An Ode to the Right Ventricle

| 10 July 2019

An Ode to the Right Ventricle

“The right ventricle (RV) is not the left ventricle’s (LV) weaker sibling. It has a distinct embryological origins and remarkable capabilities. When all is right, this dexterous ventricle supports all of life’s great challenges. The RV handles the transition from placentally-oxygenated fetus to air-breathing newborn. The RV allows you to get up off the couch and run a marathon. The RV has the adaptive capacity to support life at sea level or life at high altitude. However, if the RV fails beware….for If the RV’s not happy, ain’t nobody happy!”

This blog is a loving tribute to the right ventricle (RV). Before you laugh (or yawn), consider the following. This 3mm thick bit of heart muscle pumps enough blood to propel you to Mt Everest’s peak, or more likely to ride your bicycle, jog, or be a hockey playing, weekend warrior. Disclosure: I have full respect for the left ventricle (LV), the RV’s more muscular roommate within the pericardium, but increasingly I recognize that it is the function of the diminutive RV that best predicts a person’s exercise capacity and survival.

The heart, drawn as if sliced top to bottom through the middle, by Dr. Frank Netter. Note how thin the RV free wall is (leftmost side of image) relative to the muscular LV (right side of image).

In healthy adults the RV pumps 6 litres of blood every minute; however, during exercise even non athletes can triple this output, delivering17 L/minute of blood to the lungs. To illustrate…during exercise your RV could fill the largest barrel in the image below in 1 minute (albeit not with red wine). Elite athletes can more than double the amount of blood pumped by the RV (aka the cardiac output), delivering 40 L/minute to the lung circulation!

This cardiac magnetic resonance (MRI) movie shows a cross-sectional image of a normal beating human heart seen as if look from the head down into the chest. Compare the wall thickness of the RV (the triangle-shaped ventricle on the left side of image) versus the more muscular LV (on the right). The triangle-shaped ventricle RV has a distinct geometry from the cone-shaped LV.

Interestingly the RV has a different array of myocytes than the LV. In the LV circumferential arrays of muscle cells cause that chamber's walls to primarily move closer together in systole (when the heart contracts). In the RV there are both circumferential and longitudinal fibres. The longitudinal fibres make the RV shorten in systole (top to bottom), in addition to circumferential contraction. - see Cardiac MRI below.

Cardiac MRI showing the differing wall thickness and systolic motion of the RV (on the left) vs the LV (on the right)(Source: https://giphy.com/gifs/mri-wRRSKpilZf9le)

Mathematical modeling shows this even more clearly. In this complex mathematical model fibre orientation is shown for both chambers. The fibres in the RV are more vertical (red, green) than those more horizontal fibresin the LV (blue).

If you’re interested in the discovery of how the blood circulates in humans read, Out of the Flames by the Goldstones (cover page below). William Harvey’s description of the circulation of the blood as a one way, closed circulatory system in De Motu Cordis published in 1628 was accurate and revolutionary (and probably the most comprehensive understanding). However, truth be told, he was likely scooped by almost three quarters of a century by Michael Servetus’, the Spanish physician and humanist who buried his accurate description of the circulation of blood in an inflammatory treatise called Christianismi Restitutio, published in 1553. This religious tome challenged both Calvin and the Catholic church. It sufficiently inflamed Calvin that he hunted Servetus down and ultimately burned on a pyre of his own books! Servetus was himself (partially) beaten to the punch by Arab scholar, Ibn-an Nafis, writing in Arabic centuries before and proposing a modern circulatory structure that debunked Galen’s mythical septal pores as channels for blood circulation! But I digress…back to the RV!

The main role of the RV after birth is to pump blood to the lungs. There oxygen is picked up and carbon dioxide eliminated. In utero of course the maternal placenta is the oxygenator and blood from the RV goes to the left heart through two connections which (usually) disappear at birth, the ductus arteriosus and the foramen ovale. Once the blood is oxygenated (shown below as the transition from blue to pink) it then enters the left atrium and thence the left ventricle. The LV pumps the blood (loaded with oxygen) to the entire body (see cartoon below).

The cross-sectional image of a normal rat heart (below), which is structurally similar to the human heart, shows the thin walled, sail-like RV, as compared to the circular, muscular LV. Remarkably the two chambers convey the same amount of blood, the RV into the pulmonary artery at a systolic pressure of 20 mmHg versus the LV which pumps into the aorta at a systolic pressure of 120mmHg.

So why circulate blood at all? The role of the RV is simply to deliver blood to our membrane oxygenator (the lungs). Oxygen is critical to the manufacture of ATP, our source of energy. Mitochondria in every cell then use the oxygen we picked up from the air to accept electrons. That’s right, we are electrical creatures and in every cell electrons are flowing through the mitochondria in an elaborate cascade of proteins called the mitochondrial electron transport chain (ETC). These electrons originate from donor compounds (called NADH and FADH) that we generate by metabolising the food we eat. The electrons run down a redox gradient in the mitochondria toward their target-molecular oxygen. As they cascade downhill hydrogen ions are pumped across the mitochondrial membranes and generate potential energy that powers the production of ATP by an enzyme that has a spinning propeller (no kidding!). In case you thought it couldn’t get weirder…this trick of using oxygen as an electron acceptor was stolen from a free living bacteria that took up residence in some early eukaryotic cell (a great, great, great, X 10²⁰ancestor of our modern eukaryotic human cells). Thus, the RV is a way of more effectively delivering oxygen to mitochondria but it’s what allowed us to rise from the swamp and get moving! I can’t resist showing you a mitochondria or two-since they are the main beneficiaries of the RV’s ability to power oxygen delivery.

Mitochondria

Mitochondria permeate this pulmonary artery smooth muscle cell in the lung circulation. The blue oval is the nucleus. The green dots are nucleoid bodies that contain mitochondrial DNA. On the right is a movie in which the flow of matrix within the mitochondria is seen. At the beginning of the movie we photoactivate GFP within the mitochondrial matrix and over the net minute it diffuses along the length of 1 mitochondrion. Images by Mr Jeff Mewburn

Here are some fun facts about the origins and functions of the RV. Master these and you too can become an RV geek and join me in boring people at cocktail parties.

Fun fact 1: The RV and LV are distinct chambers with different cellular origins in the fetus and different patterns of gene expression even in adults. One might assume that the heart is a single, solid organ and that its cells all originate from the same source within the embryo. This seems logical since the adult heart appears to be a solid structure. However, that assumption is wrong. Although the RV and LV appear to be part of the same organ, divided by a shared interventricular septum, these chambers have different embryologic origins. In utero (when you were a fetus) your RV came from a group of cells that is distinct in both location and molecular signaling from the cells that form the LV. In fact, molecular biologists can selectively fate-mapcells and observe them selectively becoming RV or LV. We can actually see these cell populations (also called heart fields) and watch the formation of each ventricle. The left heart forms first, from a primary heart tube. The RV forms slightly later from cells that lie in front of the developing heart tube. This region, called the second or anterior heart field. It gives rise to the RV and its outflow track. Like a house, the heart was built a chamber at a time!

It is the geographically specific, localization of a few master gene regulators (called transcription factors) that determines the developmental fate of primitive cardioblasts (baby heart cells). Transcription factors bind to a gene’s promoter and cause the gene to be “read” (transcribed). Local differences in the amount of transcriptional factor determines a cell’s fate-RV vs LV! Lots of a transcription factor called d-HAND, you become an RV myocyte; lots of a transcription factor, called e-HAND, and your fate is to form the LV. In the image below note the distinct origins of the RV and LV. In this image, the fate of future RV myocytes was tracked using a reporter of gene transcription that turns cells blue if an RV-specific transcription factor, called Mef2C, is active. Note that the LV does not have blue stain because this transcription factor is primarily involved (at this stage) in creating the RV and pulmonary arteries (PA).

Mef2c-AHF-Cre fate mapped cells were evident in the pulmonary artery (PA) as well as the right ventricle (RV) and the portion of the left ventricle (LV) proximal to the septum and throughout the entire ventricularseptum (asterisk) (G, P). No staining was observed in the atria. In thepostnatal heart frommef2c-AHF-lacZmic.

Let’s consider the time lines of the formation of the LV and RV. As your heart forms it’s just a collection of cells (not the 4 chambered structure we know in adults). The first step is that the first heart-field cells (future LV) gain the ability to contract. Next, the cells of the second heart field (the future RV) direct the shaping of the first heart-field so that it forms a heart tube (see timelines below). Once this is completed, the second heart-field cells begin to beat (Buckingham et al., 2005).

Now watch the movie and see this process happen by time-lapse videography. The LV form from the green cells in the primary heart field. Subsequently the secondary heart field cells (in red) begin to develop and guide the formation of the heart tube. These red cells will later form the RV. https://elifesciences.org/articles/30668/figures

Even after birth the heart’s two pumping chambers remain distinct. For example when one looks at the expression of genes in the adult heart, ~6% of all genes are increased in RV expression relative to the LV; whilst expression of ~2% are decreased in RV. In this study of heart rhythm problems it was noted that 11/120 “heart rhythm-related genes” are differentially expressed in RV.

Fun fact 2: Although the RV pumps the same amount of blood as the LV, it’s only 1/3 the size!

The average chamber weight (in grams) for the RV and LV suggests that the RV’s marketing tag line should be small but mighty! The RV= 41g for men and 35 g for women. In contrast the LV weighs 3-fold more, 134g for men and 98g for women. In the Multi-Ethnic Study of Atherosclerosis study (MESA), MRI was used to establish normal values for RV size and function in normal people. In normal adults, the percentage of blood emptied with each beat (known by docs as the ejection fractionor “EF”) is 62 ±6%, very similar to the LV (65 ± 5%). Men had greater RV mass (by ~8%) and larger RV volumes than women; but males had slightly lower RVEF (~4%). As mentioned before, the RV free wall is only ~3mm thick whilst the LV is 11mm thick). In normal adults, moderate and vigorous physical activity increased the size and thickness of the RV (which is called RVH). One example of exercise associated RV dilatation and RVH, occurs in SCUBA divers. Mukerji et al. found evidence of RV hypertrophy in otherwise normal SCUBA divers. However, the RV compensates for increased work by developing RVH in response to most forms of exercise. Up to a point this is adaptive (good) but just as with your skeletal muscle too much hypertrophy can be harmful.

Fun fact 3: You don’t need an RV …unless you want to exercise or unless you develop any disease of the lung circulation or left heart. When both the pulmonary vasculature and LV function are normal, RV function is a modest determinant of functional capacity. How do we know that people can live without an RV? There are surgical procedures to treat children with congenital heart disease that eliminate the RV from the circulation. One such operation is called the Fontan procedure. Patients who have had a Fontan procedure rely on passive venous return of blood to the pulmonary circulation with no assistance from the RV. They can function normally into adulthood; however, if they develop any form of left heart disease or pulmonary hypertension that impairs forward flow at low pressure they quickly decompensate and develop heart failure. Likewise one needs the RV to exercise. In a study of patients who had undergone Fontan prior to age 5 years, global ventricular function was preserved at 5–18-year follow-up; however maximal exercise capacity was only 60% of normal.

Another line of evidence that the RV is theoretically optional (assuming you are at rest) comes from experiments conducted in dogs. Replacement of the RV with a Dacron patch did not cause heart failure, although the amount of blood pumped with each heart beat dropped by 20–30%. How is it possible to live without an RV? The LV pulls the Dacron patch toward the septum and the LV septum bulges into the RV cavity in systole, which creates sufficient force to eject blood into a normal pulmonary circulation(17). That said… you are better off with an RV because we all need to move and most of us eventually develop left heart disease, even if that disease is just the stiffening of the LV and vasculature that occur with aging.

Fun fact 4: Exercise is good for you but extreme exercise can cause the RV to fail and even lead to life threatening arrhythmias.

The first marathon (490 BC) did not end well. Pheidippides was the sole runner in that race. He was dispatched from the town of Marathon to inform the people of Athens that the Persians had been defeated. He reached his goal after 26.2 miles, yelled out νενικήκαμεν (nenikēkamen, "we have won!"), and then… dropped dead.

http://www.lakepowell.net/marathon.html

I have a friend in Melbourne, Australia who studies modern day marathoners, Dr. Andre LaGerche. He uses state of the art imaging techniques (ultrasound and cardiac MRI) to see how the RV of elite athletes responds to marathons and ultramarathons. I visited his laboratory at the Baker Institute in 2018. His lab is designed to allow volunteers and patients to be imaged while exercising. Dr. LaGerche is committed to answering challenging questions like, how much exercise is too much? What is the normal change in heart structure and function in an athlete (and when does this cross over from being adaptive to being pathological?). In the figure below he shows the expected and presumably healthy changes in heart structure and function in an elite athlete. He notes that the athletes heart is structurally in a gray zone since “Many of these measurement values (in athletes) overlap with those of cardiomyopathies and there are currently very few diagnostic cut-off values that enable us to risk-stratify asymptomatic athletes with accuracy.”

The “Gray Zone” in Established and Novel Echocardiographic Measures of a 36-Year-Old Well-Trained Marathon Runner Echocardiographic measures are demonstrated for the healthy marathon runner exemplified in this review. As is common in athletes, all 4 cardiac chambers are enlarged. M-mode measures demonstrate moderate left ventricular dilation and mild hypertrophy (A). The 2-dimensional atrial areas are mild to moderately increased (B), while 3-dimensional volumes are moderate (LV) to severely (RV) enlarged when compared with reference ranges derived from non athletic populations (E). Color-coded Doppler derived strain (C) and strain rate (D) demonstrate mildly reduced basal strain and strain rate values (as indicated by the orange arrows).

Sometimes the findings he observes in elite athletes are concerning, raising the question, whether the observed changes in heart structure or function have crossed the line from health to disease.

Observe these videos from Dr. LaGerche. They demonstrate unusual RV dilation and altered function in 4 professional cyclists. This illustrates the difficulties in separating health from disease in asymptomatic athletes.

Another “gray zone” finding in elite athletes is ventricular scarring. One can detect subtle scars in the heart using MRI and gadolinium. When there is scarring the gadolinium (an element used as an intravenous contrast agent) leaves the blood vessels and persist longer than normal in the tissue (so call late gadolinium enhancement, LGE). LGE occurs in the heart of some elite athletes, as shown below, raising the question whether this reflects heart damage and/or a source of potential heart rhythm problems.

Dr. LaGerche (centre in the picture below) also showed that endurance athletes with ventricular arrhythmias have reduced RV reserve (meaning they can’t increase RVEF with exercise). He compared 17 endurance athletes who had documented RV arrhythmias with 10 endurance and 7 non athletes who had no arrhythmias. The elite athletes all exercised at least 6 hours a week and had monomorphic ventricular tachycardia (a dangerous heart rhythm problem) or frequent premature ventricular contractions (PVCs), related to their RV. Their hearts were normal structurally (or at least normal for athletes).

3 friends sitting at table drinking coffee

As these graphs show the athletes with arrhythmias could not increase their RV performance with exercise; suggesting they suffer from some form of RV disease. Note in panel B for example while the control groups increase the RV fractional area change (RVFAC), a surrogate for RVEF, elite athletes with arrhythmias (red line) are stuck at resting RV performance levels.

4 different graphs showing echocardiograph results in athletes

The image above shows what this failure to increase RV function looks like anatomically (using cardiac MRI). Note the endurance athlete with the arrhythmia on the right. Their RV gets bigger with exercise whilst that of the normal person’s RV shrinks (reflecting the normal improvement in RV function with exercise).

Dr. LaGerche concluded that while resting studies were not very predictive of outcome/arrhythmias, both exercise-CMR and echocardiographic RV stress testing show promise. So, exercise is good but in the extreme one needs to be cautious and respect the RV!

Fun fact 5: The RV determines prognosis in patients with pulmonary hypertension: Perhaps the ultimate challenge for any RV is pulmonary hypertension. In this condition, pressures in the lung circulation rise above a mean value of 20 mmHg and there is often obstruction and constriction of the pulmonary arteries. This all means that in patients with pulmonary hypertension the RV must work harder. The diagram below shows the changes in the lung blood vessels and RV in one form of pulmonary hypertension, called pulmonary arterial hypertension (PAH). This form of pulmonary hypertension is caused by an obliterative form of lung blood vessel disease; however, it is the response of the RV [(which can be good (adaptive) or bad (maladaptive)] that determines whether the patient will feel well and live a long time.

photo showing transition from normal to diseased pulmonary vasculature

In the upper panel we see the transition from normal pulmonary vasculature to the diseased state seen in patients with PAH. In health the pulmonary vascular bed’s extensive arbor of vessels resembles a tree in summer; in PAH the withered bed resembles a tree in winter. In a patient with PAH, the cardiac MRI (above on left) shows a paucity of small pulmonary arteries, particularly in the right lung. On the right in the upper image is a schematic showing the hypertrophy of the RV (RVH) that attempts to compensate for this increase in afterload. The bottom right is a cross section of the heart from a patent that died with PAH…note that the RV is larger than the LV and it is thickened in some areas and scarred in others. This is an example of maladaptive RVH. This person patient died from RV failure.

Understanding the RV is becoming more important because the incidence of pulmonary hypertension is becoming more common, as Dr. Thiwanka Wijeratne from our Division of General Internal Medicine reported in a recent article. In this retrospective study of 50,000 patients with a diagnosis of pulmonary hypertension it was noted that in all 4 major PH groups are becoming more common. Group 1 is PAH, Group 2 is pulmonary hypertension associated with left heart disease, Group 3 is pulmonary hypertension associated with chronic lung diseases and Group 4 is pulmonary hypertension associated with unresolved pulmonary emboli. In all forms of pulmonary hypertension the standardized mortality rates are increased 7-fold, a reminder that for patients with left heart disease or lung disease, superimposed pulmonary hypertension is a dire finding.

graph showing rate of incidence of hypertension in Ontario

Evidence that in Ontario the incidence of all forms of pulmonary hypertension is increasing

While the role of diminished RV function in the high mortality rate observed in this epidemiologic study is unknown, it is well established that RV function is the major determinant of outcome in PAH (Group 1 PH). Patients with virtually identical hemodynamic severity of pulmonary hypertension do well or poorly based on the success/failure of the RV to adapt to the afterload increase caused by pulmonary hypertension.

For example in this paper by Ben Freed, then a Cardiology fellow the University of Chicago, it was shown that RVEF and RV LGE were the best predictors of poor outcome in patients with PAH.

chart showing how RV predicts prognosis in PAH

At the basic science level we know that the adaptive response of the RV is predicted by changes in mitochondrial metabolism, fibrosis, angiogenesis and inflammation. Using transcriptomics (measuring all the messenger RNA produced in the RV) we showed that all 4 of these pathways are disordered in the RV of rats with experimental PAH. Essentially, maladaptive RVH is a state in which mitochondrial metabolism and angiogenesis are impaired whilst inflammation and fibrosis are increased.

In preclinical models we can see adaptive vs maladaptive RVH clearly. We created an adaptive model of RVH by surgically placing a metal clip on the main pulmonary artery (so called, PA banding-PAB). We compared the function of the RV in this model with equally severe RVH produced in two preclinical models of PAH: one induced by the combination of hypoxia plus an antiangiogenic factor (SU5416) and the other caused by injection of a plant-derived alkaloid, monocrotaline (MCT). The RVH caused by MCT (see figure below) is maladaptive. This form of RVH results in accelerated heart failure and death. Note how the in the MCT-PAH model the RV compresses the LV, making the LV small and “D-shaped”, just as occurs in patients with PAH.

Control Rat Heart MCT Rat Heart

MRI Normal Rat Heart

chart showing adaptive vs maladaptive RVH

The figure above shows that despite similar severity of RVH (left graph showing weight ratio of RV/LV+S) these 3 models of RVH have very different functional consequences for the rats, with the MCT rats having the lowest cardiac output, shortest walking distance on a treadmill and the most severe reactivation of the fetal gene package. One of the factors that makes the MCT RV maladaptive is its mitochondrial metabolic response to the pressure overload and/or pulmonary hypertension. For example, in the MCT model we find the mitochondria (shown in red below) are fragmented, depolarized (they lose their red stain) and make damaging reactive oxygen species. Note the difference between the healthy, polarized (red) mitochondria in a normal rat RV (left) vs the MCT RV below (right). These images taken in live hearts with a confocal microscope using the red potentiometric dye TMRM.

Abnormal Cardiomyocyte Mitochondria in the MCT RV

control mitochondria

Control Monocrotaline RV

Lest I leave you with the impression that the RV’s only disease is PAH let me mention a few of its other afflictions. The RV is also afflicted in congenital heart diseases. The RV often fails acutely causing cardiogenic shock in it's patients with a heart attack due to (RV infarction from occlusion of the rightcoronary artery). The RV is the target of an inherited, autosomal dominant disease called arrhythmogenic right ventricular cardiomyopathy (ARVC), in which fibrofatty infiltration leads to lethal heart rhythm problems and/or heart failure in young people. The RV fails in patients with left heart diseases, caused by valve disease, systemic hypertension etc. and is often the ultimate cause of decompensation in these patients. Acute RV failure if often the cause of death in patients with large acute pulmonary emboli. Finally the RV is affected by infiltrative diseases such as amyloidosis and sarcoidosis…but those are topics for another day.

So now you are an RV expert. I hope you are as impressed as I am with this mighty muscle.