By Rick McGuire

It is a clinical reality that the heart does not exist in isolation, thus explaining the European Society of Cardiology (ESC) Congress spotlight this year: "The Heart Interacting with Systemic Organs." When there is cardiovascular disease (CVD), pretty much any organ can play a leading or supporting role: brain, kidneys, lungs, pancreas, and liver, as well as the gastrointestinal and reproductive systems.

Keith A. A. Fox, BSc, MB, ChB, chairman of the ESC program committee, said, "What our patient ultimately experiences is this cross-talk between these different systems." The whole idea of the focus on organs beyond the heart is to better understand how these disease processes cross boundaries, which means bringing in experts from these other areas "to get the best science across the bridges."

It's hard to pick favorites, but Christopher J. White, MD, channeled his inner Woody Allen when stating his own preference recently in a JACC Interventions commentary, "Don't Hurt My Brain... It's My Second Favorite Organ."¹ At least half-agreeing with the famous Allen quote, Dr. White eloquently argues that the brain is underappreciated in clinical practice. While an emphasis on door-to-balloon time has dramatically improved time-to-treatment for patients with myocardial infarction, acute stroke therapy languishes without a mandate—or even a standard of care—for early reperfusion.

While his main interest is PCI, Dr. White said he and his partners appreciated early on the significant overlap of peripheral vascular disease in their coronary patients that was amenable to percutaneous intervention. "We undertook to gain the skills necessary to extend our interventional practice beyond the borders of the heart," including acute stroke intervention, which they perform with the support and guidance of their colleagues in neurology and neuroradiology at the Ochsner Clinic in New Orleans.

Petr Widimsky, MD, agrees with Dr. White. In his Andreas Grüntzig prize–winning lecture at the 2013 ESC Congress, he estimated that treatment of stroke today is about 25 years behind that for acute MI, noting an in-hospital mortality rate for moderate-to-severe stroke of 25–30% compared to 5–8% for moderate-to-large MI. Beyond thrombolysis, Prof. Widimsky said, "I firmly believe that properly organized use of CBT (catheter-based thrombectomy) would do more than anything to move the treatment of stroke out of the dark ages."

Recently several new devices have been introduced involving stent retrievers for clot removal, and these, said Prof. Widimsky, have reduced complications to where they are now lower than those for thrombolysis. Moreover, data suggest this latest generation of stent retrievers can recanalize up to 90% of occluded intracranial arteries—approximately two to three times more than that achieved through thrombolysis.

Save the Brain

Just weeks before the ESC meeting, in the August 6 issue of JACC, Raffaele Marfella, MD, PhD, and colleagues reported that subclinical episodes of atrial fibrillation (AF) occur frequently in people with type 2 diabetes and significantly increase the risk of neurologic events.² The investigators enrolled 464 type 2 diabetic patients younger than 60 years of age in a longitudinal, observational study who were matched to patients without diabetes. After quarterly 48-hour Holter monitoring, subjects with diabetes were significantly more likely to have at least one subclinical episode of AF lasting at least 10 minutes (9.0% vs. 1.6%). Those with silent episodes of AF had higher baseline prevalence of silent cerebral infarcts than controls (61% vs. 29%) and higher stroke rates (17.3% vs. 5.9%) during the follow-up period.

A second paper in the same issue of JACC, this time by a team of Australian researchers, described subtle post-procedural cognitive dysfunction in 60 patients following AF ablation compared to 30 patients scheduled for radiofrequency ablation.³ In an accompanying commentary, Eric N. Prystowsky, MD, and Benzy J. Padanilam, MD, said if the neurological sequelae of AF are not limited to stroke, have we omitted an important endpoint in the current state of AF management?⁴ Studies of anticoagulation in AF have only addressed endpoints of strokes and systemic embolization, not silent cerebral infarcts or cognitive deterioration. Indeed, it's possible that anticoagulation itself may lead to cerebral microhemorrhages and neurological dysfunction. Thus, they said, future studies of AF should evaluate silent cerebral infarcts and cognitive dysfunction as endpoints. We must do more, they stressed, "to fulfill the first commandment of therapy for patients with AF: preserve the brain."

While unrelated to stroke treatment, given his predilection for the brain, Dr. White may still be pleased to hear that high-dose statins seem to prevent dementia. Investigators used a database of about 1 million people to identify nearly 58,000 patients older than 65 years with no history of dementia in 1997 and 1998. According to Tin-Tse Lin, MD, of Taiwan, "The adjusted risks for dementia were significantly inversely associated with increased total or daily equivalent statin dosage. Patients who received the highest total equivalent doses of statins had a three-fold decrease in the risk of developing dementia. Similar results were found with the daily equivalent statin dosage."

While we did not even mention eyes in the organ list above, another paper presented at ESC reported the results of a meta-analysis of 2.4 million people: statin use was associated with a 20% lower rate of cataracts. John B. Kostis, MD, director of the Cardiovascular Institute at UMDNJ-Robert Wood Johnson Medical School (which became a part of Rutgers University as of July 1, 2013), added that the risk of cataract was reduced by 50% when treatment was initiated in younger individuals (in their 40s) and the duration of therapy was longer (up to 14 years).

Kidneys Get Respect

While their profile is lower than the brain, the humble kidneys have garnered a deeper appreciation from cardiologists in recent years. A particularly ominous risk for CHD arises in the setting of chronic kidney disease (CKD). As renal function declines below a glomerular filtration rate (GFR) of 60 ml/min/1.73 m², the relative risk for CV mortality progressively increases by three-fold compared with those without CKD, and almost 10-fold in the setting of CKD with diabetes. As a matter of fact, the CV risk conveyed by CKD exceeds that conveyed by diabetes.

Francois Schiele, MD, PhD, chief of cardiology, University Hospital of Besancon, France, put it this way at ESC: "The take-home message is very simple: Medical observation without data on kidney function is a poor observation. We have to assess renal function in any situation because it impacts the diagnostic tools you choose, the drugs you choose, and it will impact strategy and outcome."

Routine assessment of renal function is particularly important, said Christian Mueller, MD, University Hospital of Basel, Switzerland, in patients with acute coronary syndrome (ACS). This is evident in about 30% of ACS patients and worsening renal function during hospitalization is a predictor of mortality in both STEMI and NSTEMI. As for why impaired renal function is such a bad prognostic sign, one important reason may be the multiple comorbidities associated with renal dysfunction. In addition, ACS is usually more severe in these patients and their complication rates, including bleeding and stent thrombosis rates, are higher.

But is impaired renal function an argument for or against an early invasive strategy? Dr. Schiele acknowledged at ESC that coronary angiography and intervention may further impair renal function, but noted that coronary intervention is recommended by guidelines in patients with renal dysfunction. There are registry data, she said, suggesting that renal dysfunction no longer predicts mortality after PCI and there is evidence, too, indicating clear benefits of intervention over conservative management in patients with renal dysfunction. However, Prof. Schiele added that it is crucial to adjust medications and contrast volume to minimize risk in patients with CKD. Adequate hydration and use of radial access are important in this context. Overall, with adequate precautions, an individual approach and patient education, coronary intervention is probably still beneficial in patients with advanced renal dysfunction.

Robert Harrington, MD, now of Stanford University Medical School, attended ESC and discussed the choice of antithrombotic therapy in patients with renal dysfunction. As the ACS population ages, risk of renal dysfunction also increases. Renal dysfunction increases the risk of bleeding independently of choice of treatment. To reduce this risk, he said, the first step is to consistently assess GFR in these patients. Many drugs, including statins, are underutilized in patients with renal dysfunction. On the other hand, he said, many patients with severe renal dysfunction, including dialysis patients, receive drugs that have not been tested. According to Dr. Harrington, many of these patients are routinely overdosed with antithrombotic medications, thus contributing to their risk. The presence of renal failure does not negate the benefit of antiplatelet therapy, but the risk of bleeding is clearly increased.

Earlier this year, an interesting paper in JACC suggested that ischemic post-conditioning provides a renoprotective effect during PCI.⁵ Spyridon Deftereos, MD, and colleagues studied the efficacy of remote ischemic post-conditioning (RIC) for preventing acute kidney injury in patients undergoing PCI. Eligible patients were randomized to receive RIC by cycles of inflation and deflation of the stent balloon during PCI or a sham procedure. The rate of acute kidney injury, defined as an increase of ≥0.5 mg/dl or ≥25% in serum creatinine, was 12% versus 30% in controls. The 30-day rate of death or rehospitalization for any cause was 22% in controls versus 12% in RIC patients. If confirmed, RIC during PCI appears to confer protection against acute kidney injury and may be a relatively easy way to improve 30-day clinical outcomes.

An even simpler approach was detailed at ESC and published in Lancet.⁶ Using a BP cuff right before heart surgery cuts heart damage; talk about safe, cheap, and simple! Patients underwent three cycles of 5 minutes of ischemia and 5 minutes of reperfusion in the left upper arm after induction of anesthesia or no ischemic preconditioning (control). Investigators enrolled 329 patients and found that cardiac troponin I release was an average 17% lower at 72 hours after surgery with preconditioning (p = 0.001). The researchers followed patients for up to 4 years to determine if remote preconditioning had any effect on long-term health. By 1.54 years, patients who had remote ischemic preconditioning were 73% less likely to have died of any cause and 86% less likely to have died from an MI or stroke compared to those in the control group.

"The results of our study are very encouraging that remote ischemic preconditioning not only reduces heart muscle injury but also improves long-term health outcomes for heart bypass patients, and we hope that these benefits will be confirmed in larger prospective studies which are currently taking place," said study co-leader Professor Gerd Heusch, of the University School of Medicine Essen, Germany.

Other Favorites

The pancreas has been given its due for years now considering the wide variety of cardiovascular effects associated with diabetes. A team of investigators from Sarasota, Florida, headed by Mahfouz El Shahawy, MD, presented a poster at ESC suggesting that even men with prediabetes show cerebrovascular and CV structural and functional abnormalities. Abnormal carotid intima media thickness and small artery stiffness was statistically higher in men but not women with prediabetes (defined by American Diabetes Association criteria). Whether the difference is due to protective hormonal effects in females or other factors is unclear, but in this study of 2,286 asymptomatic patients, men with prediabetes show structural and functional abnormalities that might be worth targeting with risk reduction in an effort to avoid progression of such changes.

Erectile dysfunction (ED) is often an early clinical manifestation of generalized vascular disease and at ESC, Christodoulos Stefanadis, MD, and colleagues from Athens Medical School, reported the results of a meta-analysis of more than 100,000 men followed for a mean of 6.4 years. Compared to men with no or mild ED, the pooled relative risk for total CV events was 1.32 for men with moderate ED (p < 0.001) and 1.92 for men with severe ED (p < 0.001). The authors said the results imply a gradient effect based on the severity of ED, augmenting the link between ED and CVD. There was a significant increased risk of all-cause mortality, too, associated with ED but the effects of ED severity were less apparent for all-cause mortality.

Finally, unless smothered in onions, it's hard to find many people who choose liver as one of their favorite organs. But maybe it should get a little more respect, particularly in patients with heart failure (HF). As part of the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF), 39.0% of all patients hospitalized for HF presented with liver dysfunction and these patients were at higher risk of rehospitalization during 180 days of follow-up. The investigators said regular assessment of liver function might help predict patients at greater risk of readmission.

For the final word, Joep Perk, MD, from Linneaus University, Sweden, said on an ESC video program, "A good Congress to me is when you leave you feel wiser and still confused at a higher level."

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References

1. White CJ. JACC Cardiovasc Interv. 2013;6:392-3. http://interventions.onlinejacc.org/article.aspx?articleid=1670498
2. Marfella R, Sasso FC, Siniscalchi M, et al. J Am Coll Cardiol. 2013;62:525-30. http://content.onlinejacc.org/article.aspx?articleid=1691024
3. Medi C, Evered L, Silbert B, et al. J Am Coll Cardiol. 2013;62:531-9. http://content.onlinejacc.org/article.aspx?articleid=1691026
4. Prystowsky EN, Padanilam BJ. J Am Coll Cardiol. 2013;62:540-2. http://content.onlinejacc.org/article.aspx?articleid=1691031
5. Deftereos S, Giannopoulos G, Tzalamouras V, et al. J Am Coll Cardiol. 2013;61:1949-55. http://content.onlinejacc.org/article.aspx?articleid=1667417
6. Thielmann M, Kottenberg E, Kleinbongard P, et al. Lancet. 2013;382:597-604.

Keywords: Risk, Myocardial Infarction, Stroke, Follow-Up Studies, Risk Reduction Behavior, Acute Kidney Injury, Standard of Care, Renal Insufficiency, Cerebral Infarction, Erectile Dysfunction, Dementia, Cardiovascular Diseases, Glomerular Filtration Rate, Kidney, Diabetes Mellitus, Brain

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