The following is a collection of our Editors’ favorite cardiovascular stories published in a variety of journals in recent months. A potpourri, if you will, of stem cells, circadian rhythms, mechanical pumps, and more.
Bedtime Is Best
The time of day affects the heart’s ability to recover from ischemia, according to Martin Young, David Durgan (both at the University of Alabama at Birmingham) and colleagues.
It is well known that heart attacks are more common between 6 am and noon, which is quite possibly the best argument for sleeping in! But, no one knows exactly why. Perhaps the strain of getting out of bed in the morning is enough to cause the rupture of a vulnerable plaque in the coronary arteries. Or, it may be a period of high physiologic vulnerability determined by our internal clocks. Like all other animals, we have a master clock, located in the hypothalamus, which is regulated by light and which synchronizes the molecular clocks present in almost all the cells of the body. Together these clocks regulate our behavior—feeding, physical activity, etc—to the cycles of night and day.
Young and colleagues1 previously discovered that oscillations of circadian clock genes are rapidly attenuated in the heart following ischemia/reperfusion. This made them question whether the outcome, as well as the chance of a heart attack, might depend on the time of day.
The team investigated the tolerance to ischemia/reperfusion in wild-type mice and in those that lacked a functional circadian clock in their hearts. Heart attacks were induced just as mice were transitioning from wake to sleep or from sleep to wake, after which the mice hearts were assessed for infarct volume, fibrosis, and contractile function.
Wild-type hearts that infarcted at the sleep-to-wake transition showed a 3.5-fold increase in infarct size after 1 day of reperfusion compared with the wake-to-sleep-infarcted hearts. After 1 month, the hearts infarcted at sleep-to-wake exhibited greater adverse heart remodeling and fibrosis and reduced contractile function. In mice lacking the cardiac clock, the time-of-day differences disappeared, and all hearts looked as though they had been infarcted at wake-to-sleep, regardless of their actual infarction time. That’s because, says Young, “their hearts are essentially suspended at the time that the mice are about to go to sleep.” Circadian rhythms in the mutant mice are otherwise normal. ⇓
Could heart attack victims have their reperfusion tolerance improved by similarly tricking their systems into thinking it is time for sleep? Indeed, thinks Young: “In the future, it may be possible to provide agents to reset the clock so that at the time of reperfusion, the cardiomyocytes are temporally suspended at a cardioprotective time of day.” It might even be as simple as giving patients melatonin, he reckons. Better still, he adds, “in theory you could use melatonin in a protective manner,” and so reduce the chance of at-risk patients having heart attacks in the first place.
Gene Hunt Success
Paul Grossfeld (University of California, San Diego) and colleagues identified a new mammalian heart development factor.2 The transcription factor ETS-1 and its target genes are possible culprits in congenital heart defects, says the team. Almost 1% of babies are born with some form of congenital heart defect.
Grossfeld and his colleagues are hunting for the underlying genetic causes. They were able to home in on one particular region of the genome, thanks to patients with a rare disorder called Jacobsen syndrome. Patients with Jacobsen syndrome lack the distal region of the long arm of chromosome 11 and often, though not always, have congenital heart defects.
In 2004, by mapping Jacobsen patients’ missing chromosome regions and tallying their symptoms, the team managed to narrow the search area to a 7-Mb cardiac critical stretch containing approximately 50 genes. Working out which of these 50 genes might be responsible for heart defects was not going to be an easy task. As luck would have it, however, the team recently identified three Jacobsen patients (all with heart defects) that had interstitial rather than terminal deletions of 11q. This narrowed the search region to a more manageable 1.2 Mb, containing just 6 genes. One of them was ETS-1.
“No one had previously implicated ETS-1 in mammalian heart development,” explains Grossfeld, “[but] there was some very compelling data from the seasquirt.” Thus, the team looked at heart development in mouse embryos lacking functional ETS-1 and found that, “these mice had indeed some of the same major congenital heart defects that our patients with Jacobsen syndrome have,” says Grossfeld.
Interestingly, the team also showed that in normal developing mouse hearts, ETS-1 is expressed in the neural crest and the endocardium, but not in the myocardium itself. “Yet there clearly appears to be a myocardial defect,” says Grossfeld, which suggests that ETS-1 regulates some sort of signaling between tissue types. The group now plans to make neural crest and endocardium-specific ETS-1 knockouts to determine what that signaling mechanism is.
That inheritance of single-gene defects, such as in ETS-1, could predispose to congenital heart defects has revolutionized scientists’ understanding of these relatively common disorders. But, the relationship between the primary genetic defect and the anatomical flavor of the resulting heart disease has proved to be substantially more complex than first imagined. For example, the discovery that mutations in the transcription factor NKX2.5 can result in congenital heart disease has been complicated by the surprising range of phenotypes observed, including atrial, ventricular, and atrioventricular septal defects. Beginning to unlock the basis of this variation are Patrick Jay (Washington University School of Medicine, St. Louis) and colleagues. After a large-scale genetic study in mice, they proposed that a number of interacting genetic loci, superimposed on the primary genetic defect, influenced the ultimate pattern of anatomical disease.3 Importantly, they suggest that the predominant effect of these modifier genes is to confer health.
Pick of the Pumps
A new pump for boosting blood output of failing hearts has outperformed its predecessor in a trial led by Mark Slaughter (University of Louisville, Kentucky).4
Some patients with advanced heart failure are not eligible for transplants because of age or underlying illness, and others have a long wait. A 2001 study showed that such patients fare better when their hearts are surgically installed with a mechanical pump, compared with when given medication alone.
The pump from the 2001 study was not problem free, however. “It was a big pump, there was motion, it vibrated,” says Slaughter. This caused a lot of infections, he explains, as it prevented the skin from healing around the driveline, the cable that runs from the pump to the external powerpack and motor. “Despite the proven benefits of the pump, the problems were putting patients off,” says Slaughter.
Slaughter and colleagues have now trialed a new improved device—the HeartMate II-that uses a continuous-flow pump, rather than a pulsatile pump, as in the original study. This means that the new device has fewer moving parts and thus should help keep the driveline, which is also smaller and more flexible, in place. The continuous-flow pump is also smaller, approximately one third of the size of the pulsatile version. “It requires less space to put the pump in,” says Slaughter, “meaning that more people could get it, including smaller people, particularly women.” ⇓
In the trial, patients fitted with the new device had a better chance of survival than those with the old device and had a reduced chance of needing device repair or replacement within 2 years of follow-up. “The study demonstrated clear superiority of continuous-flow pumps over pulsatile pumps,” says Francis Pagani (University of Michigan).
The HeartMate II is the first continuous-flow device to get approval for use in the United States, but further improvements are in the pipeline. The next aim, says Slaughter, is to further miniaturize the devices and perhaps even make them fully implantable, “just like a pacemaker.”
The Blood-Filled Fountain of Youth
Youthful blood may hold the key to reversing the signs of aging, according to a report by Amy Wagers (Harvard University, Boston, MA) and colleagues.5 The team has found that an unknown factor, or factors, in blood from young mice can rejuvenate the stem cell niches of older mice.
Stem cell niches provide the progenitor populations of cells responsible for repairing and renewing our tissues, a functionality that decreases as we age. “We have known for some time that intrinsic and age-dependent changes occur in stem cells that alter their ability to self-renew and differentiate into more mature progeny,” says Gary van Zant (University of Kentucky), “But we also knew that intrinsic regulation wasn’t the whole story.”
“The rationale behind thinking there might be a systemic regulator of aging,” says Wagers, “comes from the observation that multiple tissues experience declines in function with advancing age.” A good way to send out such a systemic signal, they reasoned, is via the blood. So, that is where they looked. ⇓
To investigate the effect of blood age on niche and stem cell age, the team surgically joined pairs of mice (one young and one old) such that they shared a circulatory system. After 4 to 5 weeks of this parabiotic union, older partners’ hematopoietic stem cells and osteoblastic niche cells (which regulate hematopoietic stem cells) resembled those of their youthful counterparts. Similar effects were seen when old stem and niche cells were exposed to young blood serum in culture.
“That you can somewhat undo the effects of many, many months of life on a cell in a relatively short period of time, I think that is surprising,” says Wagers, “and very encouraging!”
Encouraging because if researchers can figure out which factors in the blood are responsible, it might be possible to boost their activity and enhance functionality of aged tissues and organs. “The challenge now is to identify this youth juice and see if it has broad-based effects throughout the body,” says van Zant.
Borrowed bone cells boost heart function after heart attack, according to a clinical study led by Joshua Hare (Miami, Florida).6
Using a heart attack patient’s own bone marrow stem cells to fix the heart damage has shown promising results in trials, but obtaining and culturing the cells is an unreliable, time-consuming, not to mention painful step in the treatment. If commercially available pre-cultured cells could be used, this step could be avoided. But wouldn’t the patient then require immune-suppressing drugs to prevent rejection? Apparently not.
In what Hare describes as, “a paradigm shift in transplantation,” he and his colleagues have injected heart attack patients with commercially available bone marrow-derived mesenchymal stem cells, with no accompanying immune-suppression. “The cells have an immunoprivilege feature that allows them to be given as an allogeneic graft,” explains Hare. “It is an inherent feature of mesenchymal stem cells.”
In Hare’s phase I trial, patients received mesenchymal stem cells intravenously and were then assessed for general health and heart function during a period of 6 months. Patients showed no ill effects, suggesting the cells were safe, and also showed improved heart function—increased ejection fraction and reduced episodes of ventricular tachycardia, suggesting the cells had trafficked to the hearts and, to some extent, mended the damage. “That cell therapy may prevent or reverse ventricular dilation and wall thinning constitutes a major breakthrough,” says Piero Anversa (Harvard Medical School).
Concerns over the safety of stem cells include the possibility of tumor formation and ectopic tissue growth. Computed tomography scans were used to detect abnormal growths, and none were found. But, as Hare admits, 6 months may not be a long enough observation period. “The 6 months was the primary end point for this study, but every patient then rolled in to another phase of the study for a further 18 months.”
With the hope that treatment is indeed safe long-term, Hare is already working on ways to optimize treatment outcome. Says Mark Sussman (San Diego State University, San Diego, CA) enthusiastically, “the report by Hare et al. provides the important rationale to proceed forward.”
The opinions expressed in News and Views are not necessarily those of the editors or of the American Heart Association.
↵*Edited by Aruni Bhatnagar and Houman Ashrafian
Ye M, Coldren C, Liang X, Mattina T, Goldmuntz E, Benson DW, Ivy D, Perryman MB, Garrett-Sinha LA, Grossfeld P. Deletion of ETS-1, a gene in the Jacobsen syndrome critical region causes ventricular septal defects and abnormal ventricular morphology in mice. Hum Mol Genet. 2010; 19: 648–656.
Winston JB, Erlich JM, Green CA, Aluko A, Kaiser KA, Takematsu M, Barlow RS, Sureka AO, Lapage MJ, Janss LL, Jay PY. Heterogeneity of genetic modifiers ensures normal cardiac development. Circulation. 2010; Mar 8.
Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D, Sun B, Tatooles AJ, Delgado RM 3rd, Long JW, Wozniak TC, Ghumman W, Farrar DJ, Frazier OH, HeartMate II Investigators. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med. 2009; 361: 2241–2251.
Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, Gerstenblith G, DeMaria AN, Denktas AE, Gammon RS, Hermiller JB Jr, Reisman MA, Schaer GL, Sherman W. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 2009; 54: 2277–2286.