What is the quality rate of intrinsic autoregulation in the heart?

Autoregulation is the maintenance of constant blood flow to an organ in spite of fluctuations in Blood pressure. It involves the relaxation of myocardium and contraction. It is local.

I know that autoregulation is best done in the brain, well in kidneys and badly in skeletal muscle. I am interested how it is in the heart. I think it should be at least good. Brain can be thought more important. However, I am not sure.

How good is the autoregulation of the blood flow in the heart?

My conjecture: Intrinsic regulation is done in the heart the second best, after the brain. This idea is based on the fact that the brain controls heart's some autonomic functions.

It is an open research question how the autonomic nervous system affects the intrinsic functions of the heart - and the reverse is true too.

To answer this question, we need to understand the autonomic regulation of the heart better i.e. the inner-physiology of the heart's electrical activity.

Heart Rate and its Regulation (With Diagram)

Normal heart rate is about 60-90 beats per minute. On an average, the rate at which the heart beats is about 75 per minute. It depends on the balanced activity between the sympathetic and parasympa­thetic nerve influence that are acting on it.

Heart rate can be increased because of either an increased activity of sympathetic nerve fibers or a decreased activity of parasympathetic nerve fibers and vice versa for a decrease in heart rate.

In a newborn infant, the heart rate is about 120 beats per minute. The rate at which the heart beats is proportionate to the metabolic rate of the body. In canary birds, it can be as much as 1000 beats per minute.

An increase in heart rate is known as tachycardia and a decrease is known as bradycardia.

Innervations to the Heart (Fig. 3.27):

i. The efferent nerve supply to the heart is from both sympathetic and parasympathetic nerves.

ii. The parasympathetic nerve supplying the heart comes along the vagus whereas sympathetic is from the lateral horn cells of T1-T5 segments of spinal cord. The sympathetic fibers reach heart as superior, middle and inferior cardiac nerves.

iii. Vagus nerve takes origin from the cardioinhibitory center present in the reticular formation of the brainstem. The preganglionic fibers synapse in the ganglion cells present in the walls of the atria. From these the short postganglionic fibers supply almost all parts of heart except the apex.

The neurotrans­mitter liberated both at the pre- and postganglionic regions will be acetylcholine. The receptors through which acetylcholine acts at the preganglionic region are termed as nicotinic receptor and at the post­ganglionic region are muscarinic receptor. The right vagus predominantly supplies the SA node whereas the left vagus predominantly supplies the AV node.

iv. Even under normal resting conditions, there is some amount of constant activity of the vagus on heart. This is termed as vagal tone. Because of this, the normal heart rate is maintained around 75 beats per minute. If there is bilateral vagotomy (cutting of vagi on either side), even at rest the heart rate may increase to about 140-180 beats per minute.

v. The sympathetic fibers take origin from the lateral horn cells of the upper five thoracic segments. The preganglionic fibers that have emerged out of the spinal cord ascend up and synapse in the superior, middle and inferior cervical ganglia. From these ganglia, the postganglionic fibers take origin and supply the heart.

The neurotransmitter liberated by the preganglionic fibers is acetylcholine and the postganglionic fibers release noradrenaline. The influences of parasympathetic and sympathetic nerve stimulation on various activities of the heart have been indicated in Table 3.7.

Phases of Respiration and Heart Rate:

During inspiration, the heart rate is increased and during expiration, it is decreased.

a. During inspiration, there will be irradiation of the impulses from the inspiratory center to the cardioinhibitory center which is present nearby in the reticular formation of the brainstem. These impulses from the respiratory center will inhibit the activity of the cardioinhibitory center and this in turn decreases the activity of vagus nerve and hence vagal tone. Consequently, heart rate gets increased.

b. During inspiration as air enters the alveoli, the stretch receptors present in the walls of the alveoli get stimulated. The impulses are carried to the brainstem through afferent vagal fibers. These afferent impulses not only inhibit the inspiratory center but also the cardioinhibitory center. Hence vagal tone is decreased and heart rate increases.

Regulation of Heart Rate:

Baroreceptor Mechanism:

i. There are specialized receptors namely the baroreceptors in the walls of carotid sinus and arch of aorta. The carotid sinus is located at the beginning of the internal carotid artery.

ii. The baroreceptors are stretch receptors present in the walls of the above blood vessels. Whenever there is an increase in blood pressure, the receptors get stimulated. They respond better when the blood flow in the above vessels is pulsatile.

iii. The afferent impulses from the carotid sinus are carried by sinus nerve a branch of glossopharyngeal nerve and from arch of aorta by aortic nerve a branch of vagus.

iv. The afferent impulses will stimulate the cardio inhibitory center present in the brainstem. This will increase the number of efferent impulses along the vagus to heart. The end result will be a decrease in heart rate (Fig. 3.28). The vagal tone depends on the impulses coming from the baroreceptors. When the baroreceptors are denervated vagal tone is lost completely.

v. There is an inverse relationship between blood pressure and heart rate. Heart rate is inversely proportional to blood pressure and this is termed as Marey’s law. Accordingly, when blood pressure increases the heart rate is decreased. In certain conditions, like muscular exercise, anxiety, etc., there is increase of both blood pressure and heart rate (exception to Marey’s law).

From baroreceptors (BR) to CIC—IX and X cranial nerves.

Chemoreceptor Mechanism:

i. These receptors are called as carotid and aortic bodies.

ii. The carotid body is present at the bifurcation of the common carotid artery (at the commencement of occipital artery) and aortic bodies are present at the arch of aorta.

iii. The afferent nerve that carries impulses from these receptors will be sinus nerve and aortic nerve respectively.

iv. They respond for chemical changes in blood namely, decrease in pO2, increase of pCO2 and increase in hydrogen ion concentration.

v. When chemoreceptor get stimulated by any of the above factors, the afferent impulses from these receptors are carried by sinus and aortic nerves.

vi. The end result will be an increase in heart rate.

Bainbridge Reflex (Fig. 3.29):

i. In the walls of great veins, there are stretch receptors present. They are termed as low pressure or volume receptors.

ii. Distension of the great veins leads to stimulation of these receptors.

iii. Afferent impulses from these receptors will be carried by vagus nerve.

iv. The afferent impulses inhibit the activity of cardio­inhibitory center and thereby leading to increase in heart rate.

v. The afferent impulses along the vagus will also stimulate the neurons present in the brainstem which can increase the activity of sympathetic nerves. This leads to increased sympathetic activity on heart and heart rate increases.

The other factors which can influence the heart rate are (Table 3.8):

1. Pain receptor stimulation will have differential effect. When pain is from superficial parts of body (cutaneous pain), it brings about an increase in heart rate and if pain is visceral in origin, it leads to decrease in heart rate.

2. Joint receptors that are present in and around the joint will get stimulated during muscular exercise and increase the heart rate during exercise.

3. Increased intracranial tension: When there is an increased intracranial tension (e.g. in improper drainage of CSF), this will bring about a reflex bradycardia.

4. Oculocardiac reflex: When pressure is applied on the eyeball, it will bring about a decrease in heart rate.

5. Increase of body temperature will bring about an increase of heart rate.

6. Effect of adrenaline and noradrenaline: In an intact heart, adrenaline increases the heart rate while noradrenaline decreases the same. The decrease of heart rate by noradrenaline is brought about by reflex mechanism acting through baroreceptors since noradrenaline brings about an increase of mean arterial blood pressure.

Cerebral Autoregulation and Blood Pressure Lowering

From the Department of Neurology and Rehabilitation, University of Illinois College of Medicine, Chicago.

From the Department of Neurology and Rehabilitation, University of Illinois College of Medicine, Chicago.

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Despite its comparatively small size, the brain receives a disproportionate amount of blood flow compared with most other organ systems. Cerebral blood flow is closely coupled to brain metabolism and can be affected by respiratory-induced CO2 changes and arterial blood pressure. Autoregulation is the intrinsic capacity of resistance vessels in end organs, such as heart, kidney, and brain, to dilate and constrict in response to dynamic perfusion pressure changes, maintaining blood flow relatively constant (Figure). This rapid vascular response occurs within seconds of arterial pressure fluctuations. The exact mediators of cerebral autoregulation are not completely understood. However, neurogenic stimuli metabolic factors, such as adenosine accumulation during low perfusion and direct intravascular pressure effects on smooth muscle or mediated via endothelial-derived relaxation factor (ie, NO) and constriction factor (ie, endothelin-1) have been implicated. 1

Autoregulation maintains cerebral blood flow relatively constant between 50 and 150 mm Hg mean arterial pressure. The range is right shifted in chronically hypertensive patients.

The cerebral resistance vessels in normotensive individuals are known to autoregulate across a broad range of mean arterial pressures. Perfusion pressures below the lower limit result in initially increased oxygen extraction from hemoglobin and, subsequently, global ischemia. Pressures above the upper bound may result in breakthrough edema, hemorrhage, seizures, and posterior leukoencephalopathy (ie, hypertensive encephalopathy). The normal autoregulatory curve may be right shifted in chronically hypertensive patients, although the magnitude and duration over which this occurs cannot be determined on an individual basis. Hypertensive animal models have shown impaired endothelium-dependent relaxation in the basilar artery, middle cerebral arteries, and cerebral arterioles compared with controls. Studies have also suggested that this impairment is reversible with blood pressure–lowering therapy. However, the potential for acute hypoperfusion is a concern when initiating blood pressure–lowering treatment, considering the unknown lower limit of an individual hypertensive patient’s autoregulation. Impaired autoregulation and the adverse effects of acute blood pressure lowering have been clearly shown for those with malignant hypertension, although other groups, such as the elderly, those with deep white matter ischemic disease, and those with cognitive impairment, are thought to be at higher risk because of similar, albeit less profound, vascular impairment. 2

In this issue of Hypertension, Zhang et al 3 elaborately investigate the hemodynamic response to blood pressure lowering in those with mild and moderate hypertension. At 2 weeks and 3 months after initiation of therapy, there was no detectable difference in cerebral blood flow and autoregulatory response to orthostatic challenge as assessed with continuous transcranial Doppler ultrasonography of the middle cerebral artery compared with normotensive control subjects. Of note, the hypertensive patients achieved mean 24-hour blood pressure control similar to normotensive patients within the first 2 weeks of therapy. 3 These findings are reassuring given the recommendations for increasingly aggressive therapeutic strategies and treatment goals. 4

These data should be interpreted with caution considering the relatively small sample, young age, and unknown duration of pre-existing hypertension. Although the statistical differences between groups were not significant, individual subject data were not reported. Furthermore, a standardized method for dynamically assessing autoregulation has not been established, limiting direct comparison and interpretation of existing studies. The transcranial Doppler ultrasonography assessment technique allows convenient continuous noninvasive monitoring of flow velocities concomitant with blood pressure monitoring and orthostatic maneuvers. However, using transcranial Doppler ultrasonography mean velocity changes as a surrogate for flow assumes static caliber of the vessel, and current vascular imaging modalities may be insensitive to detection of these small-caliber changes.

Despite these limitations, this study complements and is consistent with previous studies regarding the cerebral hemodynamic affects of blood pressure lowering. Serrador et al, 5 using similar techniques, demonstrated preserved autoregulation with orthostatic challenge (mean arterial pressure decrease: 21 to 25 mm Hg) in elderly subjects age 72±4 years with normotension (mean systolic blood pressure [SBP]: 125 mm Hg), controlled hypertension (SBP: <140 mm Hg at screening mean SBP: 135 mm Hg), and uncontrolled hypertension (SBP: >160 mm Hg at screening mean SBP: 162 mm Hg). In addition, improved cerebral blood flow in elderly uncontrolled hypertensive subjects after 6 months of aggressive blood pressure control has been observed. 6 Another study of patients with and those without clinically silent white matter ischemic lesions demonstrated similar vasomotor responses to acetazolamide challenge despite higher baseline pulsatility in those with white matter lesions, suggesting more resistant vessels. 7

Lastly, consideration must be given to the variable effects on cerebral blood flow of different antihypertensive agents. The cerebral circulation has angiotensin receptors that may account for the improved cerebral blood flow and favorable autoregulatory responses in studies of hypertensive subjects treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. α-Adrenergic innervation of cerebral resistance vessels may result in similar effects from α-antagonists. Calcium channel blockers have variable specificity for cerebral vessels, and studies of β-blockers have shown either no effect on cerebral blood flow or a slight decrease. 8,9

Clearly, long-term blood pressure control is effective for vascular disease prevention, and normal blood pressure should be the treatment goal for most patients. 4 Rapid blood pressure normalization is generally well tolerated for most patients with mild and moderate hypertension. The report of Zhang et al 3 and other studies enhance our understanding of the physiological impact of blood pressure lowering in these groups. Hopefully, ongoing and future studies will clarify treatment strategies for special populations, such as those with cerebrovascular disease, severe hypertension, and cognitive impairment.

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

The type of heart in human is myogenic because the heart beat originates from the muscles of the heart. The nervous and endocrine systems work together with paracrine signals (metabolic activity) to influence the diameter of the arterioles and alter the blood flow. The neuronal control is achieved through autonomic nervous system (sympathetic and parasympathetic).

Sympathetic neurons release norepinephrine and adrenal medulla releases epinephrine. The two hormones bind to β – adrenergic receptors and increase the heart rate. The parasympathetic neurons secrete acetylcholine that binds to muscarinic receptors and decreases the heart beat.

Vasopressin and angiotensin II, involved in the regulation of the kidneys, results in vasoconstriction while natriuretic peptide promotes vasodilation. Vagus nerve is a parasympathetic nerve that supplies the atrium especially the SA and the AV nodes.

Cardiac cycle helps in the circulation of blood. The cardiac cycle is a normal activity of the human heart and is regulated automatically by the nodal tissues – sinoatrial node (SA node) and atrioventricular node (AV node). The variation in the cardiac cycle results in an increase or decrease in the cardiac output

There are two primary modes by which the blood volume pumped by the heart, at any given moment, is regulated:

  • Intrinsic cardiac regulation, in response to changes in the volume of blood flowing into the heart and
  • Control of heart rate and cardiac contractility by the autonomic nervous system.

The failure of the pumping action of the heart, resulting in loss of consciousness and absence of pulse and breathing: a medical emergency requiring immediate resuscitative treatment. cardiac arrest, cardiac pacemaker, cardialgic, Caria. cardiac arrest. n. cardiac inefficacity by cardiac tachycardia.

The rhythmic control of the cardiac cycle and its accompanying heartbeat relies on the regulation of impulses generated and conducted within the heart. Systole occurs when the ventricles of the heart contract and diastole occurs between ventricular contractions when the right and left ventricles relax and fill.

The principal functions of the heart are regulated by the sympathetic and parasympathetic divisions of the autonomic nervous system. In general, the sympathetic nerves to the heart are facilitatory, whereas the parasympathetic (vagus) nerves are inhibitory.

The main purpose of the heart is to pump blood through the body it does so in a repeating sequence called the cardiac cycle. The cardiac cycle is the coordination of the filling and emptying of the heart of blood by electrical signals that cause the heart muscles to contract and relax.

It induces the force of contraction of the heart and its heart rate. In addition, it controls the peripheral resistance of blood vessels. The ANS has both sympathetic and parasympathetic divisions that work together to maintain balance.

One part of the autonomic nervous system is a pair of nerves called the vagus nerves, which run up either side of the neck. These nerves connect the brain with some of our internal organs, including the heart.

Sympathetic efferent nerves are present throughout the atria, ventricles (including the conduction system), and myocytes in the heart and also the sinoatrial (SA) and atrioventricular (AV) nodes.

Heart Beat

The atria and ventricles work together, alternately contracting and relaxing to pump blood through your heart. The electrical system of your heart is the power source that makes this possible.

Your heartbeat is triggered by electrical impulses that travel down a special pathway through your heart:

  1. SA node (sinoatrial node) – known as the heart’s natural pacemaker. The impulse starts in a small bundle of specialized cells located in the right atrium, called the SA node. The electrical activity spreads through the walls of the atria and causes them to contract. This forces blood into the ventricles. The SA node sets the rate and rhythm of your heartbeat. Normal heart rhythm is often called normal sinus rhythm because the SA (sinus) node fires regularly.
  2. AV node (atrioventricular node). The AV node is a cluster of cells in the center of the heart between the atria and ventricles, and acts like a gate that slows the electrical signal before it enters the ventricles. This delay gives the atria time to contract before the ventricles do.
  3. His-Purkinje Network. This pathway of fibers sends the impulse to the muscular walls of the ventricles and causes them to contract. This forces blood out of the heart to the lungs and body.
  4. The SA node fires another impulse and the cycle begins again.

At rest, a normal heart beats around 50 to 99 times a minute. Exercise, emotions, fever and some medications can cause your heart to beat faster, sometimes to well over 100 beats per minute.

How fast does the normal heart beat?

How fast the heart beats depends on the body's need for oxygen-rich blood. At rest, the SA node causes your heart to beat about 50 to 100 times each minute. During activity or excitement, your body needs more oxygen-rich blood the heart rate rises to well over 100 beats per minute.

Medications and some medical conditions may affect how fast your heart-rate is at rest and with exercise.

How do you know how fast your heart is beating?

You can tell how fast your heart is beating (your heart rate) by feeling your pulse. Your heart-rate is the amount of times your heart beats in one minute.

You will need a watch with a second hand.

Place your index and middle finger of your hand on the inner wrist of the other arm, just below the base of the thumb.

You should feel a tapping or pulsing against your fingers.

Count the number of taps you feel in 10 seconds.

Multiply that number by 6 to find out your heart-rate for one minute:

Pulse in 10 seconds x 6 = __ beats per minute (your heart-rate)

When feeling your pulse, you can also tell if your heart rhythm is regular or not.

Normal Heart Beat

1. The SA node sets the rate and rhythm of your heartbeat.

2. The SA node fires an impulse. The impulse spreads through the walls of the right and left atria, causing them to contract. This forces blood into the ventricles.

3. The impulse travels to the AV node. Here, the impulse slows for a moment before going on to the ventricles.

4. The impulse travels through a pathway of fibers called the HIS-Purkinje network. This network sends the impulse into the ventricles and causes them to contract. This forces blood out of the heart to the lungs and body.

5. The SA node fires another impulse. The cycle begins again.

Introduction to the Cardiac Electrical Signal

The heart generates its own electrical signal (also called an electrical impulse), which can be recorded by placing electrodes on the chest. This is called an electrocardiogram (ECG, or EKG).

The cardiac electrical signal controls the heartbeat in two ways. First, since each electrical impulse generates one heartbeat, the number of electrical impulses determines the heart rate. And second, as the electrical signal "spreads" across the heart, it triggers the heart muscle to contract in the correct sequence, thus coordinating each heartbeat and assuring that the heart works as efficiently as possible.

The heart's electrical signal is produced by a tiny structure known as the sinus node, which is located in the upper portion of the right atrium. (The anatomy of the heart's chambers and valves includes two atria at the top of the heart with two ventricles at the bottom.)

From the sinus node, the electrical signal spreads across the right atrium and the left atrium (the top two chambers of the heart), causing both atria to contract, and to push their load of blood into the right and left ventricles (the bottom two chambers of the heart).   The electrical signal then passes through the AV node to the ventricles, where it causes the ventricles to contract in turn.


Physiological data obtained in patients with acute ischemic stroke provide no clear evidence that there are alterations in the intrinsic autoregulatory capacity of cerebral blood vessels. While it is likely safe to modestly reduce blood pressure by 10–15 mm Hg in most patients with acute ischemic stroke, to date there are no controlled trial data to indicate that reducing blood pressure is beneficial. There may be subgroups, such as those with persistent large vessel occlusion, large infarcts or chronic hypertension, in which blood pressure reduction may lead to impaired cerebral perfusion.


The c-FLOW is an ultrasound tagged light based device, which utilizes near infrared laser light (808nm) modulated by low power 1MHz ultrasound, to perform continuous real time blood flow monitoring in the tissue microcirculation. Being a non-invasive device, its sensors are usually placed on the patient’s forehead and provide local microcirculation CBF monitoring in approximately 1cm 3 volume, located 2cm deep underneath them. Due to the use of ultrasound, placement of the sensors on every other location but the forehead requires pre-shaving of the region of interest. The c-FLOW provides a Cerebral Flow Index (CFI) which describes changes in cerebral blood flow in arbitrary units between 0–100, where 0 represents no flow. It is also capable of setting a baseline flow value and presenting the percent flow change from this baseline. Each CFI value represents a moving average of the last 30 seconds of ultrasound tagged near infra red (UT-NIR) signal and is updated every 2–3 seconds. The specifics on how it operates and eliminates the effect of superficial flow are detailed elsewhere[30].

Due to the use of ultrasound and light, the c-FLOW has several inherent limitations. As every other NIR based device, its measurement depth is confined to the cortex only because of light absorption in tissues. In addition, since it includes ultrasound, good coupling between the sensors to the skin is obtained by US gel which has to be renewed every few hours.

To enable autoregulation monitoring, a modified version of the c-FLOW that includes a BP unit was developed, termed c-FLOW-AR. This unit connects to a standard invasive blood pressure (IBP) sensor, and enables tracking MAP concurrently with CFI and display both trends synchronically. The real time combination of these two parameters enables the calculation of a correlation index (termed ARI), which reflects the interrelationship between changes of MAP to those of CFI. ARI values range between 0 to 100, where 0 represents a condition of no correlation between MAP and CFI changes, while 100 represents a perfect one. Accordingly, when cerebral autoregulation is intact, a change in MAP is not followed by a corresponding change of CBF, as the brain autoregulates. In this case, ARI will get lower values (approaching zero). If autoregulation is impaired, it is expected that changes in MAP will cause corresponding changes in CBF and ARI should get higher values.

ARI is calculated only for time intervals in which marked MAP changes exist. Identification of notable MAP changes is obtained by a Relevance Vector Machine (RVM) linear classifier based on the trend slope and derivatives. For all other time intervals, in which MAP is approximately constant, no ARI is calculated. The ARI is therefore the reflection of the autoregulation status, once changes in marked MAP occur.

The ARI value is obtained by calculating the cross correlation maxima in a predetermined time interval (5 minutes). In this interval, the correlation values between CFI and MAP are calculated for all time shifts. They are then multiplied by a time-shift dependent weight function, in which the weight decays as time shift increases, and the maximum obtained value is selected. In this way, the ARI compensates for the intrinsic physiological time delays between changes in systemic blood flow and pressure to those of the brain.

In-vitro experiments

CBF was modeled using a previously described acousto-optic phantom which mimics blood flow in tissues[30, 31]. The phantom is made of Dermasol (CA medical innovations) which is a synthetic polymer matrix soaked with oil. Titanium Dioxide (TiO2) particles (0.1% by weight) were added as light scattering agents. The optical and acoustic properties of the phantom are similar to those of tissue, as detailed in Table 1.

Simulating tissue microcirculation, we designed a Dermasol slab containing 20 hollow parallel channels with an outer diameter of 1mm through which scattering fluid (similar to blood) can flow. A schematic diagram of the experimental set-up is presented in Fig 1.

The C-FLOW’s measuring sensor is placed above the tissue phantom. Flow within the phantom’s tubes is generated using the syringe pump.

Flow within the phantom’s tubes was generated using a calibrated computer-controlled syringe pump (Chemix, Model Infusion 200) and measured using the c-FLOW-AR’s (Ornim Medical, Israel) sensor which was placed above. Though flow within cerebral microcirculation is multidirectional, flow within the phantom’s channels was linear. As the c-FLOW is insensitive to flow direction, this simplified model was sufficient to demonstrate the device’s capabilities.

BP was modeled using a hydraulic pressure system that was able to generate periodical hydrostatic pressure, similarly to blood pressure. The following experimental setup was utilized (Fig 2A).

(A) Schematic illustration of the pressure modeling experimental setup comprising of a water column connected to a computer controlled hydraulic pump and a peristaltic pump. Pressure was measured using a standard disposable pressure transducer (DPT) connected directly to the C-FLOW-AR. (B) An example of a pressure wave generated by the hydraulic pressure system designed to mimic blood pressure. All pressure properties, such as average pressure (MAP), oscillations magnitude (Systolic-Diastolic pressures), and frequency (HR), are controlled and can be predetrmined.

Constant static pressure was created by a water column of a predetermined height (h), as illustrated on the left of Fig 2(A). The height (h) relative to the pressure sensor was digitally changed using a computer controlled hydraulic pump and a pressure controller, thus creating different static pressure levels, corresponding to different MAP values. To create pressure oscillations around the static pressure (pulsatile pressure), the water column was hydraulically connected to a ring-like tube filled with water. A peristaltic pump (MasterFlex L/S easy-load II, model 77200–62) connected to that tube was used to create pressure variations over time. The water column was hydraulically connected to a standard disposable pressure transducer (DPT), similar to the one used in arterial lines (Art-Line TM Biometrix, Israel), and directly connected to the c-FLOW-AR. Example for a pressure wave generated by the described hydraulic pressure system, measured by the c-FLOW-AR is illustrated in Fig 2(B).

A designated LabView® program was used to control both the flow and the pressure systems synchronically. To examine the ARI performance in different AR conditions, the following protocol was applied. Each of the two cFLOW-AR’s sensors was placed on a different acousto-optic flow phantom (depicted in Fig 1) to enable the implementation of different flow protocols to each of the sensors. Average pressure (MAP) was raised and lowered with a notable amplitude change (from 100mmHg to 180mmHg). Flow in phantom number 1 (measured by sensor number 1) was changed in accordance with MAP changes (modeling pressure passive condition), while flow in phantom number 2 (measured by sensor number 2) was kept constant (modeling intact AR). In such a way, both cases of impaired and intact AR were simulated simultaneously (with sensors 1 & 2 respectively).

Mean pressure, flow index and the correlation (ARI) between them were real-time displayed on the C-FLOW-AR’s screen and automatically saved to the device hard drive for post processing purposes. The coefficient of variance was used to estimate the homogeneity of CFI as measured by the two c-FLOW-AR’s sensors and validate the applied flow protocols. ARI values measured for the two different flow protocols were compared using independent t-test. Significance level was defined as α = 0.05.

Preclinical case study

A case study of real-time assessment of a swine autoregulatory state is presented. The procedures were approved by “Asaf Harofe” medical center Institutional Animal Care and Use Committee (IACUC) and conducted in strict accordance with the guideline for animal care and use established by the IACUC.

Animal preparation.

A female piglet (Sus domestica, 2–3 months old), weighing 25.6Kg was anaesthetized with an initial bolus of IM Ketamine, 1.5mg/Kg and Xylazine 2mg/Kg. After induction, the animal was intubated and mechanically ventilated, keeping SaO2 above 93% and ETCO2 at 35–40mmHg. Anesthesia and analgesia was maintained using IV Propofol 0.02–0.1 mg/Kg/min and Fentanyl 0.015 mcg/Kg/min. An arterial line was inserted to the carotid artery for BP monitoring. To avoid hair and enable both sensors adhesion to the skin and good US coupling, the animal’s head was shaved (

10x10cm area) and cleaned with alcohol solution. The skin remained intact with no visible scratches or wounds.


MAP was measured using c-FLOW-AR monitor (Ornim Medical, Israel) via arterial line introduced to the carotid artery. CFI was monitored with a non-invasive sensor (5x2.5x1.5cm) placed on the skin surface of animal’s forehead connected to the c-FLOW-AR. Correlation Index between MAP and CFI (ARI) was calculated in real time and presented on the monitor.

Heart rate and ventilation parameters (respiratory rate, end tidal CO2, arterial saturation) were continuously monitored using non invasive pulse oximetry and capnography (Novametrix, USA).

Experimental procedure.

Cardiac preload, and therefore cardiac output, was optimized using fluid boluses of 5–10 ml/kg, while monitoring BP and PaO2. After MAP stabilization, experiment began. Baseline CFI was recorded for a period of 15–30 minutes prior to starting each manipulation.

To create MAP variations, BP was pharmacologically manipulated. Intravenous (IV) Phenylephrine (50 mcg/ml) was used to increase MAP. Incremental dosages were infused, starting at 2.5 ml/hr and increasing in 2.5 ml/hr every 7–10 minutes, until MAP doubled from baseline. Once targeted MAP was reached, Phenylephrine injection was stopped for 30–60 minutes and a new baseline was acquired.

IV Nitropruside (2 mg/ml) was used to decrease BP. Incremental dosages, starting at 2 ml/hr and increasing in 2 ml/hr were infused every 7–10 minutes, until MAP dropped by 50% or reached 40 mmHg. Once targeted MAP was reached, Nitroprusside stopped for 30–60 minutes allowing the animal to stabilize in a new baseline.

Data Collection.

MAP, CFI, and the calculated correlation index (ARI) were digitally saved to the c-FLOW-AR device. Other physiologic parameters were sampled using a designated LabView program and saved to an excel worksheet for analysis.

Data Analysis.

Changes in CFI were correlated with changes in MAP throughout the monitoring period. To demonstrate the autoregulation assessment ability, CFI was plotted as a function of MAP, to illustrate the AR curve and detect its boundaries (upper and lower limits). The slope and 95% confidence interval (CI) between MAP and CFI was calculated for the two MAP regions.

ARI values were binned into groups according to their corresponding MAP values (10mmHg segments). Averaged values for each bin were presented using a columns diagram. Receiver Operating Curve (ROC) analysis was used to estimate the ARI performance in classifying MAP as under or over the limits of autoregulation.

Analyses were carried out using SPSS 23.0.01 and Matlab R2014a (


Department of Chronomics and Gerontology, Tokyo Women’s Medical University, Tokyo, Japan

Department of Integrative Biology and Physiology, Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA

Kuniaki Otsuka & Germaine Cornelissen

Department of Medicine, Tokyo Women’s Medical University, Medical Center East, Tokyo, Japan

Yutaka Kubo, Mitsutoshi Hayashi, Naomune Yamamoto & Koichi Shibata

Space Biomedical Research Group, Japan Aerospace Exploration Agency, Tokyo, Japan

Daniele Catalucci

Our lab aims to dissect the molecular mechanisms underlying cardiac diseases, to increase our knowledge about the function of the physiologic vs pathologic heart, and to develop novel and more effective therapeutic approaches for the treatment of the failing heart. To achieve this goal, we use multidisciplinary methodologies encompassing molecular and cellular biology, biochemistry, single- and multiple-cell functional assay, microscopy, nanotechnology, aptamer technology, and experimental models of cardiac disease.

Molecular mechanisms for the regulation of cardiac muscle contraction: remodeling of calcium handling, signal transduction, and identification of new therapeutic drugs.

The proper excitation and contraction of the heart is governed by the L-Type Calcium Channel (LTCC) complex, a pivotal trigging player of the so-called Calcium Induced Calcium Release (CICR) mechanism in cardiac cells. Several acquired and genetic based conditions of cardiac pathologies are causally associated to alterations of the LTCC protein density and function. Our team studies the molecular mechanisms contributing to LTCC defects and aims to identify and design new LTCC-targeting molecules with therapeutic properties.

Maintenance of calcium (Ca2+) homeostasis is critical for preserving the physiology of the heart. Complex mechanisms intervene in the regulation of intracellular levels of Ca2+ and of its compartmentalization between the cytosol and the sarcoplasmic reticulum (SR). Ca2+ release from the SR, the major intracellular Ca2+ store, to the cytosol is regulated through CICR, which triggers the release of Ca2+ from the SR to the cytoplasm through the ryanodine receptor (RyR). A close association between LTCCs and RyRs is required for efficient CICR and is dependent on the density of LTCCs within the T-tubular invagination of the plasma membrane. The increase in free intracellular Ca2+ allows Ca2+ to bind to troponin C, initiating muscle contraction. This is subsequently terminated by the removal of cytosolic Ca2+ through its reuptake into the SR via the cardiac SERCA and, to a lesser extent, by other transport systems. This process is a major regulator of cardiac excitation-contraction coupling, and a major determinant for intrinsic properties of the heart for physiological roles. The LTCC, and thus Ca2+ handling, has also been associated with the modulation of cell structural integrity and gene expression, critical processes during heart development and physiology, which are deregulated in cardiovascular pathologies. As such, factors influencing the expression, half-life, subcellular trafficking, dynamics, and gating of LTCCs are key determinants for the function and structural integrity of cardiac cells both in physiology and disease. A central focus of the lab is the in-depth understanding of the mechanisms underlying LTCC life cycle and function and to address fundamental questions related to translational applications of regulation of the LTCC and its molecular chaperone, Cavβ2, in cardiac physiology, development, and disease.

Biomimetic nanoparticle formulations for cardiac-specific drug delivery.

The difficulties associated with the use of conventional pharmacological therapies (i.e. drug instability, insufficient efficacy, collateral side effects due to unspecific tissue targeting, and invasive drug administration in end-stage disease) drastically challenge the therapeutic management of cardiac diseases. Our lab aims to establish an unconventional and novel effective strategy for non-invasive (via inhalation) nanoparticle-based delivery of therapeutic biomolecules to the diseased heart.

Heart failure (HF) is a disorder of the heart resulting from an impaired ability of the cardiac muscle to pump sufficient blood to the body. This leads to an “unmatching” between oxygen needs and its consumption in peripheral tissues, ultimately resulting in loss in quality of life. Despite improvements in care, 1-year mortality rates for HF patients remain high, and up to 1 in 4 of HF patients die within 1 year, dependent on the stage of the disease at the time point of diagnosis. In addition, mortality rates in HF are high even for patients compliant with the best available treatments. As such, new approaches for safe, efficient, and cardiac-specific delivery of therapeutic drugs are strongly required. The lab is working for the development of innovative bioinspired and self- assembling nanoparticle formulations for drug delivery, which are i) biocompatible and biodegradable, ii) designed for crossing biological barriers, iii) specifically guidable to the target site, and iv) properly designed for a non-invasive therapeutic approach, which is “patient-friendly” (easy to administer) and thus facilitates the patient compliance (adherence to the treatment plan).

Selected Publications

Daniele Catalucci Publications

Selected Publications (20-25 publications listed in details with all the contributing authors, title of the papers, journal, dates): Cardiovascular nanomedicine: the route ahead. Iafisco M, Alogna A, Miragoli M, Catalucci .

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