Why the patient's murmur can be heard at other listening posts

Pathophysiology of Heart Disease by Leonard S. Lilly 

ECG Changes in Right and Left Bundle Branch Blocks

In right bundle branch block (RBBB), normal depolarization of the right ventricle is interrupted. In this case, initial depolarization of the ventricular septum (which is stimulated by a branch of the left bundle) is unaffected so that the normal small R wave in lead V1 and small Q wave in lead V6 are recorded. As the wave of depolarization spreads down the septum and into the left ventricular free wall, the sequence of depolarization is indistinguishable from normal, because left ventricular forces normally outweigh those of the right. However, by the time the left ventricle has almost fully depolarized, slow cell-to-cell spread has finally reached the “blocked” right ventricle and depolarization of that chamber begins, unopposed by left ventricular activity (because that chamber has nearly fully depolarized). This prolonged depolarization process widens the QRS complex and produces a late depolarization current in the direction of the anteriorly situated right ventricle. Since the terminal portion of the QRS complex in RBBB represents these right ventricular forces acting alone, the ECG records an abnormal terminal upward deflection (known as an R′ wave) over the right ventricle in lead V1 and a downward deflection (S wave) in V6 on the opposite side of the heart. The appearance of the QRS complex in lead V1 in RBBB (upward R, downward S, then upward R′) is often described as having the appearance of “rabbit ears.” 

Left bundle branch block (LBBB) produces even more prominent QRS abnormalities. In this situation, normal initial depolarization of the left septum does not occur; rather, the right side of the ventricular septum is first to depolarize, through branches of the right bundle. Thus, the initial forces of depolarization are directed toward the left ventricle instead of the right (see Fig. 4-19B; see also Fig. 4-30). Therefore, an initial downward deflection is recorded in V1, and the normal small Q wave in V6 is absent. Only after depolarization of the right ventricle does slow cell-to-cell spread reach the left ventricular myocytes. These slowly conducted forces inscribe a widened QRS complex with abnormal terminally upward deflections in the leads overlying the left ventricle (e.g., V5 and V6),

Lung Cancer Image

Lung Cancer, CT scan with 3D reconstruction, presents dry cough and left chest pain.

https://app.figure1.com/images/56b67fefbb09089d1f2310d4

Licorice

Stewart et al.4 have proposed that licorice acts by inhibiting Cortisol oxidase, a component of the widely distributed 11β-hydroxysteroid dehydrogenase system that converts Cortisol to cortisone, producing a state of apparent mineralocorticoid excess similar to that in children with 11/3-hydroxysteroid dehydrogenase deficiency5 (Fig. 1FIGURE 1Overview of Cortisol Metabolism.). In vitro, cortisol has the same binding affinity for mineralocorticoid receptors as aldosterone,6whereas that of cortisone is much less. Licorice, by inhibiting 11β-hydroxysteroid dehydrogenase in aldosterone-responsive tissues such as the kidney, where it is found in high concentrations,7 , 8 produces high renal levels of cortisol, which then binds to and activates mineralocorticoid receptors.4 The degree to which licorice inhibits 11β-hydroxysteroid dehydrogenase activity can be measured by examining the ratio of the metabolites of cortisone to those of cortisol in urine.

Heart Failure - Bowditch Phenomenon

Cardiovasc J Afr. 2009 Feb; 20(1): 37–38.

From Bowditch to beta-blockers: evolution of the understanding of the importance of heart rate and myocardial energetics in cardiomyopathy

James Ker, MB ChB, MMed, MRCP, PhD, FESC, FACC, L Akad SA

Author information ► Article notes ► Copyright and License information ►

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Summary

Summary

During the past three decades, every aspect of cardiomyopathy has undergone dramatic change. When examining the literature on the physiological aspects of the failing heart, one immediately recognises that South Africa has made a contribution: Brink, Bester and Lochner evaluated the possible therapeutic aspects of the Bowditch phenomenon and myocardial energetics in cardiomyopathy almost four decades ago, at a time when the condition even had another name, myocardiopathy.

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Summary

All aspects of cardiomyopathy – from our knowledge on ultra-structural and physiological alterations, to pharmacological approaches to therapy, surgical treatment modalities and later device-based therapies – have undergone dramatic changes during the last three decades. Even the terminology has changed. If one scrutinises articles from the 1950s to the 1970s one will find that the preferred term then was ‘myocardiopathy’.

When analysing the progression of knowledge on the physiology of the failing heart that has made an impact on therapeutic advances over the past 30 years, I am proud to state that South Africa has made a contribution. In 1972, the following article by Brink, Bester and Lochner appeared:1 A comparison of stimulation frequency and electro-augmentation on myocardial function, extensibility, coronary flow rate, oxygen consumption and glucose metabolism.

Thirty years later, we would see dramatic paradigm shifts regarding the importance of heart rate in cardiomyopathy. Today we understand the importance of heart rate variability and heart rate turbulence as prognostic markers in various cardiovascular disorders and we have conclusive evidence from clinical trials that reducing heart rate in cardiomyopathy confers a survival advantage.

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The Bowditch phenomenon

When cardiac myocytes are stimulated at faster rates, they increase their force of contraction.2 This ability of the vertebrate heart is central to survival and is known as the Bowditch phenomenon. 2,3 It is also known as the ‘treppe’ or staircase phenomenon.

Henry Pickering Bowditch, famed physiologist (nephew of the well-known Boston physician Henry Ingersoll Bowditch) and later dean of Harvard Medical School,4 published his classic article in 1871, describing the positive inotropic response of the heart when the heart rate increases. The next 100 years would see many articles examining the response of the myocardium to various stimulation frequencies, effected by electrical devices external to the heart.2

It would be many years after Bowditch’s article before it became apparent that the failing heart behaves very differently to an increase in heart rate. The failing heart does not exhibit a Bowditch phenomenon – there is no increase in the inotropic response to an increase in heart rate,5-7 with some failing hearts even exhibiting a reverse Bowditch response. It was during this era that the article by Brink et al.1 raised the issue that it was doubtful whether the phenomenon of increasing heart rate could be used for therapeutic purposes in the failing heart. Today we have ample clinical and laboratory evidence that reducing the heart rate improves the prognosis of patients with heart failure.

In 1967, Brink et al.8 published an article on the work performance of the isolated, perfused, beating heart in Syrian hereditary cardiomyopathic hamsters. In 2007, exactly 40 years later, work on similar Syrian cardiomyopathic hamsters clearly demonstrated that the chronic administration of carvedilol (a beta-blocker) improved cardiac function.9 This was in striking contrast to the line of thought in 1972, when the Bowditch staircase phenomenon was being explored as a possible therapeutic modality in heart failure. Already in 1972, work by Brink et al.1 had raised the question that this would not be a viable therapeutic option, thus paving the way for a major paradigm shift and the current therapeutic knowledge to use beta-blockers in heart failure patients.

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The failing heart as ‘an engine out of fuel’

Another important concept realised today in ‘modern’ cardiology is that the failing heart, as opposed to the normal heart, can be viewed as ‘an engine out of fuel’.10 In 1939, Herrmann and Decherd11 published an article on the chemical nature of heart failure. However, interest waned over the next few decades, only to be revived in the 2000s with Taegtmeyer12 elegantly summarising the situation as: ‘Metabolism – the lost child of cardiology’.

The human heart displays an enormous energy requirement – 6 kg of ATP every day.10 If this requirement is not met, it will result in the reduction of mechanical energy delivered to the actin–myosin interaction process and a drop in the contractile ability of the myocardium. However, we still do not possess an accurate method for determining the levels of ATP and phosphocreatine near the sarcoplasmic reticulum in the intact, in vivo human heart – they are extrapolated from global measurements using 18F-FDG PET imaging.10

Already in their 1972 article, Brink, Bester and Lochner1 had realised the importance of ‘myocardial energetics’,10 and glucose uptake and lactate production were analysed when evaluating the Bowditch phenomenon in the isolated, perfused rat heart. Unfortunately, in this case scenario, more than 30 years later we still do not possess the ideal, reliable way to measure myocardial energetics where we need to – in the peri-myofibrillar space, near the sarcoplasmic reticulum and sarcolemmal ion pumps.10

Therefore, I conclude that this historical article by Prof AJ Brink et al.1 was one of the bricks that paved the way to the current understanding and use of beta-blockers in patients with heart failure and, furthermore, that it should also be an inspiration to find new and better methods for measuring ‘myocardial energetics’ – cardiology’s lost child, in order to find a whole new therapeutic armamentarium to treat the ‘engine out of fuel’.

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References

1. Brink AJ, Bester AJ, Lochner A. A comparison of stimulation frequency and electro-augmentation on myocardial function, extensibility, coronary flow rate, oxygen consumption and glucose metabolism. Eur J Clin Invest. 1972;2(4):250–258. [PubMed]

2. Lakatta EG. Beyond Bowditch: the convergence of cardiac chronotropy and inotropy. Cell Calcium.2004;35:629–642. [PubMed]

3. Piot C, Lemaire S, Albat B, Seguin J, Nargeot J, Richard S. High frequency-induced upregulation of human cardiac calcium currents. Circulation. 1996;93(1):120–128. [PubMed]

4. Putnam JJ, Henry P. Bowditch dead. The Harvard Crimson. 1911 Mar 14;

5. Hajdu S, Posner CJ. Absence of Bowditch phenomenon in the ventricular muscle of hamsters with hereditary cardiomyopathy. Am Heart J. 1971;81(6):781–789. [PubMed]

6. Mulieri LA, Hasenfuss G, Leavitt B, Allen PD, Alpert NR. Altered myocardial force-frequency relation in human heart failure. Circulation. 1992;85:1743–1750. [PubMed]

7. Feldman MD, Alderman JD, Aroesty JM, Royal HD, Ferguson JJ, Owen RM. et al. Depression of systolic and diastolic myocardial reserve during atrial pacing tachycardia in patients with dilated cardiomyopathy. J Clin Invest. 1988;82:1661–1669. [PMC free article] [PubMed]

8. Brink AJ, Lochner A. Work performance of the isolated perfused beating heart in the hereditary myocardiopathy of the Syrian hamster. Circulation Res. 1967;XXI:391–401. [PubMed]

9. Cruz N, Arocho L, Rosario L, Crespo MJ. Chronic administration of carvedilol improves cardiac function in 6-month-old Syrian cardiomyopathic hamsters. Pharmacology. 2007;80:144–150. [PubMed]

10. Neubauer S. The failing heart – an engine out of fuel. New Engl J Med. 2007;356(11):1140–1151.[PubMed]

11. Herrmann G, Decherd GM. The chemical nature of heart failure. Ann Int Med. 1939;12:1233–1244.

12. Taegtmeyer H. Metabolism – the lost child of cardiology. J Am Coll Cardiol. 2000;36:1386–1388.[PubMed]

Cardiovascular in the News

Fit Young Woman Having Strokes -Why

Adrenergic effects with normal baroreceptor reflex

Notice:  norepinephrine causes an increase on heart rate and blood pressure and PVR as a direct effect on the heart and vessels.  BUT, the increase in pressure triggers the barorecptor reflex leading to a decreased heart rate.

SO, you always need to know whether you are considering the direct effect versus the response in the presence of reflex controls.  😎

Dromotropy

cvpharmacology.com

Regulation of Conduction

The conduction of electrical impulses throughout the heart, and particularly in the specialized conduction system, is influenced by autonomic nerve activity. This autonomic control is most apparent at the AV node. Sympathetic activation increases conduction velocity in the AV node by increasing the rate of depolarization (increasing slope of phase 0) of the action potentials. This leads to more rapid depolarization of adjacent cells, which leads to a more rapid conduction of action potentials (positive dromotropy). Sympathetic activation of the AV node reduces the normal delay of conduction through the AV node, thereby reducing the time between atrial and ventricular contraction. The increase in AV nodal conduction velocity can be seen as a decrease in the P-R interval of the electrocardiogram.

Sympathetic nerves exert their actions on the AV node by releasing the neurotransmitter norepinephrine that binds to beta-adrenoceptors, leading to an increase in intracellular cAMP. Therefore, drugs that block beta-adrenoceptors (beta-blockers) decrease conduction velocity and can produce AV block.

Parasympathetic (vagal) activation decreases conduction velocity (negative dromotropy) at the AV node by decreasing the slope of phase 0 of the nodal action potentials. This leads to slower depolarization of adjacent cells, and reduced velocity of conduction. Acetylcholine, released by the vagus nerve, binds to cardiac muscarinic receptors, which decreases intracellular cAMP. Excessive vagal activation can produce AV block. Drugs such as digitalis, which increase vagal activity to the heart, are sometimes used to reduce AV nodal conduction in patients that have atrial flutter or fibrillation. These atrial arrhythmias lead to excessive ventricular rate (tachycardia) that can be suppressed by partially blocking impulses being conducted through the AV node.

Phase 0 of action potentials at the AV node is not dependent on fast sodium channels as in non-nodal tissue, but instead is generated by the entry of calcium into the cell through slow-inward, L-type calcium channels. Blocking these channels with a calcium-channel blocker such as verapamil or diltiazem reduces the conduction velocity of impulses through the AV node and can produce AV block.

Because conduction velocity depends on the rate of tissue depolarization, which is related to the slope of phase 0 of the action potential, conditions (or drugs) that alter phase 0 will affect conduction velocity.  For example, conduction can be altered by changes in membrane potential, which can occur during myocardial ischemia and hypoxia. In non-nodal cardiac tissue, cellular hypoxia leads to membrane depolarization, inhibition of fast Na⁺ channels, a decrease in the slope of phase 0, and a decrease in action potential amplitude. These membrane changes result in a decrease in speed by which action potentials are conducted within the heart. This can have a number of consequences. First, activation of the heart will be delayed, and in some cases, the sequence of activation will be altered. This can seriously impair ventricular pressure development. Second, damage to the conducting system can precipitate tachyarrhythmias by reentry mechanisms. Click here to learn more about altered impulse conduction. 

Antiarrhythmic drugs such as quinidine (a Class IA antiarrhythmic) that block fast sodium channels cause a decrease in conduction velocity in non-nodal tissue.

baroreceptors & chemoreceptors innervation

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Class of 2020 Exam Question Contest

Merry Christmas

Merry Christmas

&

Happy New Year

from Steve & Linda Wood

Cardiac Cycle Tutorial

click on:

Cardiac Cycle Tutorial

Evidence Based Medicine

Evidence Based Medicine

How to Write Learning Objectives, USMLE Step 1 MCQs, and Confidence Based Practice Questions

click below for slides

How to Write Learning Objectives, USMLE Step 1 MCQs, and Confidence Based Practice Questions

2016/17

Steve Wood, PhD

How to Study in Medical School

How to Study in Medical School

What worked in undergraduate school (did well on the exam but forgot the material quickly) which was OK because you didn't need to use it again: Cram

What you need to do in medical school (do well on the exam AND remember the material for other modules and for Step1): study and re-study!


No pain, No gain (applies to learning too)

Use all the learning styles (even if they are not your preferred style)

Respiratory Failure

Respiratory Failure

Memory Tool:  Type 2 = CO2

Excerpts from the novel "Oxygen"

The entire complex human machine pivots on the pinnacle of oxygen. The bucket brigade of energy metabolism that keeps us all alive ends with oxygen as the final electron acceptor. Take it away, and the cascade clogs up in minutes, backing up the whole precisely tuned engine until it collapses, choked, cold and blue. 

Two portals connect us to oxygen—the mouth and the nose—appreciated more for all their other uses: tasting, smelling, smiling, whistling, blowing smoke and blowing kisses, supporting sunglasses and lipstick designers, perfumeries and plastic surgeons. Seal them for the duration of the morning weather report and everything you had planned for the rest of your life evaporates in a puff of imagination.



From the novel, Oxygen
By Carol Wiley Cassella, MD

Venn Diagrams for Medical Students

Step 1 Practice Questions

1. A 12-year-old male refugee from Haiti is being examined by a physician working for Médecins sans frontières.  Auscultation of the heart reveals no audible sounds but pulse exam in normal.  Electrocardiogram is normal except for an extreme axis deviation. Chest X-ray was obtained (see figure). Which of the following is a complication of this condition that the patient is most likely to develop?



A. Bronchiectasis
B. Heart failure
C. Mitral valve prolapse
D. Pneumothorax
E. Small bowel obstruction

History of Blood Pressure Measurement

Hall, W. D. (1987). "Stephen Hales: theologian, botanist, physiologist, discoverer of hemodynamics". Clinical Cardiology. 10 (8): 487–9.

Reverend Stephen Hales was the first person to measure blood pressure.  He did this in 1733 using a glass tube inserted in the carotid artery of a sedated horse.  The artist chose to depict the tube coming out of the horse's neck but it was actually in the groin:  “In December I caused a mare to be tied down alive on her back … having laid open the left crural artery about three inches from her belly, I inserted into a brass pipe whose bore was one-sixth of an inch in diameter and to that by means of another brass pipe which was fitly adapted to it, I fixed a glass tube of nearly the same diameter which was nine feet in length. Then , untying the ligature on the artery, the blood rose in the tube to eight feet in length, three inches perpendicular above the level of the left ventricle of the heart”.

8 feet 3 inches = 99 inches of blood = 185 mmHg blood pressure

Water Movement across Membranes

'Fluid Physiology' by Kerry Brandis -from http://www.anaesthesiaMCQ.com

Fluid Physiology

1.2 Water Movement across Membranes

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1.2.1 Pathways for Water Movement

Oil & water don't mix

Water and lipids are the two major types of solvent in the body. The lipid cell membrane separates the intracellular fluid from the extracellular fluid (as discussed in Section 2.1). Substances which are water soluble typically do not cross lipid membranes easily unless specific transport mechanisms are present. It might be expected that water would likewise not cross cell membranes easily. Indeed, in artificial lipid bilayers, water does not cross easily and this is consistent with our expectation.

. . . but paradoxically, water crosses nearly all the membranes in the body with ease!

Two questions spring immediately to mind:

• How can this be so?
• How does it happen? (ie. What is the route & mechanism by which water crosses membranes?)

The answer to this problem:

Water molecules cross cell membranes by 2 pathways which we can call the lipid pathway & the water channel pathway.

What is the 'lipid pathway'?

This refers to water crossing the lipid bilayer of the cell membrane by diffusion. This initially does not seem to be very credible based on the 'oil & water don't mix' idea BUT it is nonetheless extremely important because this pathway is available in ALL cells in the body.

To express this slightly differently: The 'oil & water don't mix' idea can be quantified as the partition coefficient (i.e., concentration of water in the lipid phase to the concentration in the aqueous phase). This partition coefficient is as expected, extremely low: about 10-6 which is 1 to a million.

Now there are a couple of other equally important facts to consider:

• the concentration of water in water is extremely high
• the surface area of the cell membrane is very large (relative to the contained volume)

These factors must be included when considering diffusion across the membrane (as quantified by Fick's law of Diffusion) and they significantly counteract the the very low permeability.

The lipid composition of different cell membranes varies so the rate of fluid flow across cell membranes does vary.

What is the 'water channel' pathway?

In some membranes the water flux is very high and cannot be accounted for by water diffusion across lipid barriers. A consideration of this fact lead to the hypothesis that membranes must contain protein which provide an aqueous channel through which water can pass. The water channels have now been found and are discussed below. Flow of water through these channels can occur as a result of diffusion or by filtration.

What other factors are important for the passage of water across membranes?

The above discussion refers to water moving from one side of a lipid barrier to the other and this is relevant to the cell membrane. Other 'membranes' need to be considered; in particular the capillary membrane & the lymphatic endothelial membrane. These are tubular sheets of very many endothelial cells, each with their own cell membrane, but also with a potential pathway for water & solutes existing at the junction of adjacent cells. Similarly all epithelial cell layers can be considered as 'membranes' through which water passes and these also have intercellular pathways.

1.2.2 Capillary Membranes

Water can cross capillary membranes via:

• the intercellular gaps between the endothelial cells
• pores in the endothelial cells special areas where the cytoplasm is so thinned out that it produces deficiencies known as fenestrations.
• diffusion across the lipid cell membranes of the endothelial cells

Intercellular slits in the capillary membrane have a diameter of about 7 nm which is much larger than the 0.12 nm radius of a water molecule. Because the total surface area of the body’s capillaries is huge (6,300 m2) and their walls are thin (1 mm), the total diffusional water flux across the capillaries in the body is very large indeed. (See Section 4.1). Normally this diffusional exchange does not represent any net flow in either direction because the water concentration on both sides of the capillary membrane is the same.

Fenestrations are found only in capillaries in special areas where a very high water permeability is necessary for the function of these areas. A high water permeability is clearly necessary in the glomerular capillaries and water permeability here is very much higher than in muscle capillaries. Other areas with fenestrations are the capillaries in the intestinal villi and in ductless glands.

Water also easily enters the lymphatic capillaries via gaps between the lymphatic endothelial cells. These gaps function also as flap valves and this also promotes forward lymph flow when the capillaries are compressed.

In other areas of the body the water permeability of capillary membranes is quite low. An example is the blood-brain barrier. The capillary endothelial cells here are joined by tight junctions which greatly limit water movement by the intercellular pathway.

1.2.3 Aquaporins: Cell Membrane Water Pores

The presence of specific pores (channels) in the cell membrane has long been predicted but the proteins involved in these water channels have only recently been characterised. At present at least 6 different water channel proteins (named aquaporins) have been found in various cell membranes in humans. These aquaporin proteins form complexes that span the membrane and water moves through these channels passively in response to osmotic gradients. These channel proteins are present in highest concentrations in tissues where rapid transmembrane water movement is important (eg in renal tubules).

Aquaporin 0 is found in the lens in the eye. It has a role in maintaining lens clarity. The gene for this protein is located on chromosome 12.

Aquaporin 1 (previously known as CHIP28) is present in the red cell membrane, the proximal convoluted tubule and the thin descending limb of the Loop of Henle in the kidney, secretory and absorptive tissues in the eye, choroid plexus, smooth muscle, unfenestrated capillary endothelium, eccrine sweat glands, hepatic bile ducts and gallbladder epithelium. The Colton blood group antigen is located on extracellular loop A of aquaporin 1 in red cells. The gene is located on chromosome 7.

Aquaporin 2 is the ADH-responsive water channel in the collecting duct in the inner medulla. Insertion of the channel into the apical membrane occurs following ADH stimulation. The gene is located on chromosome 12.

Aquaporins 3 and 4 are present in the basolateral membrane in the collecting duct. They are not altered by ADH levels. Recently, aquaporin 4 has been found in the ADH-secreting neurones of the supraoptic and paraventricular nuclei in the hypothalamus and it has been suggested that it may be involved in the hypothalamic osmoreceptor which regulates body water balance. (See Section 5.3). The gene for aquaporin 3 is located on chromosome 7.

Aquaporin 5 is found in lacrimal and salivary glands and in the lung. It may be the target antigen in Sjogren’s syndrome.

The aquaporins all have a similar topology consisting of 6 transmembrane domains

Aquaporin research is currently an active field. These proteins have been identified in all living organisms. New aquaporin inhibitors may prove to be useful diuretic agents. Mercurial compounds used to treat syphilis were noted in 1919 to have a diuretic action. More potent mercurial diuretics were subsequently developed and were once used widely until replaced by less toxic diuretics. These mercurial diuretics act by binding to a specific site on aquaporin 2 with blocking of renal water reabsorption. (See Section 5.6)

1.2.4 Effect on Cell Volume

The movement of water across cell membranes is essential for cellular integrity but can cause problems. A small difference in solute concentration results in a very large osmotic pressure gradient across the cell membrane and the cell membranes of animal cells cannot withstand any appreciable pressure gradient. Water movement can eliminate differences in osmolality across the cell membrane but this alone is itself a problem as it leads to alteration in cell volume. Consequently regulation of intracellular solute concentration is essential for control of cell volume.

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'Fluid Physiology' by Kerry Brandis -from http://www.anaesthesiaMCQ.com