereux RB, Chien S, et al. Relation of blood viscosity to demographic and physiologic variables and to cardiovascular risk factors in apparently normal adults. Circulation 1990; 81:107-17.

Rosenson RS, McCormick A, Uretz EF. Distribution of blood viscosity values and biochemical correlates in healthy adults. Clin Chem 1996; 42:1189-95.

Tamariz LJ, Young JH, Pankow JS, et al. Blood viscosity and hematocrit as risk factors for type 2 diabetes mellitus: The Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol 2008; 168:1153-60.

Jax TW, Peters AJ, Plehn G, Schoebel FC. Hemostatic risk factors in patients with coronary artery disease and type 2 diabetes – a two year follow-up of 243 patients. Cardiovasc Diabetol 2009; 8:48.

Ernst E, Weihmayr T, et al. Cardiovascular risk factors and hemorheology. Physical fitness, stress and obesity. Atherosclerosis 1986; 59:263-9.

Hoieggen A, Fossum E, et al. Whole-blood viscosity and the insulin-resistance syndrome. J Hypertens 1998; 16:203-10.

Carroll S, Cooke CB, Butterly RJ. Plasma viscosity, fibrinogen and the metabolic syndrome: effect of obesity and cardiorespiratory fitness. Blood Coagul Fibrinolysis 2000; 11:71-8.

Ernst E, Koenig W, Matrai A, et al. Blood rheology in healthy cigarette smokers. Results from the MONICA project, Augsburg. Arteriosclerosis 1988; 8:385-8.

Ernst E. Haemorheological consequences of chronic cigarette smoking. J Cardiovasc Risk 1995; 2:435-9.

Lowe GD, Drummond MM, Forbes CD, Barbenel JC. The effects of age and cigarette-smoking on blood and plasma viscosity in men. Scott Med J 1980; 25:13-7.

Kameneva MV, Watach MJ, Borovetz HS. Gender difference in rheologic properties of blood and risk of cardiovascular diseases. Clin Hemorheol Microcirc 1999; 21:357-363.

Fowkes FG, Pell JP, Donnan PT, et al. Sex differences in susceptibility to etiologic factors for peripheral atherosclerosis. Importance of plasma fibrinogen and blood viscosity. Arterioscler Thromb 1994; 14:862-8.

Coppola L, Caserta F, De Lucia D, et al. Blood viscosity and aging. Arch Gerontol Geriatr 2000; 31:35-42.


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Curator: Aviva Lev-Ari, PhD, RN

Intravascular Stimulation/Ablation of Autonomics are procedures, aka Renal Arterial Denervation, that since 1999 has greater promise for treatment of a diseases assumed to be related to an imbalance of autonomic tone.  Dr. Scherlag prefers the name “cardiac sympathetic denervation”.  As he has outlined, the ablation of autonomics in the renal artery has more of an effect on the heart than it does on the kidneys. I do agree that the procedure has  a cardiac effect obtained by autonomic modulation in essence.


Pioneering work in this field, the first to stimulate/ablate autonomic nerves effecting the heart from the intravascular space was accomplished by Dr. Scherlag and others. The greatest accomplishment was “Method and apparatus for  transvascular treatment of tachycardia and fibrillation. US Patent 6,292,695. Filed June 17, 1999.

Dr. Scherlag writes, [T]he possibility that parasympathetic or sympathetic nerves running on blood vessels  could be stimulated or ablated from inside the vasculature was initially demonstrated using basket electrode catheters in a series of experimental studies (1-6) and formally patented in 1999 (7).

Treatment of Hypertension by renal arterial denervation from inside the vasculature using a basket electrode catheters by ultra sound or by RF energy is fully documented in my post Treatment of Refractory Hypertension via Percutaneous Renal Denervation


Clinical Trials and the Ecosystem of all leading manufacturers of Medical Devices for Renal Arterial Denervation, including videos for demonstration of the procedure are presented in my post, link above.

Benefits and New Indications for Usage of Intravascular Stimulation/Ablation of Autonomics

1. Reduction in Heart Rate and Heart Rate Variability

Dr. Scherlag experiments noted changes in heart rate which have also been reported in SYMPLICITY HTN-1 and SYMPLICITY HTN-2 (8-9).  The SYMPLICITY HTN-2 study demonstrated profound bradycardia in 13% of patients that was treated with atropine.

The intra-procedure effect on heart rate during renal artery denervation documented in the  SYMPLICITY trials is also manifest long term by measuring heart rate variability (10). Indeed, cardiac effects would be expected with autonomic modulation.  Besides the two example above showing that cardiac sympathetic denervation effects heart rate, there are many more that are just beginning to be reported in the literature.

These articles shows the effects of renal denervation on heart rate.


A Cleveland Clinic review article states: “Additionally, the resting heart rate was lower and heart rate recovery after exercise improved after the procedure, particularly in patients without diabetes.”

2. Renal Sympathetic Denervation lowers Atrial Fibrillation

This article discusses the effect of renal sympathetic denervation on atrial fibrillation.


3. Regression of Left Ventricular Hypertrophy, Increase in Ejection Fraction (EF) and improved Diastolic Dysfunction

“Brandt reported regression of left ventricular hypertrophy and significantly improved cardiac functional parameters, including increase in ejection fraction and improved diastolic dysfunction, in a study of 46 patients who underwent renal denervation. This findings suggests a potential beneficial effect on cardiac remodeling.” (Brandt MC, Mahfoud F, Reda S, et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol 2012; 59:901–909)

4. Reduction in Ventricular Tachyarrhythmias (VT)

“Ukena reported reduction in ventricular tachyarrhythmias in two patients with congestive heart failure who had therapy-resistant electrical storm.” (Ukena C, Bauer A, Mahfoud F, et al. Renal sympathetic denervation for treatment of electrical storm: first-inman experience. Clin Res Cardiol 2012; 101:63–67)

5. Intravascular Stimulation of Autonomics Effects on Heart Failure

The most recent data from Europe shows the following effects on heart failure:


Dr. Scherlag, writes, [N]early ten examples of the effects of “CARDIAC SYMPATHETIC DENERVATION” and what are the effects on the kidney?

No change in GFR.  No change in creatinine.

Medical Debate on the Procedure – The candidates are hypertensive patients receiving blood-pressure-lowering medication that are truly “resistant.”

The Symplicity system (Medtronic) is the far-and-away front runner, having demonstrated average office-based BP drops of 32/12 mm Hg at six months in the SYMPLICITY HTN 2 trial, as reported by heartwire, with 84% of patients having had a >10-mm-Hg drop in systolic blood pressure from baseline.

Upwards of 20 other companies, according to Dr Ron Waksman (Washington Hospital, DC), are busy developing competing systems, some of which were featured in a EuroPCR session devoted to emerging technologies in May 2012 in Paris.

Leading this pack is St Jude’s EnligHTN system, which received CE Mark on the opening day of the meeting. Dr Stephen Worthley (Royal Adelaide Hospital, Australia) presented 30-day results in 47 resistant-hypertension patients treated with the multielectrode, RF-ablation-based system. Mean office BP changes at one month in EnligHTN 1 were -28 systolic and -10 diastolic (p<0.0001 from baseline), with 78% of patients having systolic BP drops of >10 mm Hg.


In terms of safety, no serious complications were seen in the renal artery or at the access site in the EnligHTN study; minor procedure-related events included four hematomas, three vasovagal responses to sheath removal, and two postprocedure transient bradycardias.

Other devices featured in the session included a second RF-energy system and two ultrasound systems, see below technology description by supplier.

The risk of cardiovascular death doubles with every 20 point increase in systolic blood pressure, so an average blood pressure reduction of 28 points is quite significant and demonstrates just how effective the technology is. Principal investigator Prof. Stephen Worthley said in prepared remarks. “From other clinical trials studying the impact of renal denervation we have learned that blood pressure continues to be reduced over time, so I would not be surprised to see this trend continue and see an even greater benefit for patients.” St. Jude’s study included 47 patients with high blood pressure that wasn’t managed with drug therapy. Participants had an average of 176/96 mmHg baseline blood pressure, despite taking multiple medications, before the denervation procedure and an average of 148/87 mmHg after. More than 40% had systolic rates below 140 mmHg.


Interventionalists who spoke with heartwire were unvaryingly excited about the potential of renal denervation, with some caveats.

“You need enthusiasm to develop new things, and in hypertension we haven’t seen an innovation in decades,” Dr Thomas Lüscher (University Hospital Zürich, Switzerland) told heartwire. “So just the possibility that you would be able to have a persistent treatment effect by a procedure that helps severe hypertension patients and maybe in the future even the option to cure hypertension is very exciting indeed. But I agree it’s a dream at this point. I think we need the SYMPLICITY HTN 3 trial, which hopefully will confirm what the other studies have shown.”

Now enrolling at as many as 90 US centers, SYMPLICITY HTN 3, Lüscher pointed out, has design characteristics addressing two concerns with the earlier trials, namely a sham procedure for the control group and ambulatory blood-pressure monitoring in all patients.

During the same emerging-technologies session, Lüscher explored the albeit-scant data supporting a role for renal denervation in other conditions: everything from metabolic syndrome and obstructive sleep apnea to heart failure, atrial fibrillation, and polycystic-ovary syndrome.

But his counterpoint, Dr Jean Renkin (UCL St Luc University Hospital, Brussels, Belgium), was skeptical, pointing to the myriad unanswered questions with the technology.

“Currently, reasonably solid data are available only for patients with hypertension resistant to pharmacotherapy, which cannot necessarily be extrapolated to other forms of hypertension or conditions referred to [by Dr Lüscher]. However, at this point in time, no clouds have appeared in the sky, so let us dream on.”

Dr Renkin had one staggering number for the audience to consider: of 5000 patients who have undergone renal denervation, only 250 were actually treated as part of clinical studies. While no device has US approval, five denervation systems already hold CE Mark in Europe and are being used with increasing frequency.

Treating the Truly Medication Treatment “Resistant”

For a comprehensive presentation of Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes, refer to


Another talking point is the proportion of patients who are truly “resistant.” The number agreed on by Lüscher, Waksman, and session comoderator Dr Robert Whitbourn (St Vincent’s Hospital, Fitzroy, Australia) was that just 3% of all hypertensive patients receiving blood-pressure-lowering medication are truly “resistant.” Numbers as high as 30% have been suggested in other reports, he noted.

“Interestingly, when we’ve been involved in various trials, every cardiologist says they have hundreds of these patients, but when we actually go to get them, no one actually has any,” Whitbourn quipped. “I think it should be a sobering thought—the numbers are actually quite small.”

Dr William Wijns (Cardiovascular Center Aalst, Belgium), also speaking with heartwire, agreed that the subset was “small” but argued it was “still big numbers, millions of people,” and “a massive unmet need.”

Waksman, insisting he was “excited” by what he called “robust reductions in blood pressure,” nevertheless urged eager interventionalists to work with hypertension experts and resist the urge “to jump on patients before we truly verify that they are resistant to medical treatment.”

In the vast majority of people even for whom renal denervation is appropriate, it “won’t be a cure,” Waksman said. “Most of these patients will have to continue on medical treatment—this is not replacing medical treatment, it is just getting [patients] more in control.”



1. Schauerte P, Scherlag BJ, Scherlag MA, Goli S, Jackman WM, Lazzara R. Transvenous parasympathetic cardiac nerve stimulation: an approach for stable sinus rate control. J Electrophysiol. 1999 Nov;10(11):1517-24.

2. Schauerte P, Scherlag BJ, Scherlag MA, Goli S, Jackman WM, Lazzara R. Ventricular rate control during atrial fibrillation by cardiac parasympathetic nerve stimulation: a transvenous approach. J Am Coll Cardiol. 1999 Dec;34(7):2043-50.

3. Schauerte P, Scherlag BJ, Pitha J, Scherlag MA, Reynolds D, Lazzara R, Jackman WM. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation. 2000 Nov 28;102(22):2774-80.

4. Scherlag MA, Scherlag BJ, Yamanashi W, Schauerte P, Goli S, Jackman WM, Reynolds D, Lazzara R. Endovascular neural stimulation via a novel basket electrode catheter: comparison of electrode configurations. J Interv Card Electrophysiol. 2000 Apr;4(1):219-24.

5. Scherlag BJ, Yamanashi WS, Schauerte P, Scherlag M, Sun YX, Hou Y, Jackman WM, Lazzara R. Endovascular stimulation within the left pulmonary artery to induce slowing of heart rate and paroxysmal atrial fibrillation. Cardiovasc Res. 2002 May; 54(2):470-5.

6. Hasdemir C, Scherlag BJ, Yamanashi WS, Lazzara R, Jackman WM. Endovascular stimulation of autonomic neural elements in the superior vena cava using a flexible loop catheter. Jpn Heart J. 2003 May;44(3):417-27.

7. Webster W Jr, Scherlag BJ, Scherlag MA, Schauerte P. Method and apparatus for   transvascular treatment of tachycardia and fibrillation. US Patent 6,292,695. Filed June 17, 1999.

8. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275-1281.

9. Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903-1909.

10. Frank Himmel MD, Joachim Weil MD, Michael Reppel MD, Kai Mortensen MD, Klaas Franzen, Leidinger Ansgar MD, Heribert Schunkert MD, Frank Bode MD.  Improved Heart Rate Dynamics in Patients Undergoing Percutaneous Renal Denervation. Letter to the Editor. JCH. 31 MAY 2012.1751-7176.

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