Function of papillary muscle

During ventricular filling, the papillary muscles are relaxed and the AV valves are opened by the pressure gradient between the atrium and the respective ventricle.

This illustration may be helpful: http://www.youtube.com/watch?v=rgY7Ic_9K0M

At the start of ventricular systole, contraction of the papillary muscles tenses the chordae tendineae, and causes the AV valves to shut (S1).  This minimizes regurgitation of blood into the atrium during ventricular contraction.

When both papillary muscles are damaged in the left ventricle (such as by papillary muscle infarction), the clinical consequence is typically mitral regurgitation.

Poorly contracting papillary muscles (in the left ventricle) may allow the cusps of the mitral valve to prolapse into the left atrium during left ventricular systole.  When the leaflets of the valve prolapse into the atrium, the inner margins of the cusps are further separated making regurgitation more likely.

Of course, additional factors may contribute to mitral regurgitation depending on the presence of other predisposing factors. For example, an abnormally dilated left ventricle may widen the mitral valve annulus, and regurgitation can occur in the absence of pathology in the mitral (or tricuspid) valve per se.  This phenomenon is called “functional” regurgitation.

Does hyperkalemia prolong ventricular repolarization?

Potassium efflux is the major mechanism of repolarization of ventricular myocytes.  This current is sensitive to extracellular potassium level, and in hyperkalemia, potassium conductance is increased so that more potassium leaves the myocyte in any given time period.  This leads to an increase in the slope of phases 2 and 3 of the action potential and a shortening of the repolarization time.  This is thought to be the mechanism responsible for some of the early electrocardiographic manifestations of hyperkalemia, such as ST-T segment depression, peaked T waves, and Q-T interval shortening.

See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413606/

Normal intrinsic heart rate in humans

Jose and Collison (1970) defined <strong>“intrinsic heart rate (IHR)”</strong>, as the heart rate under the simultaneous presence of the nonselective β-adrenoceptor antagonist propranolol (0.2 mg/kg) and the muscarinic receptor blocker atropine (0.04 mg/kg) 5 min after these injections, and this definition continues to be used in mainstream cardiology literature.  In their study of over 400 apparently healthy human subjects age (ranging from 18-60 yr) intrinsic heart rate of the SA node in humans ranged from 80-120 (mean 104) beats per minute.  Another important observation they made was a reduction in intrinsic heart rate with age.  Based on their data, the relationship between age and IHR was as follows:

IHR = 118 – (age * 0.57); even for someone 60 years old, IHR would be 80 bpm.

If resting HR is lower (as it is in most healthy individuals) than an individual’s intrinsic HR, it means that, at rest, vagal influences dominate over sympathetic influences on the SA node’s intrinsic firing rate.

Sick sinus syndrome (or sinus node dysfunction) is by definition an abnormally low “intrinsic heart rate”.  Someone with an intrinsic sinus rate of 60 bpm would likely be very prone to the consequences of bradycardia (low cardiac output and hypotension and its consequences).

The “intrinsic rate” of the AV node or the Purkinje system is not as easily determined in healthy humans and indirect electrophysiologic methods are used, but it is true that even with autonomic support AV nodal firing frequency is significantly lower than that of the SA node. That is why the SA node normally is the pacemaker.  Similarly, even with sympathetic stimulation, an infranodal rhythm originating in the Purkinje system may result in a ventricular rate as low as 20 bpm (but this rate is not to be called intrinsic rate of the Purkinje system).

If you encounter someone with a resting heart rate of say 40-50 bpm, there are only two broad possibilities:
– Increase in vagal tone;
– Abnormally low intrinsic heart rate (and or disease of the cardiac conduction system);

Individuals whose low resting HR is as low as 40 bpm because of heightened vagal tone at rest may be going about their work as usual (example, well trained athletes), because they have a larger stroke volume.  On the other hand someone whose resting HR is 40 bpm because of sinus node dysfunction or disease of the conduction system will be very vulnerable to hypotension from low cardiac output.

Dissecting these two possibilities in an individual with bradycardia (HR &lt; 60 bpm) is usually achieved clinically by asking the question: HR is low – so what? Is there any evidence of cerebral hypoperfusion because the HR is as low, and with an EKG.  Someone with bradycardia due to sinus node dysfunction is less likely to demonstrate significant sinus arrhythmia (one can assess this by checking the ECG during deep breathing); normally, during deep inspiration, cardiac acceleration is apparent, and the heart rate decreases during deep expiration.  On the other hand an athlete with sinus bradycardia will have profound respiratory sinus arrhythmia (and this is a normal phenomenon  brought about by fluctuations in vagal nerve traffic to the heart with breathing).

If further evidence is needed, the response to an intravenous bolus of atropine will provide the answer.  If the resting bradycardia is due to high vagal tone, the response to atropine will consist of a profound increase in HR 20 bpm or greater.  On the other hand if bradycardia were due to SA nodal dysfunction, the heart rate increment with atropine will be negligible (not exceed 5 bpm).

 

How is the oropharyngeal phase of swallowing clinically evaluated?

See this video clip http://www.nature.com/gimo/contents/pt1/images/gimo19-v3.mov

It is a videofluoroscopic study of the oropharyngeal phase of swallowing that shows aspiration of barium sulfate into the trachea. Patients with strokes affecting the medulla, myasthenia gravis, or motor neuron disease may have defects in swallowing that increase the likelihood of aspiration pneumonia.

The link between GERD and asthma

What is the evidence on the link between gastroesophageal reflux disease (GERD) and asthma, and cough due to GERD?

Microaspiration of the gastroesophageal refluxate into the airways is an important mechanism of airway symptomatology (cough, wheeze) secondary to GER.  But with regard to reflex mechanisms inducing cough and or bronchospasm without micro- or macroaspiration, there is evidence for the presence of an active vagally mediated esophageal-bronchial reflex.  Instillation of acid into the lower esophagus has been demonstrated to increase airway resistance and result in cough in the absence of radiologic evidence of aspiration.  This response is abolished with blockade of afferent signaling from the lower end of the esophagus.  The tracheobronchial tree and esophagus share origins from an embryologic standpoint with autonomic innervation through the vagus nerve [Sontag and Harding, 2006].

Sontag SJ and Harding SM.</strong> Gastroesophageal reflux and asthma. GI Motility Online 2006 http://www.nature.com/gimo/contents/pt1/full/gimo47.html

Interaction between heart rate, rhythm and ventricular filling

At least in healthy adult humans at rest, about 80% of ventricular filling is complete by the time atria contract. By definition, duration of diastole and consequently the time available for ventricular filling is reduced with a progressive elevation in HR, and the question in any situation therefore is how this might affect ventricular filling. During dynamic exercise in healthy adult humans, an increase in HR typically does not reduce ventricular filling as long as the rhythm is sinus and HR reaches about 180 bpm; rather, it is associated with an increase in ventricular filling (compared to baseline) providing that the rhythm is sinus and venous return is maintained or increased. An increase in SV is also made possible under these conditions by one or more of the following mechanisms acting in concert.

i) an increase in sympathetic outflow to the heart is normally associated with a positive lusitropic effect (i.e., acceleration of the rate of relaxation of ventricular myocardial cells) besides an increase in HR and an increase in the speed of conduction of cardiac impulse;

ii) an increase in HR in the 60-120 bpm range is typically associated with an increase in force of contraction secondary to an increase in intracellular calcium (frequency-force relationship or Treppe effect) providing that venous return is not affected;

iii) the sympathoexcitation that occurs during exercise also facilitates venous return by inducing constriction of the peripheral veins;

iv) contractions of skeletal muscles may contribute to maintaining venous return when valves in veins are competent.

How ventricular filling is affected by tachycardia in a given individual or experimental setting requires consideration of multiple factors including whether the rhythm is sinus or some other pathological rhythm, the extent of HR elevation, the presence or absence of an atrial kick effect contributing to ventricular filling, A-V valve function, ventricular diastolic function and pericardial pressure. Even in health, increases in ventricular rate beyond 180 bpm during intense exercise are not necessarily associated with a further increase in ventricular filling [Ganong]; further increases in cardiac output are achieved with a decrease in ventricular end-systolic volume, and an increase in HR. In individuals lacking the contribution of atrial contractions to ventricular filling such as in those with atrial fibrillation, ventricular filling has been observed to plateau at somewhat lower HRs (90-140 bpm) depending on the extent of the underlying disease, and the maximal cardiac output achievable is reduced compared to healthy age matched controls. If the atria are paced electrically to 180 bpm in healthy individuals at rest, little change occurs in cardiac output from baseline, because of a reduction in SV. This is because the rate of A-V nodal conduction (which is regulated by vagal and sympathetic influences) becomes limiting in the absence of an actual increase in cardiac sympathetic outflow and an actual decrease in cardiac vagal outflow; second, the positive lusitropic effects of sympathetic stimulation do not occur in this model.

What the does the pH of urine indicate?

What does the pH of urine indicate?

E.S.Prakash, Mercer University School of Medicine, Macon, GA, USA.

The pH of urine ranges from 4.5 – 8.0. This is simply an observed range of values. A given value may or may not be physiologically ‘appropriate’.

In the face of systemic acidosis, if urine pH is 4.5, it seems like it is a ‘good thing’ – physiologically appropriate.

Similarly, after a heavy meal, arterial plasma pH may increase slightly. The mechanism of this postprandial alkaline tide is that for every proton secreted by the parietal cell in the stomach, 1 bicarbonate ion is added to ECF. This may cause urine pH to hit 8, and it would be physiologically appropriate.

How can we assess if urine pH is physiologically appropriate or not?
See if urine pH is physiologically appropriate for the prevailing pH of arterial plasma. If plasma pH is 7.0 and urine pH is 6.0, it seems that the extent to which urine is acidified is suboptimal, given that the kidneys normally can acidify urine to a limiting pH of 4.5.  The cause of this may be any or a combination of the following: reduced renal plasma flow, reduced GFR, a defect in the ability of the proximal tubule or the collecting tubule and collecting ducts to secrete protons.

Also, equally, a seemingly appropriate urine pH in the context of metabolic acidosis is not necessarily a reliable index of total ‘net acid secretion’, as urine pH merely reflects the concentration of hydrogen ions in urine.

The function of the kidneys is to excrete the load of “fixed (nonvolatile) acid” – i.e., the proton load that the lungs cannot excrete without also losing bicarbonate. The daily load of fixed acid on a typical Western diet is about 1 mmol/kg body weight.  For a 70 kg healthy adult, it is about 70 mmol/day.  An equal amount of ‘net acid secretion’ is essential for acid-base balance.

Is this fixed acid load excreted by the kidneys primarily as free protons or in combination with buffers? What is the relative contribution of each?
For the purpose of understanding, although the lower limit of urine pH is 4.5, let us assume that urine can be acidified up to a pH of 4.4 (and that plasma pH is 7.4).

A pH of 7.4 corresponds to a [H+] of 40 nanomoles per liter.

A pH of 4.4 corresponds to a [H+] of 40 micromoles per liter.  [A pH of 4.4 corresponds to a 1000 fold increase in the concentration of protons compared to a pH of 7.4]

Let us say urine volume is 1 liter per day.

If urine pH were 4.4, the total amount of acid excreted as protons per day would be 40 micromoles per day, if there were no proton buffers in urine. In contrast, the daily load of fixed acid the kidneys excrete is of the order of 40-80 millimoles (1000-2000 times greater).  This underscores the importance of buffers in tubular fluid for net acid secretion (and elimination) in urine.

The contribution of renal tubular cells to acid-base balance can be classified this way:
1) Reclaiming all filtered bicarbonate (preserving buffer base)
2) “Net acid secretion” (i.e., secretion of protons coming off from hydration of CO2 or protons coming off from metabolic acids like ketoacids, lactic acid, and other fixed acids; and protons secreted in combination with NH3 as NH4+).

Renal plasma flow (RPF) is the input from which any substance including (‘fixed’ acid) is extracted and actively secreted into the tubular lumen.  Furthermore, phosphate, a major buffer in urine, is made available exclusively via glomerular filtration.  Thus, an extremely low GFR (< 10 ml/min/m2 body surface area), which is also associated with a low RPF, sustained for longer than a day or two is sufficient cause for metabolic acidosis, and it is more likely when the generation of acid load increases for any reason.   In acute severe ischemic renal failure (GFR < 15 ml/min/1.73  m2 body surface area, and it falls to such a low value rapidly over a few days), particularly when vasoconstriction is a prominent element of the pathogenesis, the decline in GFR and RPF limit the total amount of acid (as well as products of metabolism) excreted in urine.  (Renal plasma flow may be normal however in nephrotoxic ATN, and generalizations are difficult).

Likewise, in end-stage renal disease (stage 5 chronic kidney disease), a GFR (< 15 mL/min/1.73 m2 body surface area) which serves as a surrogate of functioning renal mass, is low that a reduction in GFR (and RPF) may constitute an adequate explanation for the prevailing metabolic acidosis.  Whether and additional effect at the level of generation of new bicarbonate (secretion of net acid) is present can be assessed clinically by assessing the delta AG/delta bicarbonate gap.

Are protons secreted primarily by filtration or secretion?
The concentration of protons in plasma is so low (normally 40 nanomoles/L at a pH of 7.4), and so the amount of protons filtered with a normal GFR is way below the acid load that needs to be excreted. In contrast, normal kidneys are able to concentrate protons up to approximately 1000 times relative to plasma (see above).

Buffers of protons in tubular fluid that allow acid excretion in urine:

Although HCO3 buffers protons secreted by the proximal tubule, this process essentially reclaims bicarbonate (into plasma), and does not normally contribute to excreting acid in urine.  (Reclamation of filtered bicarbonate does not contribute to net acid secretion.  It is simply conservation of plasma bicarbonate.)

Protons are lost in urine primarily in combination with two buffers – NH3 and HPO4; each of these buffers contributes to trapping approximately 50% of the total acid load excreted in urine. The relative (not absolute) contribution of NH4 to secretion of net acid in urine increases in CKD (via an adaptive increase in renal ammoniagenesis) when the availability of phosphate in tubular fluid is limited by a low GFR.  Hypophosphatemia due to any cause also limits the availability of phosphate in tubular fluid for buffering protons.

Quantification of total acid excretion in urine:
1 – Titratable acidity: We estimate the amount of alkali needed to titrate urine to the pH of plasma (from which it was derived). This provides an estimate of protons tied up with HPO4 as H2PO4.

2 – Urine anion gap, calculated as urine {[Na] + [K]} – {[Cl] + [HCO3]}, would reflect this: [Unmeasured anions] – [Unmeasured cations], in urine.  The major unmeasured cation in urine is NH4.  Thus, a negative urine anion gap would suggest normal excretion of NH4 in excess of unmeasured anions in urine. Urine anion gap has a narrow clinical application and is assessed only when renal tubular acidosis is suspected to be a cause of metabolic acidosis.

Are renal tubular acidosis and the acidosis of acute or chronic renal failure the same?
There are numerous causes of metabolic acidosis (example, diarrhea, diabetic ketoacidosis, starvation ketoacidosis etc).  When there is no obvious cause for metabolic acidosis in a patient with renal disease whose GFR and RPF are normal, one might suspect a defect in renal tubular epithelial cell secretion of protons or reclamation of bicarbonate as the cause of metabolic acidosis. This entity is called renal tubular acidosis. It should not be confused with acidosis that occurs in acute or chronic renal failure. Renal tubular acidosis is not diagnosed in a patient known to have acute or chronic renal failure because in renal failure, the low GFR and RPF are sufficient causes of acidosis. Rather, patients with renal tubular acidosis (example, associated with Fanconi syndrome) may in the long run develop chronic renal failure (now called advanced CKD).

If proximal RTA is suspected: An intravenous load of NaHCO3 that increases plasma [HCO3] to normal values [24 mM] is given; if this is followed by bicarbonaturia, then that indicates diminished renal threshold for bicarbonaturia.  Since bicarbonate is primarily reabsorbed in the proximal tubule, this would indicate a proximal RTA.

If distal RTA is suspected: If urine pH falls to below 5.3 following furosemide, that would indicate preservation of the ability of acid secretory mechanisms in the connecting tubule and the collecting ducts to acidify urine. If urine pH does not fall as expected with furosemide, then this suggests distal RTA.

How much bicarbonate (or new bicarbonate) do the kidneys generate?
If total acid excretion in urine is 70 millimoles per day, then 70 millimoles of ‘new’ bicarbonate is generated since for every proton lost in urine, one bicarbonate ion is added to ECF. The term ‘new’ in new bicarbonate might seem confusing, but the point is that if this load of protons were not excreted, there would be a corresponding drop in ECF bicarbonate concentration.

Total net acid secretion in urine is not assessed when the cause for a reduction in total acid secretion in urine is clinically apparent such as in severe acute renal failure or ESRD.  As noted above, and particularly in severe ischemic ATN, it may be that GFR and renal plasma flow is limited relative to the daily load of fixed acids, and organic and inorganic anions formed.  In ESRD, the total capacity of hyperfunctioning nephrons is overwhelmed  by normal acid loads such that persistent metabolic acidosis is typically observed in the absence of renal replacement therapy.  (The low e-GFR serves as a surrogate of total renal functional capacity.)