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Endothelial Dysfunction (release into the circulation of damaged endothelial cells) as A Risk Marker for Ischemia and MI

January 12, 2014 by larryhbern

Endothelial Dysfunction (release into the circulation of damaged endothelial cells) as A Risk Marker for Ischemia and MI

Reporter and Curator: Larry H Bernstein, MD, FCAP

Endothelial Dysfunction: An Early Cardiovascular Risk Marker in Asymptomatic Obese Individuals with Prediabete

AK Gupta, E Ravussin, DL Johannsen, AJ Stull,WT.Cefalu and WD Johnson at Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA Brit J Med & Med Res 2012; 2(3):413-423 [www.ScienceDomain.org]

provides an exceedingly interesting insight into the relationship between type 2 diabetes mellitus, obesity and risk for cardiovascular disease in patients who are asymptomatic prediabetics, defined as a fasting blood glucose between 1000 and 1240 mg/L, or a Hb A1c (may not accurate for African Americans) between 5.6 and 6.5. They would be expected to show an abnormal 5-hr GTT.

Obesity is associated with the release from adipocytes of adiponectin, which it has been reported is countered by resistin. We might also have the effect of the insulin secreting beta cell, that releases insulin without a relationship to an anabolic function, through IGF-1 related to feedback to the pituitary GH, which takes a dominant catabolic role. Thus, insulin resistance. This is an oversimplification, and far greater depth is found elsewhere.

This study is consistent with another study on Metabolism Influences Cancer

Reuben Shaw, Ph.D., a geneticist and researcher at the Salk Institute: Metabolism Influences Cancer

http://pharmaceuticalintelligence.com/2014/01/08/reuben-shaw-ph-d-a-geneticist-and-researcher-at-the-salk-institute-metabolism-influences-cancer/

Recent development on Human Stem Cell Therapies for comorbidity and Cardiovascular disease

Human Stem Cell Therapies: UCSD New Discovery addressing the Limiting Factor and Providing the Solution

http://pharmaceuticalintelligence.com/2014/01/06/human-stem-cell-therapies-ucsd-new-discovery-addressing-the-limiting-factor-and-providing-the-solution/

This study reported a potential early marker of myocardial infarction by the release into the circulation of damaged endothelial cells that are to be measured in patients suspected of severe ischemia in a clinical trial. The question that I raised in my comment was whether this would have to be a special immunochemical assay of tagged cells, and if that were the case, would it be measured on an automated flow-based hemocytometer, which can differentiate several populations of cells – granulocytes, lymphocytes, red cells, platelets, immature granuloytes, BLASTS. That would be a very practical extension of the technology for labs worldwide.

Abstract

Aims: To elucidate if endothelial dysfunction is an early CV risk marker in obese men and women with prediabetes.
Study Design: Cross-sectional study.

Place and Duration of Study: Clinical Research Unit, Pennington Biomedical Research Center, Baton Rouge, LA. United States.

Background: Overweight and obese status denotes an increasing adipose tissue burden which spills over into ectopic locations, including the visceral compartment, muscle and liver. Associated co-morbidities enhance cardiovascular (CV) risk. Endothelium which is the largest receptor-effector end-organ in our bodies, while responding to numerous physical and chemical stimuli maintains vascular homeostasis. Endothelial dysfunction (ED) is the initial perturbation, which precedes fatty streak known to initiate atherosclerosis: insidious process which often culminates as sudden catastrophic CV adverse event.

Methodology: Asymptomatic men and women; [n=42] coming in after an overnight fast had demographic, anthropometric, clinical chemistry and

resting endothelial function (EF)
increased test finger peripheral arterial tone (PAT) relative to control;
- expressed as relative hyperemia index (RHI)] assessments.

Results: Adults with desirable weight [n=12] and overweight [n=8] state, had normal fasting plasma glucose [Mean(SD)]: FPG [91.1(4.5), 94.8(5.8) mg/dL], insulin [INS, 2.3(4.4), 3.1(4.8) µU/ml], insulin sensitivity by homeostasis model assessment [HOMA-IR, 0.62(1.2), 0.80(1.2)] and desirable resting clinic blood pressure [SBP/DBP, 118(12)/74(5), 118(13)/76(8) mmHg].

Obese adults [n=22] had

prediabetes [FPG, 106.5(3.5) g/dL],
hyperinsulinemia [INS 18.0(5.2) µU/ml],
insulin resistance [HOMA-IR .59(2.3)],
prehypertension [PreHTN; SBP/DBP 127(13)/81(7) mmHg] and
endothelial dysfunction [ED;
reduced RHI 1.7(0.3) vs. 2.4(0.3); all p<0.05].

Age-adjusted RHI correlated with BMI [r=-0.53; p<0.001]; however,

BMI-adjusted RHI was not correlated with age [r=-0.01; p=0.89].

Conclusion: Endothelial dysfunction reflective of cardiometabolic changes in obese adults can be an early risk marker for catastrophic CV events.

Keywords: Fasting plasma glucose; healthy adults; reverse cholesterol transport pathway; insulin resistance; body weight; relative hyperemia index.

ABBREVIATIONS

ADA: American Diabetes association; BMI: body mass index; CVD: cardiovascular disease; CV: cardiovascular; DBP: diastolic blood pressure; ED: endothelial dysfunction; EF: resting endothelial function; FPG: fasting plasma glucose; HOMA-IR: homeostasis model assessment; INS: insulin; JNC 7: Joint National Commission 7; LDL-C/HDL-C: low density lipoprotein cholesterol to high density lipoprotein; NCEP ATP III: National Cholesterol Education Program Adult Treatment Panel III; PAT: peripheral arterial tone; PreDM: prediabetes; PreHTN: prehypertension; PBRC: Pennington Biomedical Research Center; RHI: relative hyperemia index; SBP: systolic blood pressure; Total-C/HDL-C: total cholesterol to high density lipoprotein cholestrol; TG/HDL-C: triglycerides to high density lipoprotein cholesterol; WC: waist circumference.

Introduction

Healthy adults with no chronic medical conditions, on no prescription medications (n=24) and with low cardiovascular risk, in a randomized-order, cross-over clinical trial, with a 2 week washout period, exhibitd improved endothelial function (measured with flow mediated dilatation) with a diet rich in antioxidants (Franzini et al., 2012). Healthy over weight and obese volunteers with normal glucose appear to attenuate flow mediated dilation after high
glycemic index carbohydrate meals (Suessenbacher et al., 2011). In matched (age, work place, physical activity, tobacco use, blood pressure, serum lipids and family history of premature coronary artery disease) male shift and no shift workers, peripheral endothelial function (peripheral arterial tone (PAT) index obtained with the EndoPAT technique) was impaired in shift workers, suggesting elevated cardiovascular risk (Lavi et al., 2009).

Endothelial function thus appears to be an exquisitely sensitive marker for a variety of populations, under various conditions. Although endothelial function has been evaluated in numerous disease conditions and perturbed with a variety of agents, there has, to our knowledge, not been a comparison of resting endothelial function in free living healthy lean, overweight and obese subjects. Using a noninvasive assessment for resting endothelial function (by measuring the peripheral arterial tone, Bonetti et al., 2004), we tested the hypothesis that fasting glucose escalation in otherwise asymptomatic obese men and women is functionally reflected as endothelial dysfunction.

Endothelial Function

Assessment of resting endothelial function was done with the participant in fasting state, after having avoided stimulants (caffeine, tobacco, alcohol, exercise) for 12 hours, at the same fixed clock hour (range 8-10 AM), using the EndoPAT 2000 device manufactured by ITAMAR Medical®. This assessment technique has been previously validated (Bonetti et al., 2004), has been used in numerous (>250) peer reviewed publications (Carty et al., 2012; Kuvin et al., 2003) and has been in routine use in our clinical core. Briefly: subjects coming
in from home, after an overnight fast and having avoided stimulants for 12-hours, were placed in a supine position for 20 minutes in a quiet room before the test. A patented single use finger sleeve was then placed on the index finger of each hand to continuously measure peripheral arterial tone. A blood pressure cuff applied to the upper arm of the non-dominant arm (test arm) was then used to occlude the brachial artery for 5 minutes. This was followed by a rapid release. The dominant arm without any manipulation served as the control. The
built in, validated software integrated the data gathered from the finger sleeves of the control (undisturbed) and the test arms (during the baseline, occlusion and release phases), thus providing the relative hyperemia index (RHI) for the test arm. This flow mediated dilatation induced change in the test arm, relative to the control arm, served as the measure for endothelial function (RHI).

The subjects with desirable and overweight body weight were significantly younger [36.7(19.1) and 27.4(3.9) years, respectively], than those who were obese [53.2(11.6) years]. We performed correlations between the measure for endothelial function (RHI) and confounding factors like BMI, age and gender. Age-adjusted RHI correlated with BMI [r=- 0.53, p<0.001]; however, BMI-adjusted RHI was not associated with age [r=-0.01, p=0.89]. Fig. 1 depicts panels for the regression line for RHI as a function of age, (and BMI, glucose
and HOMA-IR, respectively) superimposed on a scatter plot. No correlation was observed between endothelial function and age (r²=0.07), while endothelial function was highly correlated with body mass index, glucose and insulin sensitivity (r²=0.3).

DISCUSSION

Asymptomatic obese adults with prediabetes (when compared to asymptomatic desirable weight and overweight adults with normal glucose), exhibit above the upper limits for desirable fasting plasma total cholesterol (>200mg/dL) and triglycerides (>150 mg/dL), but due to a relatively lower HDL-C display higher cardiac risk ratios (Total-C/HDL-C; p=0.05 and TG/HDL-C; p=0.02). A lower HDL-C and the elevated cardiac risk ratios are early clinical indicators for an impaired reverse cholesterol transport (RCT) pathway, a process by which cholesterol from the periphery is transported to the liver (Tall, 1998). The RCT pathway has been shown to be a sensitive indicator of the net flux (deposition vs. removal) of cholesterol homeostasis at the endothelium (Gupta et al., 1993; Tall et al., 2000). It is at the endothelium that the first fatty streaks, which over time deteriorate into atherosclerosis, have been shown to develop (Rosenfeld et al., 2000).

Impaired endothelial dysfunction is the first step in the process of atherosclerosis, even before the development of the fatty streak (Davignon, 2004; Ross 1999). These healthy obese men and women with prediabetes, prehypertension and impaired reverse cholesterol transport pathway were assessed to have impaired resting endothelial function, which is consistent with latent early onset cardiovascular disease.

We have demonstrated a high prevalence of isolated prediabetes or prehypertension and co-existing prediabetes and prehypertension, among the otherwise healthy US adults (Gupta et al., 2011). We have also elucidated that asymptomatic obese adults with overly heightened systemic inflammation, tend to have prediabetes and prehypertension (Gupta et al., 2010a). These individuals by various conventional measures (larger waist circumference, exacerbated systemic inflammation, higher insulin resistance, elevated triglycerides, lower high-density lipoprotein cholesterol, above average cardiac risk ratios and a significant co-existence of two or three concomitant metabolic risk factors) appear to be on an accelerated pathway towards early adverse cardiovascular events (Gupta et al., 2010a, 2010b). With this study we provide a dynamic, non-invasive, functional correlate: significant resting endothelial dysfunction, as an early biomarker for pre-atherosclerosis in obese adults with prediabetes.

Increased organ ectopic adipose burden especially in the muscle and liver appears to drive clinically recognizable adverse cardio metabolic changes (Hamdy et al., 2006). Increased inflammation (local and systemic) along with enhanced insulin resistance (liver, muscle) manifests as dysglycemia, dyslipidemia, excess reactive oxygen species, hyper-coagulablility and loss of blood pressure control (Gastaldelli et al., 2010).

We demonstrate an early impairment in the reverse cholesterol transport pathway, indicating a net deposition versus removal of cholesterol at the endothelium. In asymptomatic obese men and women with predisease conditions (prediabetes and prehypertension) when contrasted with ideal bodyweight or overweight adults with normoglycemia and normal blood pressure, resting endothelial dysfunction can be an early warning sign for future catastrophic cardiovascular adverse events.

© 2012 Gupta et al.; This is an Open Access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

REFERENCES on circulating Endothelial Progenitor Cells as Biomarkers for Cardiovascular Disease and their Angiogenesis Potential.

Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964-967.

Takahashi T, Kalka C, Masuda H, et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 1999;5:434-438.

Kocher AA, Schuster MD, Szabolcs MJ, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001;7:430-436.

Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003;108:457-463.

Hill JM, Zalos G, Halcox JPJ, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593-600.

Vasa M, Fichtlscherer S, Adler K, et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001;103:2885-2890

Laufs U, Werner N, Link A, et al. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 2004;109:220-226.

Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005;353:999-1007.

Aicher A, Heeschen C, Mildner-Rihm C, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 2003;9:1370-1376.

Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141-148.

Zhang H, Vakil V, Braunstein M, et al. Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood 2005;105:3286-3294

Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001;7:1194-1201.

American Diet is LOW in four important Nutrients that have a direct bearing on Aging and the Brain

January 12, 2014 by 2012pharmaceutical

American Diet is LOW in four important Nutrients that have a direct bearing on Aging and the Brain

Reporter: Aviva Lev-Ari, PhD, RN

Four Nutrients That Will Help You Reach the Century Mark

The fact that you can manipulate your genes with happiness doesn’t mean you can completely disregard lifestyle choices, as that would be foolhardy. The basics are still important—diet, exercise, sleep, etc. Research suggests the modern American diet is increasingly low in four important nutrients that have a direct bearing on aging, and our brains are suffering for it. If you hope to one day become a healthy, happy centenarian, you must address the following:16

Vitamin D

DHA

Folate

Magnesium

Vitamin D

Vitamin D’s list of health benefits is amazingly long, including helping your brain combat the damage from free radicals, which helps prevent cognitive decline. The important factor when it comes to vitamin D is your serum level, which should be between 50-70 ng/ml year-round, and the only way to determine this is with a blood test.

Your skin produces vitamin D in response to ultraviolet light, so sun exposure or a safe tanning bed are the preferred methods of boosting your vitamin D. However, a D3 supplement can be used when necessary. Most adults need about 8,000 IUs of vitamin D3 per day to achieve serum levels of 40 ng/ml. If you take supplemental vitamin D3, you also need to make sure you’re getting enough vitamin K2, as these two nutrients work in tandem to ensure calcium is distributed into the proper areas in your body.

DHA (Docosahexaenoic Acid)

DHA is an omega-3 fat that plays a role in keeping your cell membranes healthy, flexible, and resistant to oxidative stress, which decreases inflammation. Chronic inflammation is a key factor in many degenerative diseases, including dementia. Low DHA is has been linked with depression, memory loss, and even elevated hostility, which reflect its importance to optimal brain function.

The American diet has far too many omega-6 fats and not enough omega-3 fats due to its heavy reliance on processed food. You can boost your DHA by eating more fish, such as salmon and sardines, but so much of the fish today is contaminated with mercury and other toxic compounds that I prefer to take a high quality omega-3 fat supplement such as krill oil.

Folate (Vitamin B9)

Folate helps prevent depression, seizure disorders, brain atrophy, and other neurological problems. Folate deficiencies correlate with impaired memory, slowed mental processing and overall cognitive decline, particularly in the elderly. Your body also needs folate to make red blood cells. Folate deficiency has been thought to lead to elevated homocysteine levels, which can be a major contributor to heart disease and Alzheimer’s. However, recent studies may have disproven that idea.17

People often confuse folate with folic acid, and it’s important to know the difference. Folate is the naturally-occurring form of the vitamin and contains all of the related isomers your body needs for optimal use. Folic acid is the synthetic form of the vitamin that is used in most supplements and in fortified foods.

It is always preferable to raise your folate levels by modifying your diet, as opposed to eating “enriched” foods or taking a multivitamin. Foods rich in folate include egg yolks, sunflower seeds, asparagus, avocados, broccoli, cauliflower, basil, parsley, and greens such as romaine, turnip, collards, and spinach.18 If you do think you need a supplement, make sure it lists “folate” on the label, rather than folic acid, as this suggests food sources were used.

Magnesium

Magnesium plays a role in your body’s detoxification processes and is therefore important for minimizing damage from environmental chemicals, heavy metals and other toxins. Even glutathione, considered by many to be your body’s most powerful antioxidant, requires magnesium in order to be synthesized. But this important mineral also helps your brain.

Magnesium acts as a buffer between neuron synapses, particularly those involved with cognitive functions (learning and memory). Magnesium “sits” on the receptor without activating it, in effect protecting the receptor from over-activation by other neurochemicals, especially glutamate. Glutamate is an “excitotoxin,” which can harm your brain if it accumulates, and magnesium helps prevent this. That’s why you often see magnesium advertised as a “calming” nutrient.

Good sources of magnesium are whole organic foods, especially dark green leafy vegetables, seaweed, dried pumpkin seeds, unsweetened cocoa, flaxseed, almond butter, and whey. If you choose to add a magnesium supplement, there are many forms so it can be a bit confusing. A newer type called magnesium threonate is particularly good due to its ability to penetrate cell membranes and cross your blood-brain barrier, which is important for preserving good cognitive function as you age.

SOURCE

http://articles.mercola.com/sites/articles/archive/2014/01/09/centenarians.aspx#!

Posted in Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry | Leave a Comment »

Preventive Medicine Philosophy: Excercise vs. Drug, IF More of the First THEN Less of the Second

January 12, 2014 by 2012pharmaceutical

Preventive Medicine Philosophy: Excercise vs. Drug, IF More of the First THEN Less of the Second

Reporter and Curator: Aviva Lev-Ari, PhD, RN

How Centenarians Explain Their Longenity

What the Elders Themselves Have to Say

The majority of centenarians do not feel their chronological age; on average, they report feeling 20 years younger. They also tend to have positive attitudes, optimism, and a zest for life. Could it be that personality characteristics and worldviews play a more significant role than genetics, diet, or exercise?

One way to determine this is to ask centenarians questions about how they see the world, what they value, and to what they attribute their own longevity. What are their secrets to aging well? These individuals represent centuries of wisdom that should not be overlooked. So that’s what researchers are now doing—mining the minds of centenarians for nuggets of wisdom. Regardless of which interviews you read, this is where patterns really DO emerge. In interviews and surveys with centenarians, the following themes come up time and time again when asked to explain why they’ve lived so long:¹⁰

Keeping a positive attitude Eating good food

Exercising moderately (most report basic activities, like walking, biking, gardening, swimming, etc.) Clean living (not smoking or drinking excessively, etc.)

Living independently Family

“Good genes” Friends

Staying mentally active and always learning something new Faith/spirituality

VIEW VIDEO

http://articles.mercola.com/sites/articles/archive/2014/01/09/centenarians.aspx#!

By Dr. Mercola

One of the key health benefits of exercise is that it helps normalize your glucose, insulin, and leptin levels by optimizing insulin and leptin receptor sensitivity. This is perhaps the most important factor for optimizing your overall health and preventing chronic disease, and may explain why exercise is such a potent preventive medicine.

In fact, researchers recently suggested that exercise is “the best preventive drug” for many common ailments, from psychiatric disorders to heart disease, diabetes, and cancer.¹ According to Jordan Metzl, a sports-medicine physician at New York City’s Hospital for Special Surgery and author of The Exercise Cure:

“Exercise is the best preventive drug we have, and everybody needs to take that medicine.”

And, as stated by Dr. Timothy Church,² director of preventive medicine research at the Pennington Biomedical Research Center in Baton Rouge:

“Exercise strengthens the entire human machine — the heart, the brain, the blood vessels, the bones, the muscles. The most important thing you can do for your long-term health is lead an active life.”

Non-Exercise Movement Is Equally, if Not More, Important for Health

Unfortunately, many fail to get sufficient amounts of exercise. Worse yet, a majority of people may still endanger their health simply by sitting too much. Compelling evidence actually suggests that even if you exercise regularly,prolonged sitting is itself a risk factor for chronic disease and reduced lifespan…

Overall, federal data suggest only 21 percent of American adults meet the government recommendation to engage in two and half hours’ worth of aerobic and muscle-strengthening exercise each week, so there’s clearly a lot of room for improvement. Ideally though, you’ll want to exercise regularly AND frequently interrupt your sitting in order to optimize your health and longevity. I’ll review the reasons for this below.

Exercise Benefits Found to Be EQUAL to Drugs for Heart Disease and Diabetes

A recent meta-review conducted by researchers at Harvard and Stanford³compared the effectiveness of exercise versus drug interventions on mortality outcomes for diabetes, coronary heart disease, heart failure, and stroke. After reviewing 305 randomized controlled trials, which included nearly 339,300 people, they found “no statistically detectable differences” between physical activity and medications for prediabetes and heart disease.

This is a potent reminder of the power of simple lifestyle changes, as well as the shortcomings of the drug paradigm!

Besides optimizing insulin/leptin receptor sensitivity, other beneficial biochemical changes also occur during exercise, including alterations in more than 20 different metabolites involved in fat burning and metabolism, among other things. As stated by Dr. Church, exercise indeed affects your entire body—from head to toe—in beneficial ways. This includes changes in your:

Muscles, which use glucose and ATP for contraction and movement. Tiny tears in your muscles make them grow bigger and stronger as they heal. Gaining more muscle through resistance exercises has many benefits, from losing excess fat to maintaining healthy bone mass and preventing age-related muscle loss as you age. The intensity of your resistance training can achieve a number of beneficial changes on the molecular, enzymatic, hormonal, and chemical level in your body.

Lungs. As your muscles call for more oxygen, your breathing rate increases. The higher your VO2 max—your maximum capacity of oxygen use—the fitter you are.

Heart. Your heart rate increases with physical activity to supply more oxygenated blood to your muscles. The fitter you are, the more efficiently your heart can do this, allowing you to work out longer and harder. Your blood pressure will also decrease as a result of new blood vessels forming.

Brain. The increased blood flow also benefits your brain, allowing it to almost immediately function better. Exercising regularly also promotes the growth of new brain cells, boosting your capacity for memory and learning. A number of neurotransmitters are also triggered, such as endorphins, serotonin, dopamine, glutamate, and GABA. Some of these are well-known for their role in mood control. Exercise, in fact, is one of the most effective prevention and treatment strategies for depression.

Joints and Bones. Exercise can place as much as five or six times more than your body weight on them. Weight-bearing exercise is one of the most effective remedies against osteoporosis, as your bones are very porous and soft, and as you get older, your bones can easily become less dense and hence, more brittle — especially if you are inactive.

For Optimal Benefits, Make Sure You’re Exercising Correctly

I’ve often equated exercise to a drug from the perspective that they both need to be wisely prescribed in order to optimize your health. Simply doing random exercises for the sake of “exercising” will not achieve the benefits you seek. In fact it could cause serious injury, especially if you engage in strength training with poor form and no coaching. In terms of “dosage,” it’s important to note the changes in recommendations that have taken place over the past few years. While conventional aerobic exercise was long considered the “gold standard” of a good workout, research has refuted such notions.

Instead, high-intensity interval training (which requires but a fraction of the time compared to conventional cardio) has been shown to be FAR more efficient and effective, compared to longer, slower cardio workouts. In fact, exercises such as long distance running have been shown to be among the worst forms of exercise, in terms of health benefits.

The reason for this is quite simple. High intensity interval training (HIIT) mimics the movements of our hunter-gatherer ancestors, which included short bursts of high-intensity activities, but not long-distance running. This, researchers say, is what your body is hard-wired for. Basically, by exercising in short bursts, followed by periods of recovery, you recreate exactly what your body needs for optimum health. Twice-weekly sessions, which require no more than 20 minutes from start to finish, can help you:

Lower your body fat

Improve your muscle tone

Boost your energy and libido

Improve athletic speed and performance

Naturally increase your body’s production of human growth hormone (HGH)—a synergistic, foundational biochemical underpinning that promotes health and longevity. Conventional cardio will NOT boost your HGH level

The Importance of Non-Exercise Movement

Next, let’s address the issue of non-exercise movement. I also like to call this intermittent movement. This is the latest area of physical activity that’s gaining a lot of attention, and for good reason. Studies have repeatedly found strong correlations between prolonged sitting or inactivity and reduced life expectancy—even if you exercise regularly!

It appears that temporary vigorous exercise simply cannot compensate for the damage incurred by prolonged daily sitting. For example, a recent analysis⁴ of 18 studies, found that those who sat for the longest periods of time were twice as likely to have diabetes or heart disease, compared to those who sat the least. An earlier study⁵ that highlighted much of the recent evidence linking sitting with biomarkers of poor metabolic health, also found that total sitting time correlates with an increased risk of type 2 diabetes, heart disease, and other prevalent chronic health problems—even if you exercise regularly.

The answer, fortunately, is quite simple. You simply need to make sure you move your body more often. Simply standing upfrom a seated position has been found particularly effective at counteracting the ill effects of sitting. This is something I seek to do every 15 minutes while I am sitting. I set a timer to remind me. When the timer rings I get up and do some simple hamstring or chest stretches for a minute or two. I am testing a variety of different ones and hope to report on them later this year.

Earlier this year, I interviewed Dr. Joan Vernikos,⁶ former director of NASA’s Life Sciences Division and author of Sitting Kills, Moving Heals, on this topic. Her groundbreaking research reveals why standing up is such an effective remedy—it’s because when you stand up, your body acts against gravity. Sitting actually simulates a low-gravity type environment for your body, and your body deteriorates at a far more rapid pace in anti-gravity situations… Hence, the remedy is to continuously engage in physical movements, as this increases the forces of gravity on your body.

Simple everyday activities such as housecleaning, cooking, gardening, hanging clothes to dry, bending over to pick up a stray sock, reaching for an item on a high shelf, all fall within the spectrum of movements you would ideally engage in—more or less continuously—from morning until night. To learn more about this important aspect of health, please see this previousarticle.

Variety Is the Spice of Life and the Key to Optimal Health

In short, one of the keys to optimal health is to remain as active as you can, all day long. Whenever you have a chance to move and stretch your body in the course of going about your day—do it! That said, there’s no doubt that an ideal fitness regimen requires a little more effort. Fortunately, you can accomplish the bulk of it through high intensity exercises, which require a minimal time investment—as little as 20 minutes, two to three times a week. As a general rule, I recommend incorporating a wide variety of exercises, including the following:

Stand Up Every 15 Minutes. While not intuitively obvious, emerging evidence clearly shows that even highly fit people who exceed the expert exercise recommendations are headed for premature death if they sit for long periods of time. My interview with NASA scientist Dr. Joan Vernikos goes into great detail why this is so, and what you can do about it.

Interval (Anaerobic) Training: This is when you alternate short bursts of high-intensity exercise with gentle recovery periods.

Strength Training: Rounding out your exercise program with a 1-set strength training routine will ensure that you’re really optimizing the possible health benefits of a regular exercise program. You can also “up” the intensity by slowing it down. For more information about using super slow weight training as a form of high intensity interval exercise, please see my interview with Dr. Doug McGuff.

Core Exercises: Your body has 29 core muscles located mostly in your back, abdomen and pelvis. This group of muscles provides the foundation for movement throughout your entire body, and strengthening them can help protect and support your back, make your spine and body less prone to injury, and help you gain greater balance and stability.

Foundation Training, created by Dr. Eric Goodman, is an integral first step of a larger program he calls “Modern Moveology,” which consists of a catalog of exercises. Postural exercises such as those taught in Foundation Training are critical not just for properly supporting your frame during daily activities; they also retrain your body so you can safely perform high-intensity exercises without risking injury. Exercise programs like Pilates and yoga are also great for strengthening your core muscles, as are specific exercises you can learn from a personal trainer.

Stretching: My favorite type of stretching is active isolated stretches. With Active Isolated Stretching, you hold each stretch for only two seconds, which works with your body’s natural physiological makeup to improve circulation and increase the elasticity of muscle joints. This technique also allows your body to repair itself and prepare for daily activity. You can also use devices like the Power Plate to help you stretch.

SOURCE

http://fitness.mercola.com/sites/fitness/archive/2014/01/10/exercise-preventive-drug.aspx

Posted in Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry | Leave a Comment »

Smoking Status: Effects on Heart and Blood Vessels & Meta Data Analysis on Death from Lung Cancer

January 9, 2014 by 2012pharmaceutical

Smoking Status: Effect on Heart and Blood Vessels & Meta Data Analysis on Death from Lung Cancer

Curator: Aviva Lev-Ari, PhD, RN

This article has TWO parts:

Part 1: Smoking Effects on Cardiovascular Diseases

and

Part 2: Incidence-Rate Ratios for Death from Any Cause and Death from Lung Cancer, According to Smoking Status – Meta Data Analysis

Part 1

Smoking Effect on Cardiovascular Diseases

Not Smoking as Part of a Heart Healthy Lifestyle

http://www.nhlbi.nih.gov/health/health-topics/topics/smo/lifestyle.html

How Does Smoking Affect the Heart and Blood Vessels?

Cigarette smoking causes about 1 in every 5 deaths in the United States each year. It’s the main preventable cause of death and illness in the United States.

Smoking harms nearly every organ in the body, including the heart, blood vessels, lungs, eyes, mouth, reproductive organs, bones, bladder, and digestive organs. This article focuses on how smoking affects the heart and blood vessels.

Other Health Topics articles, such as COPD (chronic obstructive pulmonary disease),Bronchitis, and Cough, discuss how smoking affects the lungs.

Overview

Smoking and Your Heart and Blood Vessels

The chemicals in tobacco smoke harm your blood cells. They also can damage the function of your heart and the structure and function of your blood vessels. This damage increases your risk of atherosclerosis (ath-er-o-skler-O-sis).

Atherosclerosis is a disease in which a waxy substance called plaque (plak) builds up in the arteries. Over time, plaque hardens and narrows your arteries. This limits the flow of oxygen-rich blood to your organs and other parts of your body.

Coronary heart disease (CHD) occurs if plaque builds up in the coronary (heart) arteries. Over time, CHD can lead to chest pain, heart attack, heart failure,arrhythmias (ah-RITH-me-ahs), or even death.

Smoking is a major risk factor for heart disease. When combined with other risk factors—such as unhealthy blood cholesterol levels, high blood pressure, and overweight or obesity—smoking further raises the risk of heart disease.

Smoking also is a major risk factor for peripheral arterial disease (P.A.D.). P.A.D. is a condition in which plaque builds up in the arteries that carry blood to the head, organs, and limbs. People who have P.A.D. are at increased risk for heart disease, heart attack, and stroke.

Smoking and Atherosclerosis

The image shows how smoking can affect arteries in the heart and legs. Figure A shows the location of coronary heart disease and peripheral arterial disease. Figure B shows a detailed view of a leg artery with atherosclerosis—plaque buildup that's partially blocking blood flow. Figure C shows a detailed view of a coronary (heart) artery with atherosclerosis.

The image shows how smoking can affect arteries in the heart and legs. Figure A shows the location of coronary heart disease and peripheral arterial disease. Figure B shows a detailed view of a leg artery with atherosclerosis—plaque buildup that’s partially blocking blood flow. Figure C shows a detailed view of a coronary (heart) artery with atherosclerosis.

Any amount of smoking, even light smoking or occasional smoking, damages the heart and blood vessels. For some people, such as women who use birth control pills and people who have diabetes, smoking poses an even greater risk to the heart and blood vessels.

Secondhand smoke also can harm the heart and blood vessels. Secondhand smoke is the smoke that comes from the burning end of a cigarette, cigar, or pipe. Secondhand smoke also refers to smoke that’s breathed out by a person who is smoking.

Secondhand smoke contains many of the same harmful chemicals that people inhale when they smoke. Secondhand smoke can damage the hearts and blood vessels of people who don’t smoke in the same way that active smoking harms people who do smoke. Secondhand smoke greatly increases adults’ risk of heart attack and death.

Secondhand smoke also raises children and teens’ risk of future CHD because it:

Lowers HDL cholesterol (sometimes called “good” cholesterol)
Raises blood pressure
Damages heart tissues

The risks of secondhand smoke are especially high for premature babies who haverespiratory distress syndrome (RDS) and children who have conditions such as asthma.

Researchers know less about how cigar and pipe smoke affects the heart and blood vessels than they do about cigarette smoke.

However, the smoke from cigars and pipes contains the same harmful chemicals as the smoke from cigarettes. Also, studies have shown that people who smoke cigars are at increased risk for heart disease.

Benefits of Quitting Smoking and Avoiding Secondhand Smoke

One of the best ways to reduce your risk of heart disease is to avoid tobacco smoke. Don’t ever start smoking. If you already smoke, quit. No matter how much or how long you’ve smoked, quitting will benefit you.

Also, try to avoid secondhand smoke. Don’t go to places where smoking is allowed. Ask friends and family members who smoke not to do it in the house and car.

Quitting smoking will reduce your risk of developing and dying from heart disease. Over time, quitting also will lower your risk of atherosclerosis and blood clots.

If you smoke and already have heart disease, quitting smoking will reduce your risk ofsudden cardiac death, a second heart attack, and death from other chronic diseases.

Researchers have studied communities that have banned smoking at worksites and in public places. The number of heart attacks in these communities dropped quite a bit. Researchers think these results are due to a decrease in active smoking and reduced exposure to secondhand smoke.

Outlook

Smoking or exposure to secondhand smoke damages the heart and blood vessels in many ways. Smoking also is a major risk factor for developing heart disease or dying from it.

Quitting smoking and avoiding secondhand smoke can help reverse heart and blood vessel damage and reduce heart disease risk right away.

Quitting smoking is possible, but it can be hard. Millions of people have successfully quit smoking and remained nonsmokers. A variety of strategies, programs, and medicines are available to help you quit smoking.

Not smoking is an important part of a heart healthy lifestyle. A heart healthy lifestyle also includes following a healthy diet, maintaining a healthy weight, and being physically active.

SOURCE

http://www.nhlbi.nih.gov/health/health-topics/topics/smo/

What Are the Risks of Smoking?

http://www.nhlbi.nih.gov/health/health-topics/topics/smo/risks.html

What Are the Benefits of Quitting Smoking?

One of the best ways to reduce your risk of coronary heart disease is to avoid tobacco smoke. Don’t ever start smoking. If you already smoke, quit. No matter how much or how long you’ve smoked, quitting will benefit you.

Also, try to avoid secondhand smoke. Don’t go to places where smoking is allowed. Ask friends and family members to not smoke in the house and car.

Quitting smoking will benefit your heart and blood vessels. For example:

Heart disease risk associated with smoking begins to decrease soon after you quit. It continues to decrease over time. Your risk is cut in half 1 year after quitting. If you have not developed heart disease within 15 years of quitting, your risk is nearly the same as the risk in someone who has never smoked.
Deaths from heart disease are reduced by one-third in people who quit smoking compared with people who continue smoking. Repeat heart attacks are reduced by about the same amount.
People who smoke and already have heart disease lower their risk of sudden cardiac death, second heart attacks, and death from other chronic diseases by as much as half if they quit smoking.
Your risk of atherosclerosis and blood clots declines over time after you quit smoking.

Quitting smoking can lower your risk of heart disease as much as, or more than, common medicines used to lower heart disease risk, including aspirin, statins, beta-blockers, and ACE inhibitors.

In recent years, communities in Montana, Colorado, New York, Massachusetts, Indiana, and Ohio have banned smoking at worksites and in public places. Some countries, including Italy, Ireland, Norway, Scotland, and France, have put similar bans in place.

Studies of these communities show a rapid drop in the number of heart attacks within the first year of the ban. The number of heart attacks continues to decrease as time goes on.

Researchers think these results are due to a decrease in active smoking and reduced exposure to secondhand smoke.

http://www.nhlbi.nih.gov/health/health-topics/topics/smo/benefits.html

Strategies To Quit Smoking

http://www.nhlbi.nih.gov/health/health-topics/topics/smo/strategies.html

Clinical Trials

http://www.nhlbi.nih.gov/health/health-topics/topics/smo/trials.html

Links to Other Information About Smoking and Your Heart

http://www.nhlbi.nih.gov/health/health-topics/topics/smo/links.html

Part 2

Incidence-Rate Ratios for Death from Any Cause and Death from Lung Cancer, According to Smoking Status

CORRESPONDENCE

Meta-Analysis and the Surgeon General’s Report on Smoking and Health

N Engl J Med 2014; 370:186-188January 9, 2014DOI: 10.1056/NEJMc1315315

http://www.nejm.org/doi/full/10.1056/NEJMc1315315?query=TOC

To the Editor:

Fifty years ago, on January 11, 1964, the landmark report on smoking and health1 was made public by U.S. Surgeon General Luther L. Terry. That report made substantial use of a meta-analysis performed by statistician William G. Cochran,2,3 who was a professor of statistics at Harvard University. Cochran had already developed statistical methods for various applications, including for the combination of results from different experiments.2 As an author of the report, Cochran followed the major steps for a modern systematic review, including a meta-analysis based on data on individual participants in seven large, prospective cohort studies that had been initiated in the 1950s. Although Cochran used modern state-of-the-art statistical methods, the presentation of the results with confidence intervals was rarely done at that time.

Using summary data provided in the report, we reconstructed Cochran’s meta-analysis, concentrating on death from any cause and death from lung cancer (Figure 1FIGURE 1Incidence-Rate Ratios for Death from Any Cause and Death from Lung Cancer, According to Smoking Status.). The results, produced with the R statistical package meta, version 3.1-2,4 show the contributions of the individual studies (for a list of the full names of the studies, see the Supplementary Appendix, available with the full text of this letter at NEJM.org). The magnitude and precision of the effects of cigarette smoking and their consistency over studies were major criteria for Cochran.1 In our analysis, the test of heterogeneity yielded a nonsignificant result for lung-cancer mortality and a significant result for all-cause mortality, with a small between-study variance. The statistical method we used to create this forest plot was slightly different from the one Cochran used, but it provided almost identical results. When added to the tables in the Surgeon General’s report, Figure 1 shows a dramatic summary of the overwhelming evidence of the harmful effects of cigarette smoking. These findings should be interpreted in light of the fact that before the report was released, as noted by Meier,3 “some of the most eminent statisticians (including Sir Ronald A. Fisher), emphasizing the potential biases in the observational material, declared that no reasonable conclusion adverse to cigarette smoking could be drawn from the available evidence.”

Cochran took an impartial systematic approach to evaluation and used a sensitivity analysis to perform a thorough appraisal of risk of bias. The first meta-analyses in medicine were conducted at the beginning of the 20th century; however, their major breakthrough came only with the activities of the Cochrane Collaboration during the 1990s.5 Although it is widely recognized that the Surgeon General’s report on smoking and health is important for public policy, the importance of this report for meta-analysis is often overlooked and also warrants attention.

Martin Schumacher, Ph.D.
Gerta Rücker, Ph.D.
Guido Schwarzer, Ph.D.
University Medical Center Freiburg, Freiburg, Germany
ms@imbi.uni-freiburg.de

References

1Smoking and health: report of the Advisory Committee to the Surgeon General of the Public Health Service. Washington, DC: Public Health Service, 1964. (DHEW publication no. (PHS) 64-1103.)

2Hansen M, Mosteller F. William Gemmell Cochran, 1909-1980: bibliographical memoir. Washington, DC: National Academy of Sciences, 1987.

3Meier P. William G. Cochran and public health. In: Rao PS, Sedransk J, eds. W.G. Cochran’s impact on statistics. New York: Wiley, 1984:73-81.

4Schwarzer G. meta: An R package for meta-analysis. R News 2007;7:40-45(http://cran.r-project.org/doc/Rnews/Rnews_2007-3.pdf)

5Chalmers I, Hedges LV, Cooper H. A brief history of research synthesis. Eval Health Prof 2002;25:12-37
CrossRef | Web of Science | Medline

SOURCE

http://www.nejm.org/doi/full/10.1056/NEJMc1315315?query=TOC

Posted in Atherogenic Processes & Pathology, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiovascular Research, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Origins of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Statistical Methods for Research Evaluation | Tagged Meta Data Analysis | Leave a Comment »

UPDATED Market Impact on Global Suppliers of Renal Denervation Systems by Pivotal US Trial: Metronics’ Symplicity Renal Denervation System FAILURE at Efficacy Endpoint

January 9, 2014 by 2012pharmaceutical

Market Impact on Global Suppliers of Renal Denervation Systems by Pivotal US Trial: Metronics’ Symplicity Renal Denervation System FAILURE at Efficacy Endpoint

Curator and Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 1/16/2025

Momentum continues for renal denervation as CMS considers national Medicare coverage

Michael Walter | January 14, 2025 | Cardiovascular Business | Interventional Cardiology

“Hypertension is a global health epidemic that impacts a wide variety of patients,” Jason Weidman, senior vice president and president of Medtronic’s coronary and RDN business, said in a separate statement. “As the leader in developing a minimally invasive treatment option for hypertension, Medtronic has been closely engaged with CMS to establish a national coverage pathway for Symplicity Spyral. We appreciate CMS’ efforts in creating new pathways to expedite access to breakthrough technologies like Symplicity Spyral and look forward to our continued partnership in developing a national coverage policy.”

The U.S. Centers for Medicare and Medicaid Services (CMS) is officially exploring the potential of a national Medicare coverage policy for the use of renal denervation (RDN) to treat uncontrolled hypertension. The agency opened a new national coverage analysis (NCA) to explore the subject, reviewing the available evidence of RDN’s safety and effectiveness while seeking public comments from various stakeholders on the potential impact of improved coverage.

“We are particularly interested in comments that include scientific evidence, specifically any peer-reviewed literature, that describes the role of RDN,” CMS said in its NCA. “We are also interested in health disparities and equity aspects that should be considered in the review.”

Recor Medical and Medtronic both shared public support of the NCA, highlighting the benefits improved Medicare coverage for RDN could have on patient care.

“The initiation of an NCA is the first step in the NCD process towards the potential expansion of coverage of Recor’s Paradise Ultrasound RDN system among Medicare beneficiaries,” Recor Medical said in a statement. “Recor appreciates CMS’ consideration of potential national coverage of RDN as a hypertension treatment option for Medicare beneficiaries and will continue to work closely with CMS throughout the NCD process.”

SOURCES

https://cardiovascularbusiness.com/topics/clinical/interventional-cardiology/momentum-continues-renal-denervation-cms-considers-national-medicare-coverage?utm_source=newsletter

Renal denervation systems from Recor Medical, Medtronic receive new outpatient payments

CMS increases inpatient payment for Recor Medical, Medtronic renal denervation systems

First US patient treated with Medtronic’s FDA-approved renal denervation system

FDA approves first renal denervation system for uncontrolled hypertension

Where renal denervation stands for the treatment of drug-resistant hypertension

VIDEO: SYMPLICITY HTN-3 and the future of renal denervation

UPDATED on 12/8/2015

New Approaches to Denervation Therapy — TCT 2015

http://www.dicardiology.com/videos/new-approaches-denervation-therapy-%E2%80%94-tct-2015/4592515437001

UPDATED on 2/22/2014

Cordis Corporation Receives CE Mark for RENLANE Renal Denervation System to Treat Resistant Hypertension

February 21, 2014 09:59 AM Eastern Standard Time

FREMONT, Calif.–(BUSINESS WIRE)–Cordis Corporation announced today that it has received European CE Mark for its RENLANE™ Renal Denervation System for the treatment of patients with resistant hypertension and has completed the first successful cases in Europe. The RENLANE™ System consists of a unique, helical shaped, irrigated, multi-electrode ablation catheter with a multi-channel radiofrequency (RF) ablation system.

“The design of the catheter also makes handling the device very easy.”

The first successful cases were performed by Hannes Reuter, M.D., at the University of Cologne Hospital in Germany. The treated patients were diagnosed with resistant hypertension and had systolic blood pressures greater than or equal to 160 mm Hg, despite undergoing traditional drug therapy with three or more anti-hypertensive medications. All procedures were performed successfully and patients were discharged after one day.

“The novel technological design of the RENLANE™ Renal Denervation Catheter with its configuration of five electrodes and irrigated technology, allows for shorter procedure duration, sparing of contrasting dye and likely more protection of the endothelium,” said Hannes Reuter, M.D., University of Cologne, Germany. “The design of the catheter also makes handling the device very easy.”

Nearly one billion people worldwide live with hypertension, or high blood pressure, and the World Health Organization estimates that it is the cause of one in every eight deaths, making hypertension the third leading cause of death worldwide.1 Chronic high blood pressure is a serious condition that can lead to increased risk of stroke, kidney disease, heart attack and heart failure. It is estimated that between 15 and 30 percent of treated hypertensive patients are resistant to traditional drug therapy, defined as failure to respond to three or more drugs.2 Uncontrolled hypertension is a major risk factor for mortality so alternative therapies such as renal denervation for treatment-resistant patients have emerged to help address this patient population. Additionally, the economic burden of the condition is significant. The International Society of Hypertension estimates the annual cost of healthcare expenditure directly related to elevated blood pressure to be almost $500 billion.3

“Chronic hypertension poses a significant health risk to patients and also places a huge burden on global health care systems,” said Celine Martin, Worldwide President, Cordis Corporation. “We are pleased to make our RENLANE™ Renal Denervation System available to European clinicians in need of solutions for patients who do not respond to traditional drug therapy. And we are looking forward to gaining more experience with this therapy and making it available to more patients in need of treatment around the world.”4

The RENLANE™ Renal Denervation Catheter features five irrigated electrodes located at the tip of the ablation catheter and is used in conjunction with the RENLANE™ Multi-Channel RF generator for energy delivery. It is indicated for use in adult patients (> 18 years) with drug resistant hypertension to denervate the renal arteries to reduce blood pressure.

The RENLANE™ Renal Denervation System is another addition to Cordis’ broad and growing portfolio of minimally invasive therapies for patients that suffer from cardiovascular disease worldwide. The company is committed to working with leading clinicians to address the significant and growing burden of cardiovascular disease with innovative endovascular solutions that address the clinical needs of our customers and the patients they treat.

About Renal Denervation

Renal denervation is a minimally invasive, catheter-based treatment for resistant hypertension, or high blood pressure that does not respond to traditional drug therapy (three or more drugs). During the procedure, a thin flexible tube called a catheter is inserted through a small incision in the groin and it is then weaved up to the renal arteries through a blood vessel in the leg. Once the catheter tip is placed inside of a renal artery, radiofrequency (RF) energy is delivered to reduce hyperactivity of the surrounding nerves, which causes the kidneys to produce less of the hormones that are responsible for chronic high blood pressure. Both of the renal arteries are treated during the procedure.

About Cordis Corporation

Cordis Corporation, part of the Johnson & Johnson Family of Companies, is a worldwide leader in the development and manufacture of interventional vascular technology. Through the company’s innovation, research and development, Cordis partners with clinicians to treat millions of patients who suffer from cardiovascular disease worldwide. More information about Cordis Corporation can be found at http://www.cordis.com.
1.     The World Health Report 2012. World Health Organization; 2012:58
2.   Pimenta E, Calhoun DA. Resistant hypertension: incidence, prevalence, and prognosis. Circulation. 2012;125:1594-6.
3.   Lawes CM, Vander Hoorn S, Rodgers A; International Society of Hypertension. Global burden of blood-pressure related disease, 2001. Lancet. 2008;371:1513-1518.
4.   The RENLANE™ Renal Denervation System is not available for sale or use in the United States.

SOURCE

From: FierceMedicalDevices <editors@fiercemedicaldevices.com>
Reply-To: <editors@fiercemedicaldevices.com>
Date: Fri, 21 Feb 2014 18:00:51 +0000 (GMT)
To: <avivalev-ari@alum.berkeley.edu>
Subject: | 02.21.14 | J&J’s Cordis scores renal denervation CE mark

UPDATED on 2/7/2014

Renal Denervation Before the Fall. Guest: Deepak Bhatt

Samuel Z. Goldhaber, MD, Deepak L. Bhatt, MD, MPH

January 24, 2014

EDITORS’ RECOMMENDATIONS

SYMPLICITY HTN-3 Complicates Renal-Denervation Field

Renal Denervation Fails in SYMPLICITY HTN-3

VIEW VIDEO

http://www.medscape.com/viewarticle/819665?nlid=47583_1984&src=wnl_edit_medn_card&uac=93761AJ&spon=2

UPDATED on 1/23/2014

Covidien bails on renal denervation

January 21, 2014 by Brad Perriello

Covidien said it’s pulling the plug on its OneShot renal denervation device, citing the slow development of the hypertension market.

Covidien (NYSE:COV) said it plans to wind down its OneShot renal denervation program, largely due to “slower than expected development of the renal denervation market,” meaning the end for a U.S. clinical trial of the high blood pressure device.

“This decision resulted from Covidien’s regular review of strategic programs and growth potential for various aspects of its product portfolio,” according to a press release. “Over the next several weeks, the company will collaborate with physicians and the renal denervation community to ensure existing OneShot patients are informed and the currently enrolling clinical trials are transitioned appropriately.”

The OneShot device already had CE Mark approval in the European Union for treating resistant hypertension in April 2012, when Covidien paid $60 million in cash and put another $170 million on the table in milestones.

SIMILAR ENTRIES

The move means the closure of Covidien’s Rapid II trial, which was projected to enroll 253 patients, comparing treatment with the OneShot device with standard drug treatment in patients with resistant hypertension, according to the release.

SOURCE

http://www.massdevice.com/news/covidien-bails-renal-denervation

UPDATED on 1/21/2014

It’s not that Symple! The Rise (and Fall?) of Renal Denervation by Amy Siegel, http://s2nhealth.com

http://s2nhealth.com/2014/01/17/the-rise-and-fall-of-renal-denervation.html#.Ut7Mmxw8JaE

Clinical Trial Results will impact negatively the following players in the Global Supplier Ecosystem for Renal Denervation Systems:

US Campbell, CA Kona Medical is attempting to address these limitations. The system delivers energy from outside the patient to the renal nerves. Ultimately, the procedure will be a “no puncture,” noninvasive technique, compatible with technologies that will allow for temperature and lesion mapping. A noninvasive procedure will allow titration of the therapy— that is, the application of patient-specific dose fractions while monitoring therapeutic effect in between fractions. The basis of the technology is focused ultrasound, not high intensity (HIFU) as one might see and expect in the treatment of tumors, but low-intensity focused ultrasound (LIFU). The biologic underpinnings of this treatment are described in past literature for treating nerves using ultrasound. Kona noninvasive system. The system is depicted in a custom chair; another version of the system is compatible with a standard fluoroscopy or MRI table. Both ultrasound (through elastography and the evolution of temperature mapping and MRI) allow further imaging and analysis of the treatment area. The dose distribution surrounding the artery is that of an annular ring around the wall of the artery. Kona has shown in animal studies that a heat/vibratory cloud at one plane along the artery is highly effective at long-term inhibition of renal nerves with no visible effect on any portion of the artery at any time point.

US, Ronkonkoma, NY & Germany – Paradise by ReCor Medical 6-F compatible catheter with a cylindrical transducer that emits ultrasound energy circumferentially, allowing for a more efficient renal denervation procedure First-in-human (15 patients at 3 months) BP drop, mm Hg -32/-16 at 3 mo. The ultrasound transducer lies within a low-pressure balloon that allows for self-centering of the transducer and gentle contact with the artery wall for uniform circumferential denervation. This means that nerves below the surface of the artery wall are damaged in 360° with a single emission. The balloon also enables cooled fluid to circulate during the energy delivery process, thereby cooling the endothelial wall and protecting it from any excessive heating that could be caused by other energy sources or designs. Preliminary F-I-M clinical data for PARADISE were reported previously at the “TRenD 2012” transcatheter renal denervation scientific meeting by cardiologist Thomas A. Mabin, M.D., Vergelegen Medi-Clinic, South Africa. The updated PARADISE data show that systolic blood pressure was reduced by a statistically significant average of 36 mm Hg in 8 patients at 90-days follow-up. The scientific literature demonstrates that only a 5 mm Hg reduction in BP results in a 14% decrease in stroke, a 9% decrease in heart disease, and a 7% decrease in mortality.

US, San Leandro, CA The Mercator Bullfrog by Mercator MedSystems, Inc. is a catheter-guided system designed to inject therapeutic agents directly, nonsystemically, and safely through blood vessel walls into adventitial tissues and has received US Food and Drug Administration 510(k) clearance. The Bullfrog catheter is tipped with a balloon-sheathed microneedle and is guided and inflated in a manner similar to an angioplasty catheter but with far lower expansion pressures (2 atm vs 6–20 atm) in vessels of 3 to 6 mm in diameter. It is compatible with 0.014-inch guidewires and 6-F introducer sheaths. When the desired injection site is reached, the balloon is inflated with saline and radiopaque contrast, securing the system for injection and sliding the microneedle through the vessel wall. Nonclinical studies have shown that the Bullfrog catheter is able to deliver up to 5 mL per injection into the renal artery adventitia with no apparent safety concerns. Guanethidine Ismelin) is delivered to the renal artery adventitia to accomplish sympathetic denervation. Given locally, guanethidine is known to induce an autonomic denervation directly and through an immune-mediated pathway. Mercator’s preclinical experiments have shown that guanethidine, injected at appropriate concentrations into the adventitial space around renal arteries, selectively ablates the nerves in the adventitia around the renal artery after a single, 20-minute procedure

J Neurosci. 1983;3:714-724

US – Laguna Hills, CA – V² Radiofrequency Baloon by Vessix Vascular, Inc.Bipolar RF balloon catheter REDUCE-HTN pilot (10 patients)

Renal Denervation Technology of Vessix Vascular, Inc. been acquired by Boston Scientific Corporation (BSX) to pay up to $425 Million

http://pharmaceuticalintelligence.com/2012/11/08/renal-denervation-technology-of-vessix-vascular-inc-been-acquired-by-boston-scientific-corporation-bsx-to-pay-up-to-425-million/

BP drop, mm Hg -30/-11 at 1 mo V ² catheter, a patented noncompliant balloon catheter with RF electrodes and thermistors mounted on the exterior of the balloon, and the proprietary V ² bipolar RF generator. Once inserted into the renal artery, a 30-second inflation/treatment per renal artery delivers simultaneous RF therapy with independent temperature control to all electrode pairs. V ² catheter is available in balloon diameters ranging from 4 to 7 mm, with a balloon length of 25 mm. Larger-diameter balloons have eight electrode pairs, and smaller-diameter balloons have four to six electrode pairs made of solid gold, which are biocompatible and facilitate good electrode contact with the renal arterial wall. In addition, the electrodes are radiopaque, allowing the V ² catheter to be easily visualized under fluoroscopy. Beginning in the first quarter of 2012, the V 2 renal denervation system will be utilized in the company’s first international, multicenter clinical study: REDUCEHTN.

Israel, Tel Aviv – Tivus by Cardiosonic A6-F transducer-tipped catheter, ultrasound energy (Animal data only) The solution for renal denervation is a high-intensity, nonfocused ultrasonic (US) catheter system named TIVUS (Therapeutic IntraVascular UltraSound) (Figure 3). By applying ultrasonic energy, the TIVUS technology enables remote, localized, controlled, and repeatable thermal modulation of the renal vessel wall tissue, resulting in safe renal nerve ablation. The remote thermal effect is located in the adventitia and perivascular region, with no thermal damage to the endothelium and media, therefore, preventing the development of vessel injury processes. Swine kidney tissue NE concentrations at 30- and 90-day follow-up have demonstrated successful renal denervation as witnessed by a 50% or more decline in tissue NE. Localized tissue thermal modulation/ablation, without damage to the blood vessel wall.

US, MN – SYMPLICITY HTN 2 by Medtronic average office-based BP drops ofBP drop, mm Hg 32/12 mm Hg at six months in the SYMPLICITY HTN 2 trial, as reported by heartwire, with 84% of patients having had a >10-mm-Hg drop in systolic blood pressure from baseline. 14 points in 30 days and 27 points after 1 year. Available in Europe. Medtronic is the furthest ahead in its development process, predicting it will get Symplicity on the American market by 2015. catheter in the renal artery near each kidney to deliver radiofrequency energy to ablate the nerves. A single electrode in contrast to St. Jude’s mutli-electrode approach, is already on the road to FDA review with clinical trials approved last summer in the U.S. Symplicity system has been safely used in nearly 5,000 patients since commercialization

1/9/2014 – Pivotal US trial of Metronics’ Symplicity Renal Denervation System for Refractory Hypertension FAILED its Efficacy Endpoint

US, MN – EnligHTN 1 by St Jude radiofrequency (RF) energy to create lesions (tiny scars) along the renal sympathetic nerves Mean office BP changes at one month in BP drop, mm Hg 28 systolic and -10 diastolic after 1 month (p<0.0001 from baseline), with 78% of patients having systolic BP drops of >10 mm Hg. St. Jude Medical’s (St. Paul, MN) announcement in late 2011 of the first patient to be enrolled in their first-in-man ARSENAL trial ¹⁵ at the University of Adelaide

Renal Denervation: EnligHTN IV Study Called Off and Potential Novel Indications – Diastolic Heart Failure

http://pharmaceuticalintelligence.com/2013/12/10/renal-denervation-enlightn-iv-study-called-off-and-potential-novel-indications-diastolic-heart-failure/

Ireland, Dublin – OneShot™ by Covidien acquisition of Maya Medical, Saratoga, CA New Irrigated RF Balloon Catheter secure first human use for the device in the third quarter of this year, followed by a CE mark for the drug-resistant hypertension treatment in 2013. Presumably, a filing with the FDA would follow that. the OneShot renal denervation system, was born out of the company’s extensive expertise in radiofrequency (RF) ablation and percutaneous coronary interventions (PCI), drawing upon the benefits and best practice standards of each distinct yet complementary clinical discipline. The result is a unique product platform that could further accelerate the paradigm shift in the management of resistant hypertension. consistent with Maya’s balloon-based approach is the ability to deliver predictable apposition of the RF electrode to the vessel wall for more controlled targeted delivery of the RF energy. By offering a more reliable single-treatment approach coupled with enhanced ease of use and reduced procedure times, Maya Medical believes its OneShot renal denervation system has the potential to significantly expand clinical adoption

http://bmctoday.net/evtoday/2012/02/article.asp?f=renal-artery-denervation-a-brave-new-frontier

1/21/2014

Covidien said it’s pulling the plug on its OneShot renal denervation device, citing the slow development of the hypertension market.

http://www.massdevice.com/news/covidien-bails-renal-denervation

US, Natick, MA Boston Scientific lags behind in the race to cash in on hypertension-treating devices, incoming CEO Michael Mahoney said at a Monday conference that it has a plan for its RDN renal denervation system. As MassDevice reports, Mahoney said Boston Sci expects to secure first human use for the device in the third quarter of this year, followed by a CE mark for the drug-resistant hypertension treatment in 2013.

Renal Denervation Technology of Vessix Vascular, Inc. been acquired by Boston Scientific Corporation (BSX) to pay up to $425 Million

http://pharmaceuticalintelligence.com/2012/11/08/renal-denervation-technology-of-vessix-vascular-inc-been-acquired-by-boston-scientific-corporation-bsx-to-pay-up-to-425-million/

Heartwire Reported on December 09, 2013

Renal Denervation: EnligHTN IV Study Called Off and Potential Novel Indications – Diastolic Heart Failure

http://pharmaceuticalintelligence.com/2013/12/10/renal-denervation-enlightn-iv-study-called-off-and-potential-novel-indications-diastolic-heart-failure/

SOURCE

http://www.medscape.com/viewarticle/817397?nlid=41903_2105&src=wnl_edit_medp_card&uac=93761AJ&spon=2

On 1/9/2014 we post that

Pivotal US trial of Metronics’ Symplicity Renal Denervation System for Refractory Hypertension FAILED its Efficacy Endpoint

In the Press

Medtronic to weigh future of Symplicity renal denervation system after US trial failure

(Ref: Yahoo!News, The Wall Street Journal, StreetInsider, Medtronic)

January 9th, 2014

By: Katie Bell

Medtronic said Thursday that a pivotal US trial of its Symplicity renal denervation system for treatment-resistant hypertension failed to meet its main efficacy endpoint. The company noted that based on the results of the SYMPLICITY HTN-3 study, it will form an independent panel “to make recommendations about the future of the global hypertension clinical trial programme, as well as provide advice on continued…access to the Symplicity technology in countries with regulatory approvals.”

Depending on the panel review, the company said that it plans to suspend enrollment in the three countries where renal denervation hypertension studies are under way, including, the SYMPLICITY HTN-4 trial in the US, the HTN-Japan study in Japan and the HTN-India trial in India. Chief medical officer Rick Kuntz remarked that “we believe this course of action…will help us thoroughly evaluate these findings and determine the appropriate next steps for renal denervation therapy.”

The Symplicity system received CE mark approval in 2008, with Medtronicannouncing last month that regulators in Europe and Australia cleared the Symplicity Spyral catheter and Symplicity G3 radio frequency generator. The device maker said Thursday that it is evaluating the value of its renal denervation assets and believes “a one-time impairment charge in the future will be likely,” but reiterated its revenue outlook and diluted earnings per share guidance for fiscal 2014.

The SYMPLICITY HTN-3 trial randomised 535 patients with treatment-resistant hypertension and systolic blood pressure higher than 160 mmHg to a treatment or a control group, with all participants continuing to take blood pressure medications. The primary endpoints of the study were the change in office blood pressure from baseline to six months and incidence of major adverse events. Co-principal investigator Deepak L. Bhatt noted that the study “met its primary safety endpoint related to the incidence of major adverse events one month following randomisation and renal artery stenosis to six months.”

Reference Articles

Medtronic Announces U.S. Renal Denervation Pivotal Trial Fails to Meet Primary Efficacy Endpoint While Meeting Primary Safety Endpoint – (Medtronic)
Medtronic hypertension device found ineffective in trial – (Yahoo!News)
Medtronic Symplicity System Misses Efficacy Goals in Study – (The Wall Street Journal)
Medtronic (MDT) Reports SYMPLICITY HTN-3 Missed Primary Endpoint – (StreetInsider)

SOURCE

http://www.firstwordmedtech.com/node/964863?tsid=28&region_id=4

This Open Access Scientific Journal has covered all the major developments reported on Renal Denervation since its inception

The Archive for Renal denervation

http://pharmaceuticalintelligence.com/category/cardiac-and-cardiovascular-surgical-procedures/renal-denervation/

Search Results for Renal Denervation

http://pharmaceuticalintelligence.com/?s=Renal+denervation

For the ORIGINAL work on

Renal Sympathetic Denervation: Updates on the State of Medicine

the Readers is called to go to the ORIGINAL SOURCES listed below:

Intravascular Stimulation of Autonomics: A Letter from Dr. Michael Scherlag

http://pharmaceuticalintelligence.com/2012/09/02/intravascular-stimulation-of-autonomics-a-letter-from-dr-michael-scherlag/

Imbalance of Autonomic Tone: The Promise of Intravascular Stimulation of Autonomics

http://pharmaceuticalintelligence.com/2012/09/02/imbalance-of-autonomic-tone-the-promise-of-intravascular-stimulation-of-autonomics/

Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

http://pharmaceuticalintelligence.com/2012/09/14/interaction-of-nitric-oxide-and-prostacyclin-in-vascular-endothelium/

Absorb™ Bioresorbable Vascular Scaffold: An International Launch by Abbott Laboratories

http://pharmaceuticalintelligence.com/2012/09/29/absorb-bioresorbable-vascular-scaffold-an-international-launch-by-abbott-laboratories/

The Molecular Biology of Renal Disorders: Nitric Oxide – Part III

http://pharmaceuticalintelligence.com/2012/11/26/the-molecular-biology-of-renal-disorders/

Treatment of Refractory Hypertension via Percutaneous Renal Denervation

http://pharmaceuticalintelligence.com/2012/06/13/treatment-of-refractory-hypertension-via-percutaneous-renal-denervation/

Renal Denervation Technology of Vessix Vascular, Inc. been acquired by Boston Scientific Corporation (BSX) to pay up to $425 Million

http://pharmaceuticalintelligence.com/2012/11/08/renal-denervation-technology-of-vessix-vascular-inc-been-acquired-by-boston-scientific-corporation-bsx-to-pay-up-to-425-million/

Posted in Cardiac and Cardiovascular Surgical Procedures, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Medical Devices R&D and Inventions, Renal Denervation | Leave a Comment »

3rd Annual Canadian Cardiac Oncology Network Conference, June 20 – 21, 2013, Ottawa Convention Centre

January 8, 2014 by 2012pharmaceutical

3rd Annual Canadian Cardiac Oncology Network Conference, June 20 – 21, 2013, Ottawa Convention Centre

Reporter: Aviva Lev-Ari, PhD, RN

The Canadian Cardiac Oncology Network was established in 2011 to bring together health care professionals interested in understanding how cancer therapies impact cardiac health. The Canadian Cardiac Oncology Network’s vision is to optimize cardiac care for cancer patients receiving potentially cardiotoxic therapies. The Network’s missions are to: 1) gain a better understanding of cardiac complications of oncology treatments, 2) develop early detection and intervention strategies to optimize cardiac health, and 3) optimize patient outcomes by collaborating with allied healthcare professionals.

To date, we have hosted two Canadian Cardiac Oncology Network conferences in Ottawa, with a growing interest from a number of health care providers including oncologists, cardiologists, radiologists, nurses, pharmacists, and basic scientists. The 3rd Annual Canadian Cardiac Oncology Network Conference will be held on June 20th-21st, 2013 at The Ottawa Convention Centre.

Dr. Susan Dent Dr. Christine Brezden-Masley

CCON Co-Chair CCON Co-Chair

Medical Oncologist Medical Oncologist

The Ottawa Hospital Cancer Centre St. Michael’s Hospital

CCON 2013 Planning Committee

Dr. Michele Turek – Cardiologist, The Ottawa Hospital, Ottawa, ON

Dr. Narinder Paul – Cardiothoracic and Medical Imaging, University of Toronto, Toronto, ON

Dr. Syed Wamique Yusuf – Cardiologist, University of Texas MD Anderson Cancer Centre, Houston, TX

Dr. S. Kishore Thain – Radiation Oncologist, Cancer Centre of Southeastern Ontario, Kingston, ON

Dr. Jeffrey Sulpher – Medical Oncology Resident, The Ottawa Hospital Cancer Centre, Ottawa, ON

Sean Hopkins– Pharmacy Professional Practice Coordinator, The Ottawa Hospital Cancer Centre, Ottawa, ON

Nadine Graham – CCON Coordinator, The Ottawa Hospital Cancer Centre, Ottawa, ON

Monica Skillen – CCON Coordinator, The Ottawa Hospital Cancer Centre, Ottawa, ON

Thursday, June 20th, 2013 Room 210

TIME	TOPIC	SPEAKER
7:30-8:00	Registration & Continental Breakfast	Room 210
8:00-8:10	Introduction	Co-Chairs: Dr. Susan Dent & Dr. Christine Brezden-Masley
8:15-8:55	2013 Oncology Treatment Landscape: What cardiologists need to know about new oncology treatments	Dr. Christine Brezden-Masley Medical Oncologist, Medicine and Hematology-Oncology, St. Michael’s Hospital, Toronto, ON Dr. S. Kishore Thain Radiation Oncologist, Cancer Centre of Southeastern Ontario, Kingston General Hospital, Kingston, ON
9:00-9:40	2013 Cardiac Treatment Landscape: What medical oncologists need to know about new cardiac drugs in the treatment of cancer patients	Dr. Jean-Bernard Durand Associate Professor, Department of Cardiology, University of Texas MD Anderson Cancer Centre, Houston TX
9:45-10:25	Old and New Cancer Drugs: Are we Killing the Heart with Toxic Agents?	Dr. Michael S. Ewer Special Assistant to the Vice President of Medical Affairs; Professor, Division of Internal Medicine, The University of Texas MD Anderson Cancer Centre, Houston, TX
10:25-10:40	Break – Light snack with coffee & beverages
10:40-11:20	The long-term cardiac complications in survivors of childhood cancer	Dr. Paul Nathan Associate Professor, Peadiatrics and Health Policy Management & Evaluation, University of Toronto; Director of the Aftercare Program & Staff Oncologist, Haematology/Oncology, The Hospital for Sick Children, Toronto, ON
11:25-12:05	Hypertension management in patients treated with VEGF inhibitors	Dr. Martin Myers Senior Scientist, Schulich Heart Research Program, Sunnybrook Research Institute; Staff Cardiologist, Sunnybrook Health Sciences Centre; Toronto, ON
12:05-1:00	Lunch – Buffet
1:00-1:40	Establishment of a cardiac oncology clinic  20 min presentation, 20 min Q&A	Ottawa Cardiac Oncology Clinic Group
1:45-2:25	Cardiac oncology clinical pathways  30 min discussion  10 min summary points	Moderators TBD
2:30-3:30	Research initiatives	Authors of submitted projects—TBD
3:30-5:00	Poster Session – wine and cheese	Rideau Canal Atrium
*OPTIONAL CONFERENCE DINNER Please RSVP with registration**
6:30-9:30	Dinner	Social Restaurant

Friday, June 21st, 2013 The Ottawa Convention Centre 7:30 am – 3:30 pm Room 210

TIME	TOPIC	SPEAKER
7:30-8:00	Breakfast – Continental breakfast
8:00-9:00	Keynote Presentation Novel cardiac biomarkers to assess cardiotoxicity in cancer patients	Dr. Peter Liu Scientific Director, University of Ottawa Heart Institute, Ottawa, ON
9:05-9:45	Identification of the molecular basis of doxorubicin induced cardiotoxicity	Dr. Edward TH Yeh Professor and Chairman, Department of Cardiology, The University of Texas MD Anderson Cancer Centre, Houston, TX
9:50-10:30	The Art of Detecting Broken Hearts in Breast Cancer	Dr. Davinder S. Jassal Associate Professor of Cardiology, Radiology and Physiology, Division of Cardiology, Cardiac Sciences Department, St. Boniface General Hospital, Winnipeg, MB
10:30-10:45	Break—Light snack with coffee & beverages
10:45-12:00	Case Studies	All
12:00-1:00	Lunch—Buffet
1:00-1:50	Radiation induced heart disease: past, present, Future Cases presented by *Dr. S. Wamique Yusuf*	Dr. Marjan Boerma Associate Professor, University of Arkansas for Medical Sciences, Department of Radiation Health, Little Rock, AR
2:00-2:40	Cardiac Oncology: What have we learned? Where are we going?	Dr. Daniel J. Lenihan Professor of Medicine; Director of Clinical Research, Division of Cardiovascular Medicine, Vanderbilt University Medical Centre, Nashville, TN
2:40-3:10	Group Discussion: Next Steps & Research Collaboration	All
3:10-3:30	Closing Comments & Poster Awards	Co-Chairs: Dr. Susan Dent & Dr. Christine Brezden-Masley

SOURCE

http://thinkottawamedicine.ca/wp-content/uploads/2013/01/CCON-2013-Agenda-Registration.pdf

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Frontiers in Cardiology and Cardiovascular Disorders | Leave a Comment »

Cardio-oncology and Onco-Cardiology Programs: Treatments for Cancer Patients with a History of Cardiovascular Disease

January 8, 2014 by 2012pharmaceutical

Cardio-oncology and Onco-Cardiology Programs: Treatments for Cancer Patients with a History of Cardiovascular Disease

Curator: Aviva Lev-Ari, PhD, RN

This article presents the Institutional response to the needs for Treatment of Cancer Patients with a History of Cardiovascular Disease, as well as Patients with Tumors in the Heart. Cardio-oncology and Onco-Cardiology Programs represent the emerging collaboration required between Cardiologists and Oncologist to optimize the care provided to the complex disease at hand. New Discipline of Cardioncology evolves as Cancer Patients now Live Longer.

Cancer and the Heart was the title of and International Conference, held for the first time in 2010. Following an overview of the issues addressed at the International conference, we present several Cardio-oncology Programs at leading Hospitals in the US. Program description and Research Intramural Agendas:

Cardio-oncology Program @ Dana Farber Cancer Institute and the cardiovascular division at Brigham and Women’s
Cleveland Clinic’s Cardio-Oncology Center
Cardio-Oncology Program @ Cedars-Sinai, Los Angeles
Cardiovascular Medicine & Oncology Program @ Yale School of Medicine – Cardio-Oncology Program
University of Michigan Cardiovascular Center Cardio-Oncology Clinic

The Program of the 3rd Annual Canadian Cardiac Oncology Network Conference, June 20 – 21, 2013, Ottawa Convention Centre, indicate the need for collaboration between Oncologists and Cardiologists, as below:

http://pharmaceuticalintelligence.com/2014/01/08/3rd-annual-canadian-cardiac-oncology-network-conference-june-20-21-2013-ottawa-convention-centre/

New Discipline of Cardioncology evolves as Cancer Patients now Live Longer

Zosia Chustecka

October 08, 2010

Nashville, TN – Growing awareness about cardiovascular side effects of anticancer drugs, plus the fact that cancer patients are now living longer, has given birth to the new clinical discipline of cardioncology.

Some of the new anticancer drugs are so effective they can keep tumors in check, but it’s their cardiac side effects that can threaten to cut life short. A death from therapy-related heart failure in a patient whose cancer is in remission may be the ultimate irony—the deathblow coming from collateral damage even while the war on cancer is being won.

This imagery of collateral damage comes from an editorial introducing the September/October 2010 issue of Progress in Cardiovascular Disease s, dedicated to the management of cardiac disease in cancer patients. It also points out that patients with early-stage breast cancer are now more likely to die of heart disease than cancer, highlighting the need for a new discipline that focuses on the treatment of cardiovascular disease in cancer patients.

The journal issue celebrates the first year of existence of the International Society of Cardioncology .

The society was launched last year at a meeting in Milan, Italy, explained Dr Daniel Lenihan(Vanderbilt University, Nashville, TN). This was the Third International Symposium of the Cardiology Oncology Partnership, and it attracted around 120 attendees. About half were cardiologists, 40% were oncologists, and the remaining 10% were “somewhere in between,” Lenihan said. The 2010 meeting started this week in Nashville and runs through October 9.

“The discipline of cardioncology has been evolving for about five years now,” said Dr Douglas Mann(Washington University School of Medicine, St Louis, MO), who coauthored the introductory editorial ^[1].

Although there had been an awareness of cardiac problems from cancer treatments for about 20 to 30 years—especially cardiotoxicity from anthracyclines leading to heart failure as well as coronary disease and valvular disease from radiation, particularly when directed at the thorax, he explained—the field was jolted into life by the totally unexpected reports of cardiac damage with novel, highly targeted anticancer agents.

Trastuzumab (Herceptin, Genentech), the HER2-targeted antibody used in breast cancer, was the “first shot across the bow,” the first time that cardiac damage leading to heart failure was seen outside of the anthracyclines, and it “was completely unexpected,” Mann said in an interview.

Then came the reports of heart failure with the tyrosine inhibitors, initially with imatinib (Gleevec, Novartis) and more recently also with sunitinib (Sutent, Pfizer). These side effects were also unexpected and also came as a shock to the medical community, Mann recalls. At the time, he wrote an editorial in Nature Medicine to highlight the problem ^[2].

SOURCE

http://www.medscape.com/viewarticle/790727

Cardio-oncology: A new focus for cardiovascular medicine

HemOnc Today, August 10, 2011
W. Gregory Hundley, MD

Albini W. Gregory Hundley, MD, is the director of the Cardiovascular Magnetic Resonance Program, and professor, Internal Medicine (Cardiology) and Radiology at Wake Forest School of Medicine in Winston-Salem, N.C. Disclosure: Dr. Hundley reports having received research grants and funding from Bracco Diagnostics and Siemens.

Worldwide efforts during the past several years have improved cancer-related survival, such that cancer survivorship has tripled from 1970 to 2000. Today, there are more than 12 million cancer survivors in the United States.

As cancer-related survival has improved, an unexpected increase in premature cardiovascular events, including myocardial ischemia and myocardial infarction, stroke, and the development of congestive heart failure, has occurred. Associations have been identified between medications used to treat cancer and CV events. Long-term cancer survivors now represent one of the largest and fastest-growing patient populations at risk for premature CV disease. In fact, increases in CV-related morbidity and mortality now threaten to offset some of the advancements in cancer-related survival.

Currently, however, research initiatives, clinical management and guidelines are lacking, regarding addressing the needs of cancer survivors. In this article, we review the current knowledge related to the etiology, diagnosis, treatment and management of CV disease in cancer survivors and present concepts by which the CV and oncology communities can work together to address the CV needs of cancer survivors.

Chemotherapeutic agents that promote CV injury

As shown in Table 1, multiple agents are linked with CV injury after treatment for cancer. The agents most commonly associated with injury include the anthracyclines such as doxorubicin and alkylating agents such as cyclophosphamide. Recently released agents such as the tyrosine kinase inhibitors have also been associated with CV complications. TKIs regulate multiple cellular functions (including cellular proliferation, differentiation and survival) and are overexpressed in certain malignancies. TKIs include a diverse group of therapies that “down-regulate” malignant cell functions.

Trastuzumab (Herceptin, Genentech) is one of the more frequently described TKIs associated with decrements in left ventricular function. This agent is a monoclonal antibody that targets extracellular HER-2 that can be overexpressed in breast cancer tumors. Interestingly, this receptor is also expressed on developing cardiomyocytes. The association of trastuzumab with CV injury is thought to be related to the drug’s affinity with the HER-2 receptors on cardiomyocytes.

W. Gregory Hundley

Sunitinib (Sutent, CPPI CV) is another TKI that has recently been associated with hypertension. Sunitinib inhibits angiogenesis by blocking the activity of VEGF. Although the association of sunitinib with hypertension is not fully understood, it may be related to the reduction in production of vasodilators such as nitrous oxide and prostacyclin, resulting in vasoconstriction and decreased renal excretion of sodium.

Androgen deprivation therapy (ADT) represents another class of cancer treatments that is associated with CV events. Androgen suppression accelerates atherosclerosis and is associated with insulin resistance, obesity, metabolic syndrome, MI and cardiac death. Among 37,443 veterans with prostate cancer, treatment with ADT was associated with diabetes (adjusted HR=1.28); coronary artery disease (adjusted HR=1.19); MI (adjusted HR=1.28); and sudden cardiac death (adjusted HR=1.35). These adverse associations are noteworthy and have prompted initiation of primary CV prevention in many older men scheduled to receive these agents.

Susceptibility and detection

Much of the data relating to susceptibilities to CV injury emanates from the study of children or adults on protocols in which they received anthracycline-based chemotherapeutic agents for the treatment of hematologic malignancies, lymphoma, breast cancer or soft tissue sarcomas. Those more likely to experience anthracycline-related injury are women, those aged older than 65 years or younger than 15 years, and those with pre-existing CV disease or CV risk factors. When compared with their siblings, 14,358 survivors of pediatric cancer followed up to 30 years after their cancer diagnosis were three times more likely to develop a chronic CV event. To date, however, there are relatively few data regarding the factors that increase the risk for a CV event in patients receiving other chemotherapeutic agents.

Currently, intramyocardial biopsies remain the gold standard methodology for identifying myocyte injury as a result of chemotherapy administration. Importantly, however, this technique requires an interventional procedure and is not well-suited for repetitive examinations. For this reason, both radionuclide ventriculography and transthoracic echocardiography (TTE) are widely used to identify marked deteriorations in left ventricular systolic performance when patients receiving chemotherapy or those surviving chemotherapy experience symptoms suggestive of congestive heart failure.

Importantly, these radionuclide ventriculography or traditional 2-D echocardiography methods only identify relatively large deteriorations in left ventricular performance that are most often only associated with clinically overt heart failure. Several recent small studies suggest that quantitative applications regarding MRI or speckle tracking TTE identify the possibility that subclinical markers of CV injury may be identified before more clinically evident overt congestive heart failure ensues. With MRI or TTE, this is achieved through identification of abnormal myocardial tissue characteristics or quantitative assessments of myocardial strain or vascular function. Currently, larger studies are necessary to determine the potential efficacy of these noninvasive modalities for identifying early evidence of myocardial injury that may forecast future CV events.

Prevention and treatment strategies

For those at risk for CV injury before receipt of potentially cardiotoxic chemotherapy, dosing changes either through dose reduction, an alteration of dosing schedules, or a change in the mode of administration of a chemotherapeutic agent have been shown to reduce the risk for CV injury after chemotherapy. Regarding anthracycline toxicity, the cardioprotective agent dexrazoxane (Zinecard, Pfizer) is known to reduce early myocardial injury during anthracycline treatment; however, it remains controversial as to whether this class of agents may reduce the efficacy of cancer treatment.

For those who have experienced CV injury upon receipt of chemotherapy, several small studies have demonstrated potential benefits of angiotensin converting enzyme inhibition or beta-blockade with carvedilol (Coreg, GlaxoSmithKline) to help avert left ventricular remodeling and further deterioration of left ventricular ejection fraction.

Addressing CV concerns in cancer survivors

To date, there are no widespread structured protocols, guidelines or programs that focus on CV care and survivorship-related issues. In 2006, a report from the Institute of Medicine, titled From Cancer Patient to Cancer Survivor: Lost in Transition, sought to raise awareness of the needs of cancer survivors through a series of recommendations. One of the strongest recommendations was to provide comprehensive summary of treatment delivered and detailed plans for undergoing care to patients at the completion of their cancer treatment. Currently, however, there are few organized groups of physicians that are assimilated who can deliver CV care to cancer survivors.

This lack of focus has several major implications. First, although there are specific CV conditions associated with the administration of cancer therapy, there are no standardized definitions for CV disease associated with cancer therapy. Second, most protocols implementing current surveillance measures for cardiac injuries are not coordinated through a central effort; therefore, the selection of outcomes (eg, biomarkers, imaging results) is inconsistent across studies. Third, because CV surveillance is not the primary outcome measure for most of the protocols implemented to test the efficacy of new cancer therapies, there has been inadequate data to provide phenotypic or genotypic characteristics of patients who may be at risk for developing CV disease. Finally, medical societies and health care delivery systems have not determined the optimal pattern for physician surveillance of CV disease in cancer survivors. Thus, although the Institute of Medicine suggests that greater needs and resources should be dedicated toward patient care for most survivors in the US, assessment and treatment of concerns related to CV care are often incomplete.

SOURCE

http://www.healio.com/hematology-oncology/news/print/hematology-oncology/%7B5194c553-a949-4605-b737-d49692389b69%7D/cardio-oncology-a-new-focus-for-cardiovascular-medicine

Building Bridges: Cardio-Oncology and Onco-Cardiology

Sandra M. Swain, MD, FACP

16 Nov 2012 11:02 AM

I recently attended the Second International Conference on Cancer and the Heart at M.D. Anderson Cancer Center, which was endorsed by ASCO. I had the privilege to be on the organizing committee because of my long-standing interest in the cardiac effects of cancer therapy in patients with breast cancer. As I listened to the lectures, which were largely from the cardiology viewpoint, I realized more than ever how much our specialties intersect and what great opportunities we have to make a difference for our patients.What is clear to me from this meeting is that it is extremely important that we continue to come together as oncologists and cardiologists to understand the underlying issues for each. For example, an audience member asked, “How many people do MUGA scans anymore?” He said, “I get referrals for a lot in my community but feel like it’s an outdated modality.” Only one or two hands out of about 200 were raised. The speaker replied with no reservation, stating: “This technique is outdated.”There will always be controversy about many topics, but I think this kind of information—backed by evidence—is important for oncologists to know. As oncologists, we order the tests. For example, in a patient on trastuzumab (Herceptin), we order regular tests of the Ejection Fraction (EF). We need to know what the best test is for our patients and why! On the other side, the cardiologists need to know that patients getting adjuvant trastuzumab need one year for the optimal survival benefit. So if a patient’s EF drops, optimal cardiac management is critical so the treatment is not stopped early. I made that point after talking about a case and the light bulb went on for the cardiologists.

We also had a panel discussion on onco-cardiology programs. Overall, it seems that the physicians who have these programs find that they are very well received and integrated into the care of patients with cancer. Dr. Edward T.H. Yeh, Chair of the Department of Cardiology at M.D. Anderson, discussed the terminology for physicians in such programs; specifically, the second part of the term should indicate the person’s position. For example, within the program, I am a cardio-oncologist, and Dr. Ana Barac, with whom I work at MedStar Heart Institute, is an onco-cardiologist.

There’s so much we can learn from one another. For example, in survivors of childhood cancers, the incidence of severe cardiac events by age 50 is 17%! This was a shocking number for me to hear. Also, many of these younger patients don’t get the appropriate follow-up they need to pick up on these events early so they can be less life-threatening.

On a related side note, I also found out that ASCO had 818 participants in the Cardiac Co-Morbidity Boards we put together for ASCO University last year. There were three modules—one for trastuzumab, one for TKIs, and one for VEGF signaling pathway inhibitors. I really thank my cardiology colleagues for their very active participation and engagement in developing these modules. ASCO members can access these modules by logging in with their ASCO.org account information. Nonmembers can access the modules by creating an ASCO.org Guest Account.

SOURCE

http://connection.asco.org/Commentary/Article/ID/3371/Building-Bridges-Cardio-Oncology-and-Onco-Cardiology.aspx

Tex Heart Inst J. 2011; 38(3): 246–247.

PMCID: PMC3113120

Cancer and the Heart

Onco-Cardiology

The Time Has Come

Edward T.H. Yeh, MD

Edward T.H. Yeh, MD, Section Editor

Author information ► Copyright and License information ►

On 3 and 4 November 2010, more than 200 physicians, scientists, and healthcare professionals from 14 countries gathered in Houston, Texas, for the First International Conference on Cancer and the Heart. This event was co-sponsored by The University of Texas MD Anderson Cancer Center and the Texas Heart Institute, two international leaders in the treatment of cancer and heart disease. Although similar meetings have been sponsored in the past, by us and by others, this meeting was remarkable for its scope and ambition. It was our intent to show that basic science can be used successfully to guide translational and clinical research. This First International Conference has heralded the coming of onco-cardiology as a research and clinical subspecialty.

In this conference, cardiovascular complications were discussed in modules that comprised heart failure, imaging, radiation, thrombocytopenia, cardiac masses, and hypertension. Clinical experts from MD Anderson and other institutions presented updates on timely clinical topics, followed by question-and-answer sessions. A significant portion of the conference was devoted to basic mechanisms that drive paradigm shifts in this emerging field. Major discoveries were reported on a new paradigm for anthracycline-induced cardiotoxicity and vascular complications caused by some targeted agents. The role of prior exposure to doxorubicin in trastuzumab-induced cardiotoxicity was also discussed. Early identification of cardiotoxicity using biomarkers or left ventricular strain imaging has commanded significant attention. The proceedings of these modules are summarized concisely in the accompanying articles. This conference was not designed to cover the entire field, but rather to create a model for future conferences. Consequently, there are many important clinical issues and basic mechanisms that remain to be covered in future meetings.

In addition to the clinical and basic-science modules, there was a session on the dialogue between patient and doctor. As physicians, we are in our comfort zone when illness is defined by medical terms and laboratory numbers. It is refreshing to hear about it from a patient’s perspective: illness is a personal affliction that alters one’s sense of wellness and self-esteem. Indeed, this conference is dedicated to all cancer patients who have suffered cardiovascular complications.

A decade ago, MD Anderson had 2 in-house cardiologists and referred most cardiovascular complications to surrounding hospitals in the Texas Medical Center. As the complexity of our patient population grew, it became difficult to obtain timely consultation and treatment for our patients. Consequently, the Department of Cardiology at The University of Texas MD Anderson Cancer Center was established in 2000. I was recruited as the founding chair with the charge to develop a comprehensive cardiology service and to develop basic and clinical research relevant to cancer and the heart. The service now consists of 11 cardiologists, 7 physician extenders, 2 pharmacists, and 5 rotating cardiology fellows who provide comprehensive cardiac care to cancer patients. We have also built a cardiac catheterization laboratory that performs cardiac biopsies, diagnostic studies, and the implantation of pacemakers. We have strong basic research laboratories that have published their findings in prestigious scientific journals. Our experience is not unique because several institutions in the United States and Europe have already established “onco-cardiology” (or “cardio-oncology”) units. These centers include Memorial Sloan-Kettering Cancer Center (New York) and the European Institute of Oncology (Milan). Each onco-cardiology unit faces different challenges that are associated with the size of the hospital, its affiliation with other general hospitals, and the scope of cancer treatments. Smaller onco-cardiology units are also emerging within major medical centers in the United States. These small units usually have cardiologists who have developed an interest in taking care of the heart problems of cancer patients, in addition to the problems encountered in a general cardiology practice. As these onco-cardiology units proliferate, it is important to establish communications between them in order to share common experiences and extraordinary challenges.

Onco-cardiology is a medical subspecialty concerned with the diagnosis and treatment of heart disease in cancer patients. Clearly, this field is not limited to cardiologists, but also includes medical oncologists, radiation oncologists, surgical oncologists, and all others who are interested in caring for cancer patients with cardiac problems. A major issue that our field must define is the scope of the core knowledge that needs to be shared by all practitioners. Furthermore, we must educate our cardiology and oncology colleagues about the importance of providing optimal cardiac care to cancer patients. These efforts should bring about improved clinical outcomes and enhance the development of new anticancer therapies. As cancer therapy becomes more effective and as more cancer patients become cancer survivors, it is the goal of the “onco-cardiologist” to ensure that our patients will have healthy hearts to enjoy their new lives.

Articles from Texas Heart Institute Journal are provided here courtesy of Texas Heart Institute

SOURCE

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113120/

Leading Cardio-oncology and Onco-Cardiology Programs in the US

Cardio-oncology Program @ Dana Farber Cancer Institute and the cardiovascular division at Brigham and Women’s

The Cardio-Oncology Program, a joint collaboration of Brigham and Women’s Hospital and Dana-Farber Cancer Institute, is one of a select few of its kind in the country. Led by Anju Nohria, MD, a cardiologist with special training in epidemiology and heart failure, and Javid Moslehi, MD, a cardiologist with additional training is molecular oncology, the Program provides care for cancer patients with a history of cardiovascular disease or those who develop cardiac complications. The program includes both clinical and research components.

About Us

This innovative program is one of the few in the United States dedicated to addressing the cardiovascular side effects of cancer therapy and maximixing cardiovascular outcomes for cancer survivors.

The specific goals of this Program are as follows:

Provide care for patients with a cardiovascular history who now have to undergo cancer treatment, both medical and surgical procedures;
Provide care for patients who present with heart failure following traditional treatments associated with cardiac dysfunction including anthracyclines, radiation, and newer agents such as herceptin;
Study the potential cardiovascular complications of novel molecular targeted therapies – including arrhythmias, cardiomyopathy, cardiac ischemia, and hypertension – and establish treatment strategies for these complications

Working together as a team in the care of the cancer patient, the goal of the Program is to minimize cardiotoxicity during cancer treatment and cardiovascular risks during cancer survival.

The cardio-oncology program brings together oncologists from the Dana-Farber Cancer Institute and expert cardiologists from Brigham and Women’s Hospital to provide optimal cardiovascular care for the cancer patient. The uniqueness of this program hinges on the close working relationship of our oncologists and cardiologists.

Both the Dana Farber Cancer Institute and the cardiovascular division at Brigham and Women’s have been world leaders in providing innovative and comprehensive care to patients with complex diseases. We are now combining these efforts to bring novel diagnostic methods and innovative therapies to patients with cardiovascular manifestations of cancer and cancer therapy.

Our comprehensive cardio-oncology program provides care for:

Patients with existing cardiovascular issues who have newly diagnosed cancer and need to be shepherded safely through the medical and surgical treatment for their cancer.
Patients who may have cardiac side-effects from traditional cancer therapies, such as anthracyclines and radiation. Working closely with our oncology colleagues, we monitor and adjust therapy for these patients with the goal of preventing further cardiovascular complications while effectively treating the underlying cancer.
Patients being treated with novel molecular targeted therapies that may have potential adverse cardiovascular effects. Our cardio-oncology specialists are fostering research that may lead to an improved understanding of the mechanisms by which novel cancer drugs affect the cardiovascular system. This work may help identify patients at risk for developing cardiovascular complications and may also help design better and less cardiotoxic cancer treatments.
Patients who are long-term cancer survivors and need to be screened and treated for cardiovascular issues that may or may not be related to their treatment.

Contact Us

Javid J. Moslehi, MD – Co-Director
Anju Nohria, MD – Co-Director

The Cardio-Oncology Program at Brigham and Women’s Hospital and Dana-Farber Cancer Institute includes both basic and clinical research components.

Dr. Javid Moslehi is a cardiologist with postdoctoral training in molecular oncology at the Dana-Farber Cancer Institute. Dr. Moslehi’s cardio-oncology research program includes both basic and translational components. Dr. Moslehi is specifically interested in cardiovascular toxicities of novel molecular targeted therapies. While novel chemotherapies have revolutionized cancer treatment, they can lead to potential adverse cardiovascular effects. Better understanding of the mechanisms underpinning adverse cardiovascular effects with novel targeted therapies can lead to better understanding of normal cardiovascular function and may lead to strategies that prevent cardiotoxicity of these agents. Dr. Moslehi seeks highly motivated medical students and postdoctoral fellows for this unique research program. Please send inquiries and CV to Javid Moslehi, M.D. Email: jmoslehi@partners.org or javidmoslehi@gmail.com.

Dr. Anju Nohria is a cardiologist with expertise in heart failure and transplantation. She has done extensive research on the management of acute decompensated heart failure and is currently focused on evaluating, prevention and treatment strategies in patients who develop cardiomyopathy and other cardiovascular complications as a consequence of cancer therapy. She has additional training in epidemiology and is interested in the cardiovascular health of cancer survivors.

Publications:

Javid Moslehi, YA Minamishima, Robert F. Padera, Sabina Signoretti, Ronglih Liao, and William G. Kaelin. “Loss of PHD Prolyl Hydroxylase Activity in cardiomyocytes phenocopies ischemic cardiomyopathy.” Circulation. 122: 1004-1016, 2010.

Ergun Sahin, Simona Colla, Marc Lissa, Javid Moslehi, Florian Muller, Mira Guo, Marcus Cooper, Darrell Kotton, Attila Fabian, Carl Walkey, Rick Maser, Giovanni Tonon, Friedrich Foerster, Robert Xiong, Alan Wang, Sachet Shukla, Mariela Jaskelioff, Eric Martin, Tim Heffernan, Alexei Protopopov, Elena Ivanova, Jon Mahoney, Maria Kost-Alimova, Samuel Perry, Roderick Bronson, Ronglih Liao, Richard Mulligan, Orian Shirihai, Lynda Chin, and Ronald Depinho. “Telomere-directed Mitochondrial Dysfunction Contributes to Degenerative Decline in the Telomerase Deficient mouse.” Nature. 470:359-365, 2011.

Christopher J. Richards, Youjin Je, Fabio A. B. Schutz. Daniel Heng, Susan Dallabrida, Javid Moslehi and Toni K. Choueiri. “Incidence and risk of congestive heart failure in patients with renal and nonrenal carcinoma treated with sunitinib.” Journal of Clinical Oncology. 29:3450-3456, 2011.

Babak Nazer, Benjamin Humpreys, and Javid Moslehi. “Effects of Novel Angiogenesis Inhibitors for the Treatment of Cancer on the Cardiovascular System: Focus on Hypertension.” Circulation. 124:1687-1691, 2011.

Imran Uraizee, Susan Cheng, and Javid Moslehi. “Reversible cardiomyopathy associated with suntinib and sorafenib.” New England Journal of Medicine. 365:1649-1650, 2011.

Javid Moslehi and Peter Libby. “You can’t run from inflammation: lower extremity ischemia, hypoxia signaling, and macrophage subtypes.”Circulation Research. 110(8):1045-6, 2012.

Javid Moslehi, Ronald Depinho, and Ergun Sahin. “Telomeres and mitochondria in the Aging Heart.” Circulation Research. 110:1226-1237, 2012.

William Querbes, Roman Bogorad, Javid Moslehi, Jamie Wong, Amy Chan, Akin Akinc, Elena Bulgakova, Satya Kuchimanchi, Victor Koteliansky, Wiliam G. Kaelin, Jr. “Treatment of Erythropoietin Deficiency with Systemically Adminstrated siRNA.” Blood. 120:1916-1922, 2012.

Nilka de Jesus-Gonzales, Emily Robinson, Javid Moslehi, Benjamin D. Humphreys. “Management of Antiangiogenic Therapy-induced Hypertension.” Hypertension. 60:607-613, 2012.

John Groarke, Dan Tong, Jay Khambhati, Susan Cheng, and Javid Moslehi. “Breast Cancer Therapies and Cardiomyopathy.” Medical Clinics of North America. 96:1001-1019, 2012.

Tomas Neilan, Otavio Coelho-Filho, Diego Pena-Herrera, Ravi Shah, Michael Jerosch-Herold, Sanjeev Francis, Javid Moslehi, Raymond Kwong. “Left ventricular mass in patients with cardiomyopathy after treatment with anthracyclines.” American Journal of Cardiology. 110:1679-1686, 2012.

Tomas Neilan, Otavio R. Coelho-Filho, Ravi V. Shah, Jiazuo H. Feng, Deigo Pena-Herrera, Damien Mandry, Francois Pierre-Mongoen, Bobak Heydari, Sanjeev Francis, Javid Moslehi, Raymond Y. Kwong, Michael Jerosch-Herold. “Myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline-based chemotherapy.” American Journal of Cardiology. 111(5):717-22, 2013.

Javid Moslehi. “The Cardiovascular Perils of Cancer Survivorship.” New England Journal of Medicine. 368(11):1055-6, 2013.

Steven Bair, Toni Choueiri, and Javid Moslehi. “Cardiovascular complications associated with novel angiogenesis inhibitors: Emerging evidence and evolving perspectives.” Trends in Cardiovascular Medicine. 23(4):104-13, 2013.

John Groarke, Paul L. Nguyen, Anju Nohria, Roberto Ferrari, Susan Cheng, and Javid Moslehi. “Radiation therapy and cardiovascular disease.” European Heart Journal. In press.

Javid Moslehi and Susan Cheng. “Cardio-Oncology: A Novel Platform for Basic and Translational Research.” Science Translational Medicine. In Press.

Bonnie Ky, Pimprapa Vejpongsa, Edward TH Yeh, Thomas Force, and Javid Moslehi. “Emerging Paradigms in Cardiomyopathies Associated with Cancer Therapies.” Circulation Research. In Press.

SOURCE

http://www.brighamandwomens.org/Departments_and_Services/medicine/services/cvcenter/cardiooncology/ourresearch.aspx

Cleveland Clinic’s Cardio-Oncology Center

Cancer survival has improved over the years due to newer and better forms of treatment with chemotherapy and radiation. When treating cancer, some of the treatments may cause lasting damage to your heart. This is especially true if you are at risk for heart disease.

The goal of Cleveland Clinic’s Cardio-Oncology Center is to help you complete your cancer treatment without developing such damage. We use state-of-the-art technology to identify and immediately treat the toxicity. Our care does not change or interrupt your cancer therapy.

Our team includes specialists from the Sydell and Arnold Miller Family Heart & Vascular Institute (including cardiac imaging, heart failure, electrophysiology and cardiac surgery) and the Taussig Cancer Institute. The team works together to provide expertise in diagnostic testing, medical management, and interventional and surgical procedures for patients.

This multidisciplinary team of doctors, nurses and healthcare professionals is dedicated to caring for patients in every stage of cancer treatment who are at risk for, develop or have established cardiovascular disease.

The Cardio-Oncology Center provides care to patients in varying stages of cancer treatment who have or are at risk for heart disease. Our range of services includes evaluation and treatment of patients:

Who will begin cancer treatment and have risk factors for heart disease
Who will begin cancer treatment and are being treated for heart disease
Who are undergoing chemotherapy or radiation and develop symptoms of weakness or fatigue;
swelling of the legs and feet; chest pain; irregular heart beats; and/or dizziness
Who have had cancer treatment in the past and develop new cardiac problems
Who have had radiation therapy in the past and need surgical or interventional treatments
Who have developed advanced heart failure due to previous cancer treatment and need advanced treatment, such as a heart pump or heart transplant
Who have a cardiac tumor

Our team of healthcare professionals offer patients:

A full range of imaging techniques and diagnostic studies. These allow for early detection of heart and blood vessel damage and arrhythmias. These tools include cardiovascular exam, electrocardiogram (ECG), and state-of-the-art echocardiography, including 3D, contrast and strain imaging.
Collaborative medical management. Our cardiologists and oncologists will discuss your test results. Together, we will design the best cancer treatment plan for you. This includes the choice of treatment, dosage and schedule.
Ongoing follow-up care during cancer treatment. This lets us find and treat heart and vascular changes early in your care and work to create the best long-term outcomes possible.
Continued care after cancer treatment. You can develop heart damage (cardiotoxicity) within the first year after therapy, and even several years after therapy. We provide follow-up care and early treatment, if needed.
Advanced surgical options for patients with valve and pericardial disease caused by previous radiation therapy.
Advanced heart failure therapies, such as specialized medical treatment, artificial heart pumps and heart transplantation, for patients with end-stage heart failure caused by chemotherapy or radiation.

Why choose Cleveland Clinic for your care?

Our outcomes speak for themselves. Please review our facts and figures and if you have any questions don’t hesitate to ask.

Leaders in the field from America’s top ranked Heart Program and one of America’s top Cancer Programs are working together to offer you the best diagnostics and treatment possible.

Cleveland Clinic’s Section of Cardiovascular Imaging pioneered the clinical use of strain imaging. This is an innovative technique that allows early detection of cardiotoxicity. This helps determine the best plan for cancer treatment and predict the amount of heart damage it will cause.

Cardio-Oncology Assessment Tool

Did you know some cancer treatments may affect your heart health? Know the signs and symptoms to look out for and see if an evaluation at the Cardio-Oncology Center is recommended for you.

References

Negishi K, Negishi T, Agler DA, Plana JC, Marwick TH. Role of Temporal Resolution in Selection of the Appropriate Strain Technique for Evaluation of Subclinical Myocardial Dysfunction. Echocardiography. 2011 Dec 9. doi: 10.1111/j.1540-8175.2011.01586.x. [Epub ahead of print]
Daher IN, Kim C, Saleh RR, Plana JC, Yusuf SW, Banchs J. Prevalence of abnormal echocardiographic findings in cancer patients: a retrospective evaluation of echocardiography for identifying cardiac abnormalities in cancer patients. Echocardiography. 2011 Nov;28(10):1061-7.
Sawaya H, Plana JC, Scherrer-Crosbie M. Newest echocardiographic techniques for the detection of cardiotoxicity and heart failure during chemotherapy. Heart Fail Clin. 2011 Jul;7(3):313-21. Review.
Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Cohen V, Gosavi S, Carver JR, Wiegers SE, Martin RP, Picard MH, Gerszten RE, Halpern EF, Passeri J, Kuter I, Scherrer-Crosbie M. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol. 2011 May 1;107(9):1375-80. Epub 2011 Mar 2.
Banchs J, Jefferies JL, Plana JC, Hundley WG. Imaging for cardiotoxicity in cancer patients. Tex Heart Inst J. 2011;38(3):268-9.
Hare JL, Brown JK, Leano R, Jenkins C, Woodward N, Marwick TH. Use of myocardial deformation imaging to detect preclinical myocardial dysfunction before conventional measures in patients undergoing breast cancer treatment with trastuzumab. Am Heart J. 2009 Aug;158(2):294-301.
Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM. Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst. 2010 Jan 6;102(1):14-25. Epub 2009 Dec 10.

SOURCE

http://my.clevelandclinic.org/heart/departments-centers/cardio-oncology.aspx

Cardio-Oncology Program @ Cedars-Sinai, Los Angeles

Cardio-Oncology Program

Carotid Intima-Media Thickness Test

Coronary Calcium Scan

Coronary Reactivity Testing

Endothelial Function Testing

External Counter Pulsation

Intravascular Ultrasound

Women’s Hormone and Menopause Program

Heart disease remains the greatest health risk in women of all ages. While we have made great strides in detection and treatment of breast cancer, the number one threat in cancer survivors is heart disease. The Cardio-Oncology Program is a highly specialized clinic in the Barbra Streisand Women’s Heart Center dedicated to the heart health of breast cancer survivors. We understand that the use of radiation and chemotherapy has adverse effects on a woman’s future heart disease risk.

The Cardio-Oncology Program is directed by two leading physicians at Cedars-Sinai: Puja K. Mehta MD, a women’s heart cardiologist and Catherine Dang MD, a breast cancer surgeon. This unique clinic brings together experts from two of the most important areas that affect women. Our clinic specializes in identifying women who may be at increased risk of heart disease by a comprehensive history and physical, including breast cancer treatment history.

As a new patient, you will complete a questionnaire prior to your first appointment, which will help us pinpoint your individual risk factors for heart disease or other diseases common to women. Based on this initial evaluation and using state-of-the-art screening tests, an individualized prevention and treatment plan will be made. We see women who want to decrease their chances of heart disease as well as those who are looking for a second opinion for their heart health concerns.

Services available include:

Personalized cardiac risk assessment with
EKG, Exercise treadmill, Holter monitoring
2D transthoracic echo with tissue doppler, contrast if needed, bubble study; trans-esophageal echo
Exercise and pharmacologic stress echo
Exercise and pharmacologic SPECT and PET
Stress cardiac MRI
Cardiac CT angiography
Coronary calcium score
Carotid IMT
Personalized, comprehensive preventive strategies for optimal heart health
Nutrition counseling
Cardiac rehabilitation
Treatment of resistant high blood pressure
Treatment of complex disorders of high cholesterol level
High risk hormone therapy counseling through the Women’s Hormone and Menopause Program
Specialized care in valvular heart disease, interventional cardiology, congestive heart failure and electrophysiology

SOURCE

http://www.cedars-sinai.edu/Patients/Programs-and-Services/Womens-Heart-Center/Services/Cardio-Oncology-Program.aspx

Cardiovascular Medicine & Oncology Program @ Yale School of Medicine

Cardio-Oncology Program

Dr. Raymond Russell, Associate Professors of Medicine in Cardiology, is Director of the Cardio-Oncology Program at Smilow Cancer Hospital at Yale-New Haven. The program is designed to help address the cardio-toxic side effects of chemotherapy treatment, as well as the confounding problem of co-existing cardiac disease and cancer. The Program also provides pre-surgical and pre-treatment cardiac evaluation for patients with cancer.

The service began in response to emerging data, which indicates that newly developed drugs for cancer treatment are having unanticipated side effects. Drugs such as Herceptin, which is very effective in the treatment of breast cancer, can have cardio-toxic side effects that are just beginning to be understood and researched.

The difficulty when dealing with cardio-toxic side effects is that they can often mask themselves as normal effects from the cancer treatment itself, such as fatigue and shortness of breath. If it is determined that a patient has a pre-existing heart dysfunction, Dr. Russell can help make decisions of how treatment can be optimized, and establish what the baseline function is for continued monitoring.

If a patient is found to have cardio-toxicities during treatment with chemotherapy, the oncologist, the patient, and Cardio-Oncology Program will work together to decide what the best course of action is. There are many methods for treating mild heart failure, which would be beneficial if the cancer is responding to the chemotherapeutic drug. In some cases, collaboration with the oncologist will need to take place in order to change the chemotherapy to something that’s less cardio-toxic. The point is to kill the cancer cells, without damaging other areas. The goal of this Program is to help patients through their treatment so they have the best chance to be cured of their cancer.

Giving a patient as much information as possible about their treatment plan and what to expect is crucial. Another goal of the Cardio-Oncology Program at Smilow Cancer Hospital is to provide specialty care for patients who have cancer to help them not only deal with the effects of their chemotherapy on heart function, but also evaluate patients with co-existing coronary artery disease and cancer for specialized therapy where there may be increased risk to the heart. With new chemotherapeutic agents being developed, people are living much longer lives and a healthy heart is crucial to being able to enjoy that.

Modern cancer therapy offers the greatest chance to patients to beat their cancer, however, some of the established therapies are associated with cardiac toxicities. Similarly, some of the new, targeted chemotherapeutic agents can affect heart function or the electrical conduction system of the heart. The Cardio-Oncology Program at Yale School of Medicine was one of the first programs in the nation developed to address the unique cardiovascular problems faced by patients with cancer.

Kerry Russell, MD, PhD and Raymond Russell, MD, PhD, co-directors of the program, focus on three important areas:

Addressing the cardiac complications of cancer as well as the cardiac complications of cancer therapy,
Treating patients with coexisting heart disease and cancer, and
Providing presurgical and prechemotherapeutic cardiovascular risk assessment.

The Cardio-Oncology Program provides both inpatient consultative services and outpatient evaluations in the Multispecialty Clinic of Smilow Cancer Hospital. Working closely with oncologists, the members of the Cardio-Oncology Program help to develop diagnostic and therapeutic plans aimed at providing the greatest protection to the heart while simultaneously supporting the optimum cancer therapy for a patient.

SOURCE

http://cardio.med.yale.edu/clinical/cardioonc.aspx

University of Michigan Cardiovascular Center Cardio-Oncology Clinic

Heart Specialists Treat Both Heart and Cancer Patients – Dr. Elina Yamada and Dr. Monika Leja evaluate patients at risk for cardiotoxicity from cancer treatment.

Better treatment with chemotherapy and radiation therapy has reduced cancer deaths significantly. But for some patients, cancer treatment can cause lasting damage to the heart by aggravating existing heart problemsor creating new ones. The University of Michigan Cardiovascular Centerhas created the state’s first Cardio-Oncology Clinic with heart specialists focused on minimizing and preventing heart damage caused by chemotherapy and radiation. Only a handful of hospitals around the world have dedicated programs of scientists and physicians working to address cancer treatment’s impact on the heart.

Clinic Heart Specialists Focus on Preventing Heart Damage Caused by Cancer Treatment

Dr . Elina Yamada and Dr. Monika Leja evaluate patients at risk of, or who developed cardiotoxicity from cancer treatment. Without interrupting treatment, they work to identify and address cardiovascular risks and reduce the toxic effects of cancer therapies on the heart, what’s known among physicians as cardiotoxicity. (View a flippable PDF of the Winter 2013 issue of Thrive magazine, a publication for cancer patients and their caregivers. In this issue is an article featuring Drs. Yamada and Leja.)

Cardiovascular issues that can arise from cancer treatment include heart failure, heart attacks, high or low blood pressure and arrhythmias. As aggressive cancer drugs are used on older patients who may already have heart disease, and researchers identify a growing number of cardiovascular side effects of cancer treatment, making sure cancer patients have a healthy heart to enjoy the rest of their lives is gaining more importance.

Both Heart Patients and Cancer Patients Can Benefit from the Clinic

For heart patients, clinic doctors perform pre-surgical or pre-treatment evaluations for those patients with cardiac conditions who are also being treated for cancer, and provide medical care to improve heart function prior to a cardiac surgery or procedure.

Cancer patients, with or without known heart disease or risk, and cancer survivors can benefit from a clinical assessment of heart function and, if needed, continued medical care for the heart. About one-third of cancer patients who receive chemotherapy drugs such as trastuzuman (Herceptin) and anthrycyclines will experience damage to their heart cells. Working with the patient’s cancer team, doctors at the Cardio-Oncology Clinic evaluate and prescribe treatment to improve heart function without interrupting cancer treatment. Doctors also evaluate and treat cancer survivors when a major illness, injury or even pregnancy triggers a reaction by the heart to the toxic effects of previous cancer treatment. The U-M will use strain imaging, a specialized form of echocardiography, to provide a detailed analysis of specific segments of the heart in order to predict damage before it occurs.

Our Location

The clinic is in the University of Michigan Cardiovascular Center, a 5-level facility that unites the U-M Health System’s cardiovascular services, located at the heart of the medical campus at the corner of Ann and Observatory streets in Ann Arbor.

SOURCE

http://www.uofmhealth.org/university-michigan-cardiovascular-center-cardio-oncology-clinic

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Frontiers in Cardiology and Cardiovascular Disorders | Leave a Comment »

Heart Tumors: Etiology and Classification

January 8, 2014 by 2012pharmaceutical

Heart Tumors: Etiology and Classification

Reporter: Aviva Lev-Ari, PhD, RN

Cancer-Related Heart Disease

Primary Heart Tumors

Originate in the Heart

Tumors that originate in the heart are called primary heart tumors. These are very rare.

May Be Cancerous or Noncancerous

They may develop in any of the heart tissues and may be cancerous or noncancerous.

Cancerous: Sarcomas

The most common primary heart tumors are sarcomas — cancers that develop from blood vessel tissue.

Noncancerous: Myxomas

Half of all primary heart tumors are myxomas, noncancerous tumors that usually are irregular in shape and jellylike in consistency. Three-quarters of myxomas occur in the left atrium. Some of these myxomas run in families. These typically develop in young men in their mid 20s. Myxomas that are not hereditary usually develop in women between the ages of 40 and 60.

Secondary Heart Tumors

Originate in Other Parts of the Body

Secondary heart tumors are those that originate in other parts of the body — most often, the lungs, breasts, blood or skin — and spread (metastasize) to the heart. These are more common.

Always Cancerous

Secondary heart tumors are always cancerous.

Secondary heart tumors are 30 to 40 times more common than primary heart tumors, but are still rare.
About 10 percent of those with lung or breast cancer will have it spread to the heart.
About 75 percent of those with malignant melanoma (a form of cancer that often arises in the skin) will see it spread to the heart.
Secondary cancers spread by direct invasion of the pericardium — the sac that surrounds the heart — or through the bloodstream or lymph system.

Relationship Between Heart Disease and Cancer

Some cancer treatments, including chemotherapy and radiation, can also cause heart disease or a weakening of the heart muscle called cardiomyopathy (see heart failure section). Another heart condition, cardiac amyloidosis, is sometimes linked to multiple myeloma.

SOURCE

http://www.bidmc.org/CentersandDepartments/Departments/Medicine/Divisions/CardiovascularMedicine/DiseasesandConditions/CancerRelatedHeartDisease.aspx#sthash.azXoEOnK.dpuf

Amongst Hodgkin lymphoma patients who have received radiation, CVD is one of the most common causes of death.

Physicians and ancillary staff frequently have to take care of patients with concomitant cancer and cardiovascular disease. Some cardiac diseases predates the diagnosis of cancer, whereas other conditions like chemotherapy-induced cardiomyopathy and radiation-related heart disease are directly related to the cardiotoxic side effects of cancer therapy. The cardiotoxic side effects of agents like 5-fluouracil, adriamycin, and tyrosine kinase inhibitors are well known. However, the cardiotoxic profiles of newer investigational chemotherapeutic agents are largely unknown.

Chemotherapy frequently induces thrombocytopenia, which in itself poses therapeutic challenge in the management of conditions like acute coronary syndrome, atrial fibrillation, stroke, and prosthetic valves. Evidence-based treatment of cardiovascular disease in cancer patients is lacking largely because all cardiology trials have excluded patients with cancer and similarly cancer trials have excluded patients with significant cardiovascular comorbidity.

While recently some single-center studies have shown the efficacy of medications like ace inhibitors and beta blockers for the treatment of chemotherapy-induced cardiomyopathy, evidence-based treatment of other major cardiovascular diseases in cancer patients is not well established.

In this issue of cancer and cardiovascular disease, we have covered some common conditions like venous thrombosis, cardiovascular effects of radiation therapy, cardiovascular effects of anthracycline in childhood cancer survivors, and management of aortic aneurysm in cancer patients. The use of newer modality, like computed tomographic angiography, may provide a pivotal role in the investigation of cancer patients with concomitant cardiac problem, as outlined in a clinical investigation in this journal. The case reports presented are some conditions that are unique to cancer population. Cardio-oncology is a growing field.

http://www.hindawi.com/journals/crp/2011/943748/

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Frontiers in Cardiology and Cardiovascular Disorders | Leave a Comment »

Radiation and Chemotherapy Therapy: The Pharmacological Risk for Developing Cardiovascular Disease

January 8, 2014 by 2012pharmaceutical

Radiation and Chemotherapy Therapy: The Pharmacological Risk for Developing Cardiovascular Disease

Reporter: Aviva Lev-Ari, PhD, RN

Cancer treatments may harm the heart

August 2012

Doctors strive to prevent the cure for one disease from causing another.

Cancer treatment can be the proverbial double-edged sword. Radiation therapy and chemotherapy are increasing the number of people who survive cancer. However, they can also cause these same people to develop cardiovascular disease.

Radiation therapy can cause heart attack, heart failure, and arrhythmias. Traditional and novel chemotherapy agents can damage the heart or peripheral blood vessels, or cause problems with clotting or blood lipids. Some serious cardiovascular effects occur while the chemotherapy is being given; others appear long after cancer has become a distant memory.

“Almost every chemotherapy drug has some effect on the cardiovascular system, and most are not good. But with the new anticancer agents, an increasing amount of cardiac toxicity is being observed,” says Dr. Mandeep R. Mehra, executive director of the Center for Advanced Heart Disease at Brigham and Women’s Hospital and a professor at Harvard Medical School.

The list of undesirable effects caused by a growing inventory of antitumor agents has overwhelmed the ability of cardiologists and medical oncologists to keep pace with heart-protection strategies. As a result, a new specialty has emerged to fill the gap. Cardio-oncology is a partnership of cardiologists and oncologists who combine their knowledge to help protect the hearts of people undergoing cancer treatment. “Being followed by a highly specialized cardiologist can benefit most people with cancer, but it is particularly important for someone who is at risk for heart disease or who already has heart disease,” says Dr. Mehra.

The scope of the problem

The cardiovascular side effects that arise from cancer therapy are frightening. Some chemotherapy agents cause the heart muscle to weaken soon after chemotherapy begins. Novel angiogenesis inhibitors that suppress new blood vessel formation cause blood pressure to rise dramatically and may increase the risk of blood clots and heart failure. Hormonal therapies can cause stroke, heart attacks, and blood clots. Other agents can trigger low blood flow to the heart (ischemia), heart attack, arrhythmias, or inflammation of the sac around the heart. When a severe reaction occurs while a drug is being infused, it may be necessary to stop the treatment.

Dr. Mehra and his cardio-oncology colleagues Dr. Anju Nohria and Dr. Javid Moslehi at Brigham and Women’s, along with oncologists at the Dana-Farber Cancer Center, are leading an effort to learn more about the effects of anticancer agents on the heart and cardiovascular system. While the oncologists test anticancer agents in clinical trials, the scientists are investigating the effects of these agents on the heart before the agents are released for widespread use, and the cardio-oncologists are searching for ways to counteract these effects.

On the flip side

In addition to preventing heart disease in people undergoing cancer therapy, it is equally important to understand the impact of chemotherapy on people with heart disease and their medications.

Some angiogenesis inhibitors may render clopidogrel (Plavix) less effective. People using blood thinners may experience excessive bleeding when their platelet counts fall as a result of cancer treatment.

Certain chemotherapy agents may interact with warfarin (Coumadin), making it less effective in preventing blood clots. Statins may render chemotherapy more potent and, therefore, more toxic.

The toxic properties of chemotherapy may decrease the ability of a person with a bacterial heart-valve infection to fight that infection, often with serious or fatal results.

These are areas where the cardio-oncologist can offer valuable advice that allows both diseases to be treated simultaneously and safely.

Radiation woes

Radiation therapy can induce heart disease if any part of the heart is exposed to radiation. Problems can occur several years after exposure and include accelerated coronary artery disease, stiffening of the heart muscle, inflammation and thickening of the pericardial sac, problems with electrical conduction, or damage to heart valves. Researchers at Brigham and Women’s Hospital are now studying the potential of statins to protect against radiation-induced heart disease.

Radiation-induced heart failure is treated according to the same protocols recommended for people who develop the condition following a heart attack.

Heart-protection strategies

In order to start treatment before irreversible heart damage occurs, individuals undergoing cancer therapy should be followed with appropriate screening tests. Drs. Mehra, Moslehi, and Nohria are currently evaluating the use of echocardiography, electrocardiography, and certain biomarkers for identifying trouble before symptoms appear.

There is encouraging news that some forms of heart disease triggered by antitumor therapy may be reversible. Recently, Dr. Moslehi and two colleagues reported cardiomyopathy from angiogenesis inhibitors that was reversed with common heart medications.

Ultimately, the prevention of heart problems from cancer therapy is the goal. Here, too, there are signs of hope. In 2011, British researchers were able to prevent heart failure from trastuzumab (Herceptin) using beta blockers.

“This suggests that all is not lost. However, it takes a partnership and teamwork to make the right decisions,” says Dr. Mehra.

“If you are having any type of cancer therapy, its impact on your heart should be considered. Ask your oncologist and radiation oncologist to add a cardio-oncologist—or if one is not available, a cardiologist—to your treatment planning team.”

A partial list of chemotherapy agents with cardiovascular effects
Chemotherapy Agent	Cardiovascular Effect
arsenic trioxide (Trisenox)	Q-T prolongation
bevacizumab (Avastin)	Severe hypertension, heart failure, cardiomyopathy, thromboembolism
bortezomib (Velcade)	Edema
cisplatin (Platinol)	Severe hypertension, ischemia, atrial fibrillation, thromboembolism
doxorubicin (Adriamycin) and other anthracyclines	Cardiomyopathy, heart failure, cardiac shock
fluorouracil 5-FU (Adrucil)	Ischemia
imatinib (Gleevec)	Edema
interleukin-2 (Proleukin)	Atrial fibrillation
lapatinib (Tykerb)	Q-T prolongation
lenalidomide (Revlimid)	Thromboembolism
melphalan (Alkeran)	Atrial fibrillation
mitomycin (Mutamycin)	Heart failure
mitoxantrone (Novantrone)	Heart failure
pazopanib (Votrient)	Severe hypertension
sorafenib (Nexavar)	Severe hypertension, heart failure, thromboembolism
sunitinib (Sutent)	Severe hypertension, heart failure, thromboembolism
thalidomide (Thalomid)	Thromboembolism, bradycardia, edema
trastuzumab (Herceptin)	Heart failure

SOURCE

http://www.health.harvard.edu/newsletters/Harvard_Heart_Letter/2012/August/cancer-treatments-may-harm-the-heart?utm_source=heart&utm_medium=pressrelease&utm_campaign=heart0812

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Frontiers in Cardiology and Cardiovascular Disorders | Leave a Comment »

Reuben Shaw, Ph.D., a geneticist and researcher at the Salk Institute: Metabolism Influences Cancer

January 8, 2014 by 2012pharmaceutical

Reuben Shaw, Ph.D., a geneticist and researcher at the Salk Institute: Metabolism Influences Cancer

Reporter and Curator: Aviva Lev-Ari, PhD, RN

Article ID #102: Reuben Shaw, Ph.D., a geneticist and researcher at the Salk Institute: Metabolism Influences Cancer. Published on 1/8/2014

WordCloud Image Produced by Adam Tubman

Dec 26, 2013

Metabolism’s Unexpected Role in Cancer

A geneticist at the Salk Institute discusses his incredible discoveries.

Mitzi Perdue

The discoveries made in Reuben Shaw’s lab could influence how we treat diabetes, Alzheimer’s, and even aging itself. [© sheelamohanachandran – Fotolia.com]

The relationship between metabolism, cancer, and genetics was for decades obscured in part by chance, but in the last decade, the relationship has been rediscovered, also at least in part by chance. Reuben Shaw, Ph.D., a geneticist and researcher at the Salk Institute, is at the center of this story, and interestingly, the discoveries made in his lab have not only resulted in new targets for cancer therapy, but longer term, they’re also likely to influence how we treat diabetes, Alzheimer’s, and even aging itself.
Lost Information

To begin with the chance part of the story, what we now know to be true—that metabolism influences cancer—was well known at least 90 years ago. Back then, Otto Heinrich Warburg, a German physiologist, observed that tumor cells utilize glycolysis more than their normal counterpart cells despite being in normal oxygen conditions (the “Warburg Effect”). In 1931, Warburg won a Nobel Prize for his work on mitochondria. Subsequently he formulated the Warburg Hypothesis, that the cause of cancer is defective mitochondria.

In the 1980s, however, the discovery of “oncogenes” that directly caused cancer led researchers to believe that the Warburg Hypothesis for cancer causation was simply wrong. As the data on cancer-causing genes became both more comprehensive and more productive, cancer research switched to decoding genes, and a generation of researchers began ignoring metabolism as a factor.
Chance Intervenes

Things changed, however, when Dr. Shaw, who was trained as a cancer researcher at MIT and Harvard Medical School, was accepted at the Molecular and Cell Biology Laboratory at the Salk Institute. As Dr. Shaw puts it, “Salk is the only place that has a strong and deep history of cancer and diabetes research that also has the laboratories for both housed in one building. This means that some of the top people in the country get to interact fluidly, including not only sharing knowledge but also their tools and equipment.”

From Dr. Shaw’s point of view, the location of both the cancer and diabetes researchers in the same building meant that he was benefiting on a daily basis from the unique tools and discoveries of both the cancer and diabetes researchers at Salk and the cross-fertilization of these two fields. He was therefore able to pursue his investigations of the connections between the two diseases in ways that might not have happened if he were in a silo-type building where all his colleagues were researching cancer alone or diabetes alone.
The Cancer-Diabetes Connection

Before coming to Salk, he was already interested in a possible connection between the two diseases. As a postdoctoral fellow at the Harvard Medical School, he made the unexpected discovery in 2003 that LKB1, a gene causing 30% of lung cancers and 25% of cervical cancers was directly activating the enzyme AMPK, known to modulate diabetes and metabolism.

At this point, Dr. Shaw asked himself two seminal questions: “What did a diabetes gene have to do with cancer? And did the cancer gene have anything to do with diabetes?”

The answer turned out to be revelatory. AMPK is an ancient metabolic checkpoint that senses energy deprivation in the cells. Early in evolution, cells needed a sensor regulating their need for energy, and AMPK is found in organisms from simple yeasts to man and everything in between. AMPK responds to caloric restriction, exercise, hypoxia, low glucose, and metabolic hormones such as ghrelin or adiponectin.

In 2005, Dr. Shaw and his lab showed that metformin operates through LKB1 and AMPK to lower blood glucose. Since it is well-tolerated, it is the frontline treatment for type 2 diabetes with more than 120 million people taking it every day. However, as Dr. Shaw had postulated, at this time it was also becoming known that metformin reduces the risk of cancer in diabetic patients.

In 2008, now at Salk, Dr. Shaw and his lab discovered that AMPK directly shuts off a major oncogene called TOR, but it only does so when nutrients are low. This oncogene is the causal biochemical event in a number of human cancers, including kidney cancer, tuberous sclerosis, and LAM.

“LKB1 and AMPK act as a fuel gauge in our cells,” he explained in a recent interview, “and when energy is low, they instruct the cells to slow their metabolism. When tumor cells lack LKB1 or other parts of its pathway, they have, in effect, lost the sensor to know if their fuel levels are low.”
Interfering with Cancer’s Sweet Tooth

Knowing that cells lacking LKB1 had lost their fuel gauges, Dr. Shaw wondered if this could be an entry point for disrupting tumor growth. Dr. Shaw already knew that factors such as exercise and calorie restriction could stimulate AMPK’s signaling ability, but were there, he wondered, drugs that could accomplish the same thing? Interestingly, the answer is yes.

The drugs metformin and phenformin both inhibit mitochondria; however, phenformin is nearly 50 times as potent as metformin. Dr. Shaw and his postdoctoral fellows tested both metformin and phenformin as chemotherapeutic agents in mice genetically engineered to mutate different cancer genes in adult lung cells, which results in the mice developing advanced-stage lung tumors. Only in mice lacking the LKB1 cancer gene did Dr. Shaw and his team observe that, after three weeks of treatment with phenformin, there was a major reduction in tumor burden in the mice.
Cancer’s Achilles’ Heel

Knowledge of this leads to a profound impact on therapies for cancer because, as Dr. Shaw now knew, it was possible to interfere pharmacologically with this pathway. Disruptions of the “fuel sensing” mechanism means that with cancer cells, they could cause nutrient and oxygen deprivation. This had the medically important effect of signaling AMPK to arrest cell growth. The cancer cells would be influenced to cease proliferating.

But that’s not the end. The other side of the coin of being able to induce a faulty fuel-sensing mechanism is that the cancer cells may act as if it they have all the energy and nutrients they need, even when they don’t. This results in the continuation of cell growth, and in the absence of fuel, the cells continue dividing until they run out of all energy stores and die.
Possible Clinical Trials

“These studies,” he said, “are the tip of the iceberg. We are in the midst of decoding new links between metabolism and cancer that are going to result in new druggable targets. They are likely to be important in treating many different cancers, and they may also be effective for other diseases such as type II diabetes. In the future we may find that aberrations in these same pathways and the metabolic disturbances that result may underpin neurodegenerative diseases and other broad disease categories as well.”

A lot is at stake. The 90-year-old Warburg Hypothesis, re-evaluated by Dr. Shaw and his colleagues, could have an outsize impact on modern medicine. Let the clinical trials begin!

Mitzi Perdue, GEN’s corresponding editor, holds degrees from Harvard and George Washington University. She has authored more than 1,600 newspaper and magazine articles on science R&D and clinical medical applications, as well as on food, agriculture, and the environment. Perdue has a strong understanding of complex scientific and mathematical concepts. For 22 years, she was a syndicated columnist for the Scripps Howard News Service and before that, California’s Capitol News. Perdue is also the author of the newsletter from the professional association, Academy of Women’s Health. She has produced and hosted more than 400 interview shows, often in conjunction with scientists at the University of California at Davis. She is a former Commissioner for the U.S. National Commission on Libraries and Information Science and a former Trustee for the National Health Museum.

SOURCE

http://www.genengnews.com/insight-and-intelligenceand153/metabolism-s-unexpected-role-in-cancer/77899990/

Reuben J. Shaw

Associate Professor
Molecular and Cell Biology Laboratory
Howard Hughes Medical Institute Early Career Scientist

“Fasting pathway” points the way to new class of diabetes drugs

HDAC inhibitors may provide a novel way to cut excessive blood glucose levels at the source

May 12, 2011

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LA JOLLA, CA—A uniquely collaborative study by researchers at the Salk Institute for Biological Studies uncovered a novel mechanism that turns up glucose production in the liver when blood sugar levels drop, pointing towards a new class of drugs for the treatment of metabolic disease.

Their findings, published in the May 13, 2011, issue of the journal Cell, revealed a crucial role for so called histone deacetylases (HDACs), a group of enzymes that is the target of the latest generation of cancer drugs. HDACs get sugar production rolling when blood glucose levels run low after prolonged periods of fasting or during the night.

“In liver cells, so-called class II HDACs are usually sequestered outside the nucleus but in response to fasting signals they quickly shuttle into the nucleus where they help turn on genes needed for glucose production,” says Howard Hughes Medical Institute early career scientist Reuben J. Shaw, Ph.D., an assistant professor in the Molecular and Cell Biology Laboratory. “Thus drugs that specifically inhibit HDACs involved in gluconeogenesis may be very useful for the treatment of diabetes and metabolic syndrome.”

VIEW VIDEO

http://www.salk.edu/news/pressrelease_details.php?press_id=485

Research

Reuben Shaw, associate professor in the Molecular and Cell Biology Laboratory and the Dulbecco Laboratory for Cancer Research, studies signal transduction pathways that underlie the development of cancer as well as type 2 diabetes.

Our work centers around a human tumor suppressor named LKB1. LKB1 is mutationally inactivated in the familial cancer disease Peutz-Jegher Syndrome as well as in a large percentage of sporadic lung adenocarcinomas. Interestingly, LKB1 encodes a threonine kinase that serves to activate a number of downstream kinases, including the AMP-activated protein kinase (AMPK), which is a critical regulator of metabolism, and the par-1/MARK family of kinases that regulate cell polarity.

Using a combination of proteomic and bioinformatics approaches, we identified AMPK as a direct substrate of LKB1. AMPK is a well known highly conserved regulator of cell metabolism that is activated under conditions of energy stress. We propose that the LKB1-dependent activation of AMPK in response to these stress stimuli may act as a low energy checkpoint in the cell. This unexpected connection between a well-known regulator of cellular metabolism and a tumor suppressor gene led to two immediate questions: Does AMPK have a role in tumor suppression and conversely, does the LKB1 tumor suppressor have a role in metabolic control in critical tissues in mammals? We have found that indeed both are true and that through the phosphorylation of specific targets by AMPK, these wide effects on physiology are regulated.

One way that LKB1 and AMPK regulate tumorigenesis is through regulation of the mTOR kinase, a conserved integrator of nutrient and growth factor signaling. We found that AMPK directly phosphorylates the TSC2 tumor suppressor and activates it to inhibit mTOR signaling. Consistent with this observation from cell culture, tumors lacking LKB1 were found to contain elevated levels of mTOR compared to surrounding epithelium. These findings culminated in the observation that three different human hamartoma syndromes, involving loss of TSC1/2, PTEN, and LKB1, all share a common biochemical underpinning: hyperactivation of mTOR signaling. We also generated a tissue-specific knockout of LKB1 in liver and also observed dramatic elevations of mTOR signaling in this context.

We chose to knockout LKB1 in liver as liver is known to be a tissue where AMPK activity is thought to be critical. Indeed, we found that loss of LKB1 led to a complete loss of AMPK activation and severe diabetes-like phenotypes in in these mice. We found that both gluconeogenic and lipogenic gene expression were upregulated in the livers of these mice, due in part to the loss of phosphorylation of a critical transcriptional coactivator termed TORC2 by AMPK and related kinases in the absence of LKB1. Finally we showed that metformin, one of the most widely prescribed type 2 diabetes therapeutics in the world, requires LKB1/AMPK signaling in the liver in order to exert its therapeutic benefit.

Future studies in our lab will focus on further elucidating these critical signaling pathways at this emerging interface between cancer and diabetes. We will employ a variety of biochemical, cell-biological, and genetic mouse models to dissect these biological processes. In addition, we will examine how existing diabetic therapeutics may be useful in the treatment of tumors with defined genetic lesions.

Selected Publications

Mihaylova, M.M. and Shaw, R.J. (2013) Metabolic reprogramming by class I and II histone deacetylases. Trends Endocrinol Metab 24:48-57.

Shackelford, D.B., Abt, E., Gerken, L., Vasquez, D.S., Atsuko, S., Leblanc, M., Wei, L., Fishbein, M.C., Czernin, J., Mischel, P.S. and Shaw, R.J. (2013) LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23:143-158.

Auricchio, N., Malinowska, I., Shaw, R., Manning, B.D., and Kwiatkowski, D.J. (2012). Therapeutic trial of metformin and bortezomib in a mouse model of tuberous sclerosis complex (TSC). PLoS ONE 7:e31900.

Shaw, R.J. and Cantley, L.C. (2012) Decoding key nodes in the metabolism of cancer cells: sugar & spice and all things nice. F1000 Biol Rep 4:2.

Shaw, R.J. and Cantley, L.C. (2012) Ancient Sensor for Ancient Drug. Science 336:813-4.

Svensson, R.U. and Shaw, R.J. (2012) Cancer metabolism: Tumour friend or foe. Nature485:590-591.

Xia, Y., Yeddula, N., LeBlanc, M., Ke, E., Zhang, Y., Oldfield, E., Shaw, R.J. and Verma, I.M. (2012) Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model. Nat Cell Biol14:257-65.

Akhtar, A., Fuchs, E., Mitchison, T., Shaw, R.J., St. Johnston, D., Strasser, A., Taylor, S., Walczak, C. and Zerial, M. (2011) A decade of molecular cell biology: achievements and challenges. Nat Rev Mol Cell Biol 12:669-674.

Mihaylova, M.M., Vasquez, D.S., Ravnskjaer, K., Denechaud, P-D., Yu, R.T., Alvarez, J.G., Downes, M., Evans, R.M., Montminy, M. and Shaw, R.J. (2011) Class IIa Histone Deacetylases are Hormone-activated regulators of FOXO and Mammalian Glucose Homeostasis. Cell 145, 1-15. [doi:10.1016/j.cell.2011.03.043]

Li, Y., Xu, S., Mihaylova, M., Zheng, B., Hou, X., Jiang, B., Park, O., Luo, Z., Lefai, E., Shyy, J.Y-J., Gao, B., Wierzbicki, M., Verbeuren, T.J., Shaw, R.J., Cohen, R.A. and Zang, M. (2011) AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-induced Insulin Resistant Mice. Cell Metab 13, 376-388.

Mair, W., Morantte, I., Rodrigues, A.P., Manning, G., Montminy, M., Shaw, R.J. and Dillin, A. (2011) Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470, 404-408.

Egan, D.F., Shackelford, D.B., Mihaylova, M.M., Gelino, S.R., Kohnz, R.A., Mair, W., Vasquez, D.S., Joshi, A., Gwinn, D.M., Taylor, R., Asara, J.M., Fitzpatrick, J., Dillin, A., Viollet, B., Kundu. M., Hansen, M. and Shaw, R.J. (2011) Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy. Science 331, 456-461.

Shackelford, D.B. and Shaw, R.J. (2009) The LKB1-AMPK pathway: metabolism and growth control in tumor suppression. Nat. Rev. Cancer, 9, 563-575.

Shackelford, D.B., Vasquez, D.S., Corbeil, J., Wu, S., Leblanc, M., Wu, C.L., Vera, D.R., and Shaw, R.J. (2009) mTOR- and HIF-1a mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. PNAS 106, 11137-11142.

Narkar, V.A., Downes, M., Yu, R.T., Wang, Y.X., Kanakubo, E., Banayo, E., Mihaylova, M.M., Nelson, M.C., Zou, Y., Juguilon, H., Kang. H., Shaw, R.J., and Evans. R.M. (2008) AMPK and PPARβ/δ agonists are exercise mimetics. Cell 134, 405-415.

Gwinn, D.M., Shackelford, D.B., Egan., D.F., Mihaylova, M.M., Mery, A., Vasquez, D.S., Turk, B.E., and Shaw, R.J. (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30, 214-26.

Shaw, R.J. Glucose metabolism and cancer (2006) Curr. Opin. Cell Biol. 18, 598-608.

Shaw, R.J. and Cantley, L.C. (2006) Ras, PI3(K), and mTOR signaling control tumor cell growth. Nature 441, 424-430.

Shaw, R.J., Lamia, K.A., Vasquez, D., Koo, S.H., Bardeesy, N., DePinho, R.A., Montminy, M., Cantley, L.C. (2005) The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin. Science 310, 1642-6.

Shaw, R.J., Bardeesy, N., Manning, B., Lopez, L. Kosmatka, M., DePinho, R.A., and Cantley, L.C. (2004). The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91-99

Shaw, R.J., Kosmatka, M., Bardeesy, N., Hurley, R.L., Witters, L.A., DePinho, R.A., Cantley, L.C. (2004). The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. PNAS 101, 3329-3335

Awards and Honors

Howard Hughes Medical Institute Early Career Scientist Award (2009-2015)
Hearst Assistant Professorship Chair (2009-2012)
American Diabetes Association Junior Faculty Award (2008-2011)
American Cancer Society Research Scholar (2007-2011)
V Scholar for Cancer Research (2006-2007)

SOURCE

http://www.salk.edu/faculty/shaw.html

Keeping a positive attitude	Eating good food
Exercising moderately (most report basic activities, like walking, biking, gardening, swimming, etc.)	Clean living (not smoking or drinking excessively, etc.)
Living independently	Family
“Good genes”	Friends
Staying mentally active and always learning something new	Faith/spirituality

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