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Hypertension and Vascular Compliance: 2013 Thought Frontier – An Arterial Elasticity Focus

Posted in Atherogenic Processes & Pathology, Bio Instrumentation in Experimental Life Sciences Research, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, tagged Antihypertensive drug, Artery, Aviva Lev-Ari, Barcelona, Blood pressure, Cardiovascular disease, Cardiovascular Disorders, Circulatory system, Conditions and Diseases, health, Hypertension, Justin D. Pearlman, Lancet, Nitrovasodilator, Oslo, Systolic Hypertension, Tel Aviv University, vasodilation on May 11, 2013| 11 Comments »

Pros and Cons of Drug Stabilizers for Arterial Elasticity as an Alternative or Adjunct to Diuretics and Vasodilators in the Management of Hypertension.

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC

and

Article Curator: Aviva Lev-Ari, PhD, RN

This article presents the 2013 Thought Frontier on Hypertension and Vascular Compliance.

Conceptual development of the subject is presented in the following nine parts:

1. Physiology of Circulation and Role of Arterial Elasticity

2. Isolated Systolic Hypertension caused by Arterial Stiffening may be inadequately treated by Diuretics or Vasodilatation Antihypertensive Medications

3. Physiology of Circulation and Compensatory Mechanism of Arterial Elasticity

4. Vascular Compliance – The Potential for Novel Therapies

Novel Mechanism for Disease Etiology: Modulation of Nuclear and Cytoskeletal Actin Polymerization.
Genetic Therapy targeting Vascular Conductivity
Regenerative Medicine for Vasculature Function Protection

5. In addition to curtailing high pressures, stabilizing BP variability is a potential target for management of hypertension

6. Mathematical Modeling: Arterial stiffening explains much of primary hypertension

7. Classification of Blood Pressure and Hypertensive Treatment Best Practice of Care in the US

8. Genetic Risk for High Blood Pressure

9. Is it Hypertension or Physical Inactivity: Cardiovascular Risk and Mortality – New results in 3/2013.

Summary By Justin D. Pearlman MD ME PhD MA FACC

1. Physiology of Circulation and Role of Arterial Elasticity

Simplistically, high blood pressure stems from too much volume (salt water) for the vascular space, or conversely, too little space for the volume. Biological signals, such as endothelin, hypoxia, acidosis, nitric oxide, can modify vascular volume by constricting muscles in blood vessel walls. Less simplistically the physics of circulation are governed by numerous factors, with essentials detailed below.
The vascular space has two major circuits: pulmonary (lungs) and systemic (body).
Compliance (C) relates change in volume (ΔV) to change in pressure (ΔP) as a measure of the strength of elasticity, where elasticity summarizes the intrinsic forces that return to original shape after deformation: C = ΔV/ΔP . Those values can be estimated by ultrasound imaging with Doppler blood velocity estimation, by MRI, or invasively. Related properties can also be measured, such as wave propagation time or fractional flow reserve.
The vascular system is dynamic, with frequency components and reactive elements. The fundamental frequency is governed by the heart rate delivering a stroke volume forward into the vasculature; a heart rate of 60/minute corresponds to the frequency of 1 Hertz (1 cycle/second). The pressure rise due to the ejection of stroke volume is called the pulse pressure.
Numerous factors affect blood flow, including blood composition (affected by anemia or blood dilution), leakiness of vessels, elasticity, wave propagation, streamlines, viscosity, osmotic pressure (affected by protein deficiency and other factors),
In a static system, the driving force relates linearly flow by way of resistance (R in units of dyn·s·cm⁻⁵): V=IR (Ohm’s law).
- Pulmonary: $\frac {80 \cdot (mean\ pulmonary\ arterial\ pressure - mean \ pulmonary \ artery \ wedge \ pressure)} {cardiac\ output}$
- Systemic: $\frac {80 \cdot (mean\ arterial\ pressure - mean \ right \ atrial \ pressure)} {cardiac\ output}$
In a dynamic, reactive system, the relation between the driving potential (pressure gradient), and current (blood flow) is governed by a differential equation. However, use of complex numbers and exponentials recovers simplicity similar to Ohm’s law:
- Variables take the form $Ae^{st}$ , where t is time, s is a complex parameter, and A is a complex scalar. Complex values simply mean two dimensional, e.g., magnitude (as in resistance) plus phase shift (to account for reactive components).
- Complex version of Ohm’s law: $\boldsymbol{V} = \boldsymbol{I} \cdot \boldsymbol{Z}$ where V and I are the complex scalars in the voltage and current respectively and Z is the complex impedance.
- Frequency dependent “resistance” is captured by the term impedance.

Breathing in increases the return of blood to the heart, adding to pulse variation.
Dynamic elastance (Ea_dyn) relates volume variation (VVS) to pressure variation (PPV): Ea_dyn=PPV/SVV
- PPV(%) = 100% × (PP_max − PP_min)/[(PP_max + PP_min)/2)]
  - where PP_maxand PP_minare the maximum and minimum pulse pressures determined during a single respiratory cycle
- SVV(%) = 100% × [(SV_max − SV_min)/SV_mean]
  - where SV_max and SV_min are the maximum and minimum standard deviation of arterial pressure about the mean arterial pressure during a single respiratory cycle
The nervous system provides both stimulants and inhibitors (sympathetic and vagal nerves) to regulate blood vessel wall muscle tone and also heart rate. Many medications, and anesthetic agents in particular, reduce those responses to stimuli, so the vessels dilate, vascular impedance lowers, pressures drop, and autoregulation is impaired.

Diuretics aim to decrease volume of circulating fluid, vasodilators aim to increase the vascular space, and elasticity treatments will aim to preserve or improve the ability to accommodate changes in volume of fluid.
- Vessel dilation near the skin promotes heat loss.

Vascular elasticity is impaired by atherosclerosis, menopause, and endothelial dysfunction (impaired nitric oxide signals response, impaired endothelin response).

Elastance in a cyclic pressure system of systole-diastole (contraction-dilation) presents impedance as a pulsatile load on the heart. Inotropy describes the generation of pressure by cardiac contraction, lusiotropy the compliance of the heart to accept filling with minimal back pressure to the lungs. Chronic exposure to elevated vascular impedance leads to impairment of lusiotropy (diastolic failure, stiff heart) and inotropy (systolic failure, weak heart).

2. Isolated Systolic Hypertension caused by Arterial Stiffening may be inadequately treated by Diuretics or Vasodilatation Antihypertensive Medications

Stiff or “lead pipe” blood vessels drop pressure precipitously to dangerously low levels in response to diuretics.
Stiff walls due to fibrosis or scar tissue have limited ability to dilate
Red clover isoflavones improve vascular compliance loss from menopause.
Fish oils may improve loss of vascular compliance from diabetes.

3. Physiology of Circulation and Compensatory Mechanism of Arterial Elasticity

Antihypertensive agents have focused on the following approaches:

Reduced volume (diuretics)
- Diuretics enhance renal excretion of sodium. Sodium is the major determinant of circulating volume. Too much blood volume for the amount of vascular space elevates blood pressure. Clinical trials show that use of diuretics to lower blood pressure can prevent strokes, non-inferior to vasodilators and recommended as first line agents.

The most common prescriptions, a mild diuretic, hydrochlorothiazide (HCTZ), is known to improve blood vessel compliance by reducing cell turgor, which explains why its full onset of benefit as well as its slow offset when stopped can take more than one month.
Chlorthalidone – Some evidence suggests that chlorthalidone may be superior to hydrochlorothiazide for the treatment of hypertension. However, a recent study concluded: chlorthalidone in older adults was not associated with fewer adverse cardiovascular events or deaths than hydrochlorothiazide. However, it was associated with a greater incidence of electrolyte abnormalities, particularly hypokalemia.

Increased vascular space (vasodilation)
- Alternatively, the pressure can be lowered by increasing the vascular space for a given vascular volume. Examples of mediators for arterial tone (degree of dilation) include nitric oxide, prostacyclin and endothelin.

Class	Description
Hyperpolarization mediated (Calcium channel blocker)	Changes in the resting membrane potential of thecell affects the level of intracellular calciumthrough modulation of voltage sensitive calcium channelsin the plasma membrane.
cAMP mediated	Adrenergic stimulation results in elevated levelsof cAMP and protein kinase A, which results inincreasing calcium removal from the cytoplasm.
cGMP mediated (Nitrovasodilator)	Through stimulation of protein kinase G.Until 2002, the enzyme for this conversion wasdiscovered to be mitochondrial aldehyde dehydrogenase.Proc. Natl. Acad. Sci. USA 102 (34): 12159–12164. doi:10.1073/pnas.0503723102 http://www.pnas.org/content/102/34/12159.long

Class	Example
Hyperpolarization mediated (Calcium channel blocker)	adenosineamlodipine (Norvasc),diltiazem (Cardizem,Dilacor XR) andnifedipine (Adalat, Procardia).
cAMP mediated	prostacyclin
cGMP mediated (Nitrovasodilator)	nitric oxide

Reduced pulsatile force (beta blockers)

These work by blocking certain nerve and hormonal signals to the heart and blood vessels, thus lowering blood pressure. Frequently prescribed beta blockers include

metoprolol (Lopressor, Toprol XL)
carvedilol (Coreg)
nadolol (Corgard)
penbutolol (Levatol).
Metabolized nebivolol increases vascular NO production, involves endothelial ß2-adrenergic receptor ligation, with a subsequent rise in endothelial free [Ca2+]i and endothelial NO synthase–dependent NO production

Angiotensin-converting enzyme (ACE) inhibitors

These allow blood vessels to widen by preventing the hormone angiotensin from affecting blood vessels. Frequently prescribed ACE inhibitors include captopril (Capoten), lisinopril (Prinivil, Zestril) and ramipril (Altace).

Angiotensin II receptor blockers

These help blood vessels relax by blocking the action of angiotensin. Frequently prescribed angiotensin II receptor blockers include losartan (Cozaar), olmesartan (Benicar) and valsartan (Diovan).
Another very commonly prescribed drug class of medication counteracts hardening of arteries.

Atheroma lipids have enzyme systems that explicitly disassemble cholesterol esters and reconstruct them inside blood vessel walls,e.g., Anacetrapib, Genetic variants that improve cholesterol levels are stimulating development of additional medications.

We can propose that atheroma build up in arterial blood vessel walls constitutes a maladaptive defense against aneurysm and risk of vessel rupture from hypertension.

Arguably, HMG-CoA reductase inhibitors, statin therapy is a second example of a medication that helps protect vascular elasticity, both by its lipid effects and its anti-inflammatory effects.

The best-selling statin is atorvastatin, marketed as Lipitor (manufactured by Pfizer) and Torvast. By 2003, atorvastatin became the best-selling pharmaceutical in history,^[4] with Pfizer reporting sales of US$12.4 billion in 2008.^[5] As of 2010, a number of statinsare on the market: atorvastatin (Lipitor and Torvast), fluvastatin (Lescol), lovastatin (Mevacor, Altocor, Altoprev), pitavastatin(Livalo, Pitava), pravastatin (Pravachol, Selektine, Lipostat), rosuvastatin (Crestor) and simvastatin (Zocor, Lipex).^[6] Several combination preparations of a statin and another agent, such as ezetimibe/simvastatin, are also available.

References for Statins from:

http://en.wikipedia.org/wiki/Statin

Clinical Considerations of Statin Therapy’s manifold effects, in

http://pharmaceuticalintelligence.com/2012/10/08/statins-nonlipid-effects-on-vascular-endothelium-through-enos-activation/

Compensatory Effects in the Physiology of Circulation

Before declaring vessel elasticity a new and highly desirable treatment target, consider that it is not firmly established that hardening of arteries (loss of elasticity) is entirely maladaptive.

In parallel with any focus on increasing vascular elasticity or compliance, each of the issues discussed, below merits scrutiny and investigation.

Cardiac Circulation Dynamics

Endothelium morphology, rheological properties of intra vasculature fluid dynamics and blood viscosity provided explanation for shear stress of vessels under arterial pressure

http://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/

and

http://pharmaceuticalintelligence.com/2012/11/28/what-is-the-role-of-plasma-viscosity-in-hemostasis-and-vascular-disease-risk/

Aging and Vasculature Diminished Elasticity

While among other reasons for Hypertension increasing prevalence with aging, arterial stiffening is one.

Yet, stiffer vessels are more efficient at transmitting pressure to distal targets. With aging, muscle mass diminishes markedly and the contribution to circulation from skeletal muscle tissue compressions combined with competent venous valves fades.

http://pharmaceuticalintelligence.com/2012/08/27/endothelial-dysfunction-diminished-availability-of-cepcs-increasing-cvd-risk-for-macrovascular-disease-therapeutic-potential-of-cepcs/

and

http://pharmaceuticalintelligence.com/2012/10/19/clinical-trials-results-for-endothelin-system-pathophysiological-role-in-chronic-heart-failure-acute-coronary-syndromes-and-mi-marker-of-disease-severity-or-genetic-determination/

and

http://pharmaceuticalintelligence.com/2012/11/13/peroxisome-proliferator-activated-receptor-ppar-gamma-receptors-activation-pparγ-transrepression-for-angiogenesis-in-cardiovascular-disease-and-pparγ-transactivation-for-treatment-of-dia/

Aging and Myocardial Diminished Contractility and Ejection Fraction

With aging heart contractility diminishes. These issues can cause under perfusion of tissues, inadequate nutrient blood delivery (ischemia), lactic acidosis, tissue dysfunction and multi-organ failure. Hardened arteries may compensate. Thus, pharmacotherapy to increase Arterial Elasticity may be counterindicated for patients with mild to progressive CHF.

http://pharmaceuticalintelligence.com/2013/05/05/bioengineering-of-vascular-and-tissue-models/

and

http://pharmaceuticalintelligence.com/2012/10/20/nitric-oxide-and-sepsis-hemodynamic-collapse-and-the-search-for-therapeutic-options/

and

http://pharmaceuticalintelligence.com/2012/10/17/chronic-heart-failure-personalized-medicine-two-gene-test-predicts-response-to-beta-blocker-bucindolol/
Our biosystems are highly interdependent, and we cannot leap to conclusions without careful thorough evidence. Increasing arterial elastance will lower vascular impedance and change the frequency components of our pulsatile perfusion system.

MOST comprehensive review of the Human Cardiac Conduction System presented to date:

http://pharmaceuticalintelligence.com/2013/04/28/genetics-of-conduction-disease-atrioventricular-av-conduction-disease-block-gene-mutations-transcription-excitability-and-energy-homeostasis/

Diminished contractility will increase the amount of energy needed to maintain circulation. It will change efficiency dramatically – consider the difference between periodically pushing someone sitting on a swing at the resonance frequency if the pendulum versus significantly off resonance.

http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

and

http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

Increased Arterial Elasticity – Potential Risk to Myocardium

The hypothesis that we should focus on cellular therapies to increase vascular compliance may decrease the circulation efficiency and result in worsening of cardiac right ventricular morphology and development of Dilated cardiomyopathy and hypertrophic cardiomyopathy (muscle thickening and diastolic failure), an undesirable outcome resulting from an attempt to treat the hypertension.

4. Vascular Compliance – The Potential of Noval Therapies

Novel Mechanism for Disease Etiology for the Cardiac Phenotype: Modulation of Nuclear and Cytoskeletal Actin Polymerization.

Lamin A/C and emerin regulate MKL1–SRF activity by modulating actin dynamics

Nature (2013) doi:10.1038/nature12105

Published online 05 May 2013

Affiliations

Cornell University, Weill Institute for Cell and Molecular Biology/Department of Biomedical Engineering, Ithaca, New York 14853, USA

Chin Yee Ho &

Jan Lammerding

Brigham and Women’s Hospital/Harvard Medical School, Department of Medicine, Boston 02115, Massachusetts, USA

Chin Yee Ho,

Diana E. Jaalouk &

Jan Lammerding

Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland

Maria K. Vartiainen

Present address: American University of Beirut, Department of Biology, Beirut 1107 2020, Lebanon.

Diana E. Jaalouk

Contributions

C.Y.H., D.E.J. and J.L. conceived and designed the overall project, with valuable help from M.K.V. C.Y.H. and D.E.J. performed the experiments. C.Y.H., D.E.J. and J.L. analysed data. C.Y.H. and J.L. wrote the paper.

Corresponding author Jan Lammerding

Laminopathies, caused by mutations in the LMNA gene encoding the nuclear envelope proteins lamins A and C, represent a diverse group of diseases that include Emery–Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (DCM), limb-girdle muscular dystrophy, and Hutchison–Gilford progeria syndrome1. Most LMNA mutations affect skeletal and cardiac muscle by mechanisms that remain incompletely understood. Loss of structural function and altered interaction of mutant lamins with (tissue-specific) transcription factors have been proposed to explain the tissue-specific phenotypes1. Here we report in mice that lamin-A/C-deficient (Lmna⁻^/⁻) and Lmna^N195K/N195K mutant cells have impaired nuclear translocation and downstream signalling of the mechanosensitive transcription factor megakaryoblastic leukaemia 1 (MKL1), a myocardin family member that is pivotal in cardiac development and function2. Altered nucleo-cytoplasmic shuttling of MKL1 was caused by altered actin dynamics in Lmna⁻^/⁻ and Lmna^N195K/N195K mutant cells. Ectopic expression of the nuclear envelope protein emerin, which is mislocalized in Lmnamutant cells and also linked to EDMD and DCM, restored MKL1 nuclear translocation and rescued actin dynamics in mutant cells. These findings present a novel mechanism that could provide insight into the disease aetiology for the cardiac phenotype in many laminopathies, whereby lamin A/C and emerin regulate gene expression through modulation of nuclear and cytoskeletal actin polymerization.

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12105.html

Genetic Therapy to Conductivity Disease

http://pharmaceuticalintelligence.com/2012/10/01/ngs-cardiovascular-diagnostics-long-qt-genes-sequenced-a-potential-replacement-for-molecular-pathology/

Regenerative Medicine for Vasculature Function Protection

http://pharmaceuticalintelligence.com/2012/08/29/positioning-a-therapeutic-concept-for-endogenous-augmentation-of-cepcs-therapeutic-indications-for-macrovascular-disease-coronary-cerebrovascular-and-peripheral/

and

http://pharmaceuticalintelligence.com/2012/08/28/cardiovascular-outcomes-function-of-circulating-endothelial-progenitor-cells-cepcs-exploring-pharmaco-therapy-targeted-at-endogenous-augmentation-of-cepcs/

and

http://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-based-pharmacological-therapy-including-thymosin/

5. Stabilizing BP Variability is the next Big Target in Hypertension Management

Hypertension caused by Arterial Stiffening is Ineffectively Treated by Diuretics and Vasodilatation Antihypertensives

Barcelona, Spain – An aging population grappling with rising rates of hypertension and other cardiometabolic risk factors should prompt an overhaul of how hypertension is diagnosed and monitored and should spur development of drugs with entirely new mechanisms of action, one expert says. Speaking here at the 2013 International Conference on Prehypertension and Cardiometabolic Syndrome, meeting cochair Dr Reuven Zimlichman (Tel Aviv University, Israel) argued that the definitions of hypertension, as well as the risk-factor tables used to guide treatment, are no longer appropriate for a growing number of patients.

Most antihypertensives today work by producing vasodilation or decreasing blood volume and so are ineffective treatments in ISH patients. In the future, he predicts, “we will have to start looking for a totally different medication that will aim to improve or at least to stabilize arterial elasticity: medication that might affect factors that determine the stiffness of the arteries, like collagen, like fibroblasts. Those are not the aim of any group of antihypertensive medications today.”

Zimlichman believes existing databases could be used to develop algorithms that take this progression of disease into account, in order to better guide hypertension management. He also points out that new ambulatory blood-pressure-monitoring devices also measure arterial elasticity. “Unquestionably, these will improve our ability to diagnose both the status of the arteries and the changes of the arteries with time as a result of our treatment. So if we treat the patient and we see no improvement in arterial elasticity, or the patient is worse, something is wrong, something is not working—either the patient is not taking the medication, or our choice of medication is not appropriate, or the dose is insufficient, etc.”

http://www.theheart.org/article/1502067.do

Oslo, Norway – New research that is only just starting to be digested by the hypertension community indicates that visit-to-visit variability in blood-pressure readings will likely become another way of looking for “at-risk” hypertensive patients and in fact is likely to be more reliable as an indicator of cardiovascular risk than the currently used mean BP.

The Goal of Stabilizing BP variability

June 29, 2010 Lisa Nainggolan

Discussing the importance of this issue for guidelines and clinical practice, Dr Tony Heagerty (University of Manchester, UK) told the recent European Society of Hypertension (ESH) European Meeting on Hypertension 2010: “We are poking around in the dark, offering treatment blankly across a large community, and probably treating a lot of people who don’t need to be treated, while not necessarily treating the highest-risk patients. We should stop being reassured by ‘occasional’ normal BPs. The whole game now is, can we improve the identification of our ‘at-risk’ individuals?”

Heagerty was speaking at a special plenary session on late-breaking research discussing BP variability as a risk factor. This issue has emerged following new analyses reported at the ACC meeting and published in a number of papers in the Lancet and Lancet Neurology earlier this year, which showed that variability in blood pressure is a much stronger determinant of both stroke and coronary disease outcome than average blood pressure.

http://www.theheart.org/article/1093553.do

Three years later, 2/1/2013, Zimlichman also argued that definitions of essential and secondary hypertension have changed very little over the past few decades and have typically only been tweaked up or down related to other CV risk factors. Diastolic hypertension has been the primary goal of treatment, and treatment goals have not adequately taken patient age into account (in whom arterial stiffening plays a larger role), and they have typically relied too heavily on threshold cutoffs, rather than the “linear progression” of risk factors and their impact on organ damage.

6. Mathematical Modeling: Arterial stiffening provides sufficient explanation for primary hypertension

Klas H. Pettersen, Scott M. Bugenhagen, Javaid Nauman, Daniel A. Beard, Stig W. Omholt

(Submitted on 3 May 2013 (v1), last revised 6 May 2013 (this version, v2))

Hypertension is one of the most common age-related chronic diseases and by predisposing individuals for heart failure, stroke and kidney disease, it is a major source of morbidity and mortality. Its etiology remains enigmatic despite intense research efforts over many decades. By use of empirically well-constrained computer models describing the coupled function of the baroreceptor reflex and mechanics of the circulatory system, we demonstrate quantitatively that arterial stiffening seems sufficient to explain age-related emergence of hypertension. Specifically, the empirically observed chronic changes in pulse pressure with age, and the impaired capacity of hypertensive individuals to regulate short-term changes in blood pressure, arise as emergent properties of the integrated system. Results are consistent with available experimental data from chemical and surgical manipulation of the cardio-vascular system. In contrast to widely held opinions, the results suggest that primary hypertension can be attributed to a mechanogenic etiology without challenging current conceptions of renal and sympathetic nervous system function. The results support the view that a major target for treating chronic hypertension in the elderly is the reestablishment of a proper baroreflex response.

Klas H. Pettersen1, Scott M. Bugenhagen2, Javaid Nauman3, Daniel A. Beard2 & Stig W. Omholt3

1Department of Mathematical and Technological Sciences, Norwegian University of Life Science, Norway

2Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

3NTNU Norwegian University of Science and Technology, Department of Circulation and Medical Imaging, Cardiac Exercise Research Group, Trondheim, Norway

Correspondence should be addressed to: KHP (klas.pettersen@gmail.com)

Keywords: hypertension, mechanogenic, baroreceptor signaling, cardiovascular model, arterial stiffening

Author contributions: K.H.P. and S.W.O. designed the study. K.H.P. constructed the

integrated model and performed the numerical experiments with contributions from

D.A.B. and S.M.B.. J.N. extracted and compiled empirical test data from the HUNT2

Survey. S.W.O, K.H.P. and D.A.B. wrote the paper.

http://arxiv.org/abs/1305.0727v2

http://arxiv.org/pdf/1305.0727v2.pdf

7. Classification of Blood Pressure and Hypertensive Treatment:

Best Practice of Care in the US

Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

8. Genetic Risk for High Blood Pressure

Hypertension.2013; 61: 931doi: 10.1161/HYP.0b013e31829399b2

Blood Pressure Single-Nucleotide Polymorphisms and Coronary Artery Sisease (page 995)

Blood pressure (BP) is considered a major cardiovascular risk factor that is influenced by multiple genetic and environmental factors. However, the precise genetic underpinning influencing interindividual BP variation is not well characterized; and it is unclear whether BP-associated genetic variants also predispose to clinically apparent cardiovascular disease. Such an association of BP-related variants with cardiovascular disease would strengthen the concept of BP as a causal risk factor for cardiovascular disease. In this issue of Hypertension, analyses within the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis consortium indicate that common genetic variants associated with BP in the population, indeed, contribute to the susceptibility for coronary artery disease (CAD). Lieb et al tested 30 single-nucleotide polymorphisms—that based on prior studies were known to affect BP—for their association with CAD. In total, data from 22 233 CAD cases and 64 762 controls were analyzed. The vast majority (88%) of BP-related single-nucleotide polymorphisms were also shown to increase the risk of CAD (as defined by an odds ratio for CAD >1; Figure). On average, each of the multiple BP-raising alleles was associated with a 3% (95% confidence interval, 1.8%–4.3%) risk increase for CAD.

Masked Hypertension in Diabetes Mellitus (page 964)

The first important finding in the IDACO study of masked hypertension (MH) in the population with diabetes mellitus and non–diabetes mellitus was that antihypertensive treatment converted some sustained hypertensives into sustained normotensives; this resulted in an increased cardiovascular disease risk in the treated versus untreated normotensive comparator group (Figure). Not surprisingly, normalization of blood pressure (BP) with treatment did not eliminate the lifetime cardiovascular disease burden associated with prior elevated BP nor did it correct other cardiometabolic risk factors that clustered with the hypertensive state.

The second important IDACO finding was that treatment increased the prevalence of MH by decreasing conventional BP versus daytime ambulatory BP (ABP) by a ratio of ≈3 to 2. The clinical implication of increased prevalence of MH with therapy in the population of both diabetes mellitus and non–diabetes mellitus was that these subjects did not receive sufficient antihypertensive therapy to convert MH into normalized ABP (ie, treated, normalized ABP being the gold standard for minimizing cardiovascular disease risk). Indeed, there is a transformation-continuum from sustained hypertension to MH and finally to sustained normotension with increasing antihypertensive therapy. These IDACO findings strongly suggest that many physicians mistakenly have their primary focus on normalizing in-office rather than out-of-office home BP and/or 24-hour ABP values and this results in an increased prevalence of MH. However, what constitutes optimal normalized ABP will remain empirical until established in randomized controlled trials.

Genetic Risk Score for Blood Pressure (page 987)

Elevated blood pressure (BP) is a strong, independent, and modifiable risk factor for stroke and heart disease. BP is a heritable trait, and genome-wide association studies have identified several genetic loci that are associated with systolic BP, diastolic BP, or both. Although the variants have modest effects on BP, typically 0.5 to 1.0 mm Hg, their presence may act over the entire life course and, therefore, lead to substantial increase in risk of cardiovascular disease (CVD). However, the independent impact of these variants on CVD risk has not been established in a prospective setting. Havulinna et al genotyped 32 common single-nucleotide polymorphisms in several Finnish cohorts, with up to 32 669 individuals after exclusion of prevalent CVD cases. The median follow-up was 9.8 years, during which 2295 incident CVD events occurred. Genetic risk scores were created for systolic BP and diastolic BP by multiplying the risk allele count of each single-nucleotide polymorphism by the effect size estimated in published genome-wide association studies on BP traits. The GRSs were strongly associated with baseline systolic BP, diastolic BP, and hypertension (all P<10–62). Hazard ratios for incident CVD increased roughly linearly by quintile of systolic BP or diastolic BP GRS (Figure). GRSs remained significant predictors of CVD risk after adjustment for traditional risk factors, even including BP and use of antihypertensive medication. These findings are consistent with a lifelong effect of these variants on BP and CVD risk.

9. Is it Hypertension or Physical Inactivity: Cardiovascular Risk and Mortality – New results in 3/2013.

Heart doi:10.1136/heartjnl-2012-303461

Epidemiology

Original article

Estimating the effect of long-term physical activity on cardiovascular disease and mortality: evidence from the Framingham Heart Study

+Author Affiliations

¹Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
²Biostatistics Unit, Group Health Research Institute, Seattle, Washington, USA
³Obesity and Population Health Unit, Baker IDI Heart and Diabetes Institute, Melbourne, Australia

Correspondence toDr Susan M Shortreed, Biostatistics Unit, Group Health Research Institute, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101, USA; shortreed.s@ghc.org

Published Online First 8 March 2013

Abstract

Objective In the majority of studies, the effect of physical activity (PA) on cardiovascular disease (CVD) and mortality is estimated at a single time point. The impact of long-term PA is likely to differ. Our study objective was to estimate the effect of long-term adult-life PA compared with long-term inactivity on the risk of incident CVD, all-cause mortality and CVD-attributable mortality.

Design Observational cohort study.

Setting Framingham, MA, USA.

Patients 4729 Framingham Heart Study participants who were alive and CVD-free in 1956.

Exposures PA was measured at three visits over 30 years along with a variety of risk factors for CVD. Cumulative PA was defined as long-term active versus long-term inactive.

Main outcome measures Incident CVD, all-cause mortality and CVD-attributable mortality.

Results During 40 years of follow-up there were 2594 cases of incident CVD, 1313 CVD-attributable deaths and 3521 deaths. Compared with long-term physical inactivity, the rate ratio of long-term PA was 0.95 (95% CI 0.84 to 1.07) for CVD, 0.81 (0.71 to 0.93) for all-cause mortality and 0.83 (0.72 to 0.97) for CVD-attributable mortality. Assessment of effect modification by sex suggests greater protective effect of long-term PA on CVD incidence (p value for interaction=0.004) in men (0.79 (0.66 to 0.93)) than in women (1.15 (0.97 to 1.37)).

Conclusions

Cumulative long-term PA has a protective effect on incidence of all-cause and CVD-attributable mortality compared with long-term physical inactivity.
In men, but not women, long-term PA also appears to have a protective effect on incidence of CVD.

Summary – PENDING

REFERENCES
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Ultrasound-based Screening for Ovarian Cancer

Posted in Bio Instrumentation in Experimental Life Sciences Research, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Ecosystems & Industrial Concentration in the Medical Device Sector, Health Economics and Outcomes Research, Imaging-based Cancer Patient Management, Medical Devices R&D and Inventions, tagged breast cancer, Cancer - General, Cancer screening, Clinical trial, Conditions and Diseases, epithelial ovarian cancer, genetics, health, medicine, national cancer institute, nci web, ovarian cancer, ovarian cancer patients, Personalized medicine, research, screening for ovarian cancer, ultrasound, ultrasound imaging, ultrasound machines on April 28, 2013| 6 Comments »

Ultrasound-based Screening for Ovarian Cancer

Author: Dror Nir, PhD

Occasionally, I check for news on ovarian cancer screening. I do that for sentimental reasons; I started the HistoScanning project aiming to develop an effective ultrasound-based screening solution for this cancer.

As awareness for ovarian cancer is highest in the USA, I checked for the latest news on the NCI web-site. I found that to-date: “There is no standard or routine screening test for ovarian cancer. Screening for ovarian cancer has not been proven to decrease the death rate from the disease.

Screening for ovarian cancer is under study and there are screening clinical trials taking place in many parts of the country. Information about ongoing clinical trials is available from the NCI Web site.”

I also found that:

Estimated new cases and deaths from ovarian cancer in the United States in 2013:

New cases: 22,240
Deaths: 14,030

To get an idea on the significance of these numbers, lets compare them to the numbers related to breast cancer:

Estimated new cases and deaths from breast cancer in the United States in 2013:

New cases: 232,340 (female); 2,240 (male)
Deaths: 39,620 (female); 410 (male)

Death rate of ovarian cancer patients is almost 4 times higher than the rate in breast cancer patients!

Therefore, I decided to raise awareness to the results achieved for ovarian HistoScanning in a double-blind multicenter European study that was published in European Radiology three years ago. The gynecologists who recruited patients to this study used standard ultrasound machines of GE-Medical. I would like as well to disclose that I am one of the authors of this paper:

A new computer-aided diagnostic tool for non-invasive characterisation of malignant ovarian masses: results of a multicentre validation study, Olivier Lucidarme et.al., European Radiology, August 2010, Volume 20, Issue 8, pp 1822-1830

Abstract

Objectives

To prospectively assess an innovative computer-aided diagnostic technology that quantifies characteristic features of backscattered ultrasound and theoretically allows transvaginal sonography (TVS) to discriminate benign from malignant adnexal masses.

Methods

Women (n = 264) scheduled for surgical removal of at least one ovary in five centres were included. Preoperative three-dimensional (3D)-TVS was performed and the voxel data were analysed by the new technology. The findings at 3D-TVS, serum CA125 levels and the TVS-based diagnosis were compared with histology. Cancer was deemed present when invasive or borderline cancerous processes were observed histologically.

Results

Among 375 removed ovaries, 141 cancers (83 adenocarcinomas, 24 borderline, 16 cases of carcinomatosis, nine of metastases and nine others) and 234 non-cancerous ovaries (107 normal, 127 benign tumours) were histologically diagnosed. The new computer-aided technology correctly identified 138/141 malignant lesions and 206/234 non-malignant tissues (98% sensitivity, 88% specificity). There were no false-negative results among the 47 FIGO stage I/II ovarian lesions. Standard TVS and CA125 had sensitivities/specificities of 94%/66% and 89%/75%, respectively. Combining standard TVS and the new technology in parallel significantly improved TVS specificity from 66% to 92% (p < 0.0001).

An example of an ovary considered to be normal with TVS.

The same TVS
false-negative ovary with OVHS-detected foci of malignancy. The presence of an
adenocarcinoma was confirmed histologically.

Conclusions

Computer-aided quantification of backscattered ultrasound is highly sensitive for the diagnosis of malignant ovarian masses.

Personal note:

Based on this study a promising offer for ultrasound-based screening method for ovarian cancer was published in: Int J Gynecol Cancer. 2011 Jan;21(1):35-43. doi: 10.1097/IGC.0b013e3182000528.: Mathematical models to discriminate between benign and malignant adnexal masses: potential diagnostic improvement using ovarian HistoScanning. Vaes E, Manchanda R, Nir R, Nir D, Bleiberg H, Autier P, Menon U, Robert A.

Regrettably, the results of these studies were never transformed into routine clinical products due to financial reasons.

Other research papers related to the management of Prostate cancer were published on this Scientific Web site:

Beta-Blockers help in better survival in ovarian cancer

Ovarian Cancer and fluorescence-guided surgery: A report

Role of Primary Cilia in Ovarian Cancer

Squeezing Ovarian Cancer Cells to Predict Metastatic Potential: Cell Stiffness as Possible Biomarker

BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

Warning signs may lead to better early detection of ovarian cancer

Read Full Post »

Association between Non-melanoma Skin Cancer and subsequent Primary Cancers in White Population

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, tagged Cancer - General, Conditions and Diseases, Harvard Medical School, Melanoma, PLoS Medicine, Skin neoplasm on April 24, 2013| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

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Word Cloud By Danielle Smolyar

Risk of a Second Primary Cancer after Non-melanoma Skin Cancer in White Men and Women: A Prospective Cohort Study

Fengju Song,
Abrar A. Qureshi,
Edward L. Giovannucci,
Charlie S. Fuchs,
Wendy Y. Chen,
Meir J. Stampfer,
Jiali Han mail

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Abstract

Background

Previous studies suggest a positive association between history of non-melanoma skin cancer (NMSC) and risk of subsequent cancer at other sites. The purpose of this study is to prospectively examine the risk of primary cancer according to personal history of NMSC.

Methods and Findings

In two large US cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS), we prospectively investigated this association in self-identified white men and women. In the HPFS, we followed 46,237 men from June 1986 to June 2008 (833,496 person-years). In the NHS, we followed 107,339 women from June 1984 to June 2008 (2,116,178 person-years). We documented 29,447 incident cancer cases other than NMSC. Cox proportional hazard models were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). A personal history of NMSC was significantly associated with a higher risk of other primary cancers excluding melanoma in men (RR = 1.11; 95% CI 1.05–1.18), and in women (RR = 1.20; 95% CI 1.15–1.25). Age-standardized absolute risk (AR) was 176 in men and 182 in women per 100,000 person-years. For individual cancer sites, after the Bonferroni correction for multiple comparisons (n = 28), in men, a personal history of NMSC was significantly associated with an increased risk of melanoma (RR = 1.99, AR = 116 per 100,000 person-years). In women, a personal history of NMSC was significantly associated with an increased risk of breast (RR = 1.19, AR = 87 per 100,000 person-years), lung (RR = 1.32, AR = 22 per 100,000 person-years), and melanoma (RR = 2.58, AR = 79 per 100,000 person-years).

Conclusion

This prospective study found a modestly increased risk of subsequent malignancies among individuals with a history of NMSC, specifically breast and lung cancer in women and melanoma in both men and women.

Please see later in the article for the Editors’ Summary

Editors’ Summary

Background

In the United Kingdom and the United States, about one in three people develop cancer during their lifetime and, worldwide, cancer is responsible for 13% of all deaths. Primary cancer, which can develop anywhere in the body, occurs when a cell begins to divide uncontrollably because of alterations (mutations) in its genes. Additional mutations allow the malignancy to spread around the body (metastasize) and form secondary cancers. The mutations that initiate cancer can be triggered by exposure to carcinogens such as cigarette smoke (lung cancer) or the ultraviolet (UV) radiation in sunlight (skin cancers). Other risk factors for the development of cancer include an unhealthy diet, physical inactivity, and alcohol use. In the United States, the most common cancer is non-melanoma skin cancer (NMSC). Although more than 2 million new cases of NMSC occur each year, fewer than 1,000 people die annually in the United States from the condition because the two types of NMSC—basal cell carcinoma and squamous cell carcinoma—rarely metastasize and can usually be treated by surgically removing the tumor.

Why Was This Study Done?

Some studies have suggested that people who have had NMSC have a higher risk of developing primary cancer at other sites than people who have not had NMSC. Such a situation could arise if exposure to certain carcinogens initiates both NMSC and other cancers or if NMSC shares a molecular mechanism with other cancers such as a deficiency in the DNA repair mechanisms that normally remove mutations. If people with a history of NMSC are at a greater risk of developing further cancers, a specific surveillance program for such people might help to catch subsequent cancers early when they can be successfully treated. In this prospective cohort study, the researchers examine the risk of primary cancer according to personal history of NMSC in two large US cohorts (groups)—the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS). The HPFS, which enrolled 51,529 male health professionals in 1986, and the NHS, which enrolled 121,700 female nurses in 1976, were both designed to investigate associations between nutritional factors and the incidence of serious illnesses. Study participants completed a baseline questionnaire about their lifestyle, diet and medical history. This information is updated biennially through follow-up questionnaires.

What Did the Researchers Do and Find?

The researchers identified 36,102 new cases of NMSC and 29,447 new cases of other primary cancers from 1984 in white NHS participants and from 1986 in white HPFS participants through 2008. They then used statistical models to investigate whether a personal history of NMSC was associated with a higher risk of subsequent primary cancers after accounting for other factors (confounders) that might affect cancer risk. A history of NMSC was significantly associated with an 11% higher risk of other primary cancers excluding melanoma (another type of skin cancer that, like NMSC, is linked to overexposure to UV light) in men and a 20% higher risk of other primary cancers excluding melanoma in women; a significant association is one that is unlikely to have happened by chance. The absolute risk of a primary cancer among men and women with a history of NMSC was 176 and 182 per 100,000 person-years, respectively. For individual cancer sites, after correction for multiple comparisons (when several conditions are compared in groups of people, statistically significant differences between the groups can occur by chance), a history of NMSC was significantly associated with an increased risk of breast and lung cancer in women and of melanoma in men and women.

What Do These Findings Mean?

These findings suggest that there is a modestly increased risk of subsequent malignancies among white individuals with a history of NMSC. Although the researchers adjusted for many confounding lifestyle factors, the observed association between NMSC and subsequent primary cancers may nevertheless be the result of residual confounding, so it is still difficult to be sure that there is a real biological association (due to, for example, a deficiency in DNA repair) between NMSC and subsequent primary cancers. Because of this and other study limitations, the findings reported here should be interpreted cautiously and do not suggest that individuals who have had NMSC should undergo increased cancer surveillance. These findings do, however, support the need for continued investigation of the apparent relationship between NMSC and subsequent cancers.

Additional Information

Please access these Web sites via the online version of this summary athttp://dx.doi.org/10.1371/journal.pmed.1001433.

The US National Cancer Institute provides information on all aspects of cancer and has detailed information about non-melanoma skin cancer for patients and professionals (in English and Spanish)
The non-profit organization American Cancer Society provides information on cancer and how it develops and specific information on skin cancer (in several languages); its website includes personal stories about cancer
The UK National Health Service Choices website includes an introduction to cancer and a page on non-melanoma skin cancer
The non-profit organization Cancer Research UK provides basic information about cancer and detailed information on non-melanoma skin cancer

Citation: Song F, Qureshi AA, Giovannucci EL, Fuchs CS, Chen WY, et al. (2013) Risk of a Second Primary Cancer after Non-melanoma Skin Cancer in White Men and Women: A Prospective Cohort Study. PLoS Med 10(4): e1001433. doi:10.1371/journal.pmed.1001433

Academic Editor: Eduardo L. Franco, McGill University, Canada

Received: September 11, 2012; Accepted: March 15, 2013; Published: April 23, 2013

Copyright: © 2013 Song et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by US NIH CA87969 and CA055075. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: AQ declares the following: Pfizer – Questionnaire licensed for clinical trials; research grant. Merck – Questionnaire licensed for clinical trials. Amgen – Research grant. Abbott – Consulting. US Centers for Disease Control – Consulting. Janssen – Consulting. Novartis – Consulting. All other authors have declared that no competing interests exist.

Abbreviations: AR, absolute risk; BCC, basal cell carcinoma; BMI, body mass index; HPFS, Health Professionals Follow-up Study; MV, multivariate; NER, nucleotide excision repair; NHS, Nurses’ Health Study; NMSC, non-melanoma skin cancer; RR, relative risk; SCC, squamous cell carcinoma; UV, ultraviolet

Introduction

Non-melanoma skin cancer (NMSC) is the most common cancer in the United States. It consists mainly of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Its incidence has been rapidly increasing over the past several decades and the incidence rate was about 6,000/100,000 in the year 2006 [1]. NMSC has a low mortality rate of 1/100,000 [2], but its high prevalence and the expense of related treatment make NMSC a major public health problem and place it among the costliest cancers in the United States [3]. Individuals with personal history of NMSC may be at an altered risk for developing other primary cancers[4]–[11]. One view is that sunlight causes NMSC but also produces vitamin D, which in turn may reduce the risk of other cancers [12]. Another view is that NMSC and other cancers may share common carcinogenic exposures or molecular mechanisms in their etiology, such as DNA repair deficiency and immune suppression, and thus the history of NMSC may indicate an increased risk of subsequent cancer development.

Previous studies suggest a positive association between personal history of NMSC and risk of subsequent cancer at other sites [4]–[11]. Most previous reports, however, were based on cancer registry data without adjustment for potential confounding lifestyle factors [4]–[10]. The only cohort study was limited by its sample size and lacked adequate power to assess individual cancer sites [11]. We carried out a cohort analysis to evaluate the association between personal history of NMSC and subsequent malignancy in the Nurses’ Health Study (NHS) and the Health Professionals’ Follow-up Study (HPFS).

Methods

Ethics Statement

Our study was approved by the Human Research Committee at the Brigham and Women’s Hospital with written informed consent from all participants.

Study Population

The NHS was established in 1976, when 121,700 registered nurses aged 30–55 y in 11 US states responded to a baseline questionnaire regarding risk factors for cancer. Participants completed self-administered, mailed follow-up questionnaires biennially with updated information on their lifestyle, diet, and medical history. The HPFS began in 1986 when 51,529 US male health professionals, including dentists, veterinarians, pharmacists, and optometrists aged 40–75 y, completed a baseline questionnaire on lifestyle, diet, and newly diagnosed diseases. The information was updated biennially with follow-up questionnaires. The follow-up rates of the participants in both cohorts exceed 90%. These studies were approved by the Human Research Committee at Brigham and Women’s Hospital. Race was self-identified in this study as White, Asian, African American, and others. Only white participants were included in this study, accounting for 95.6% of the total population in the two cohorts. The rationale for focusing the primary hypothesis on white participants only was that the patterns of incidence (and likely the risk factors) for NMSC differ widely by race.

Identification of NMSC and Other Primary Cancers

We have routinely identified cases of NMSC and other primary cancers in both cohorts (from 1984 in the NHS and from 1986 in the HPFS). Participants reported new diagnoses biennially. With their permission, participants’ medical records were obtained and reviewed by physicians to confirm their self-reported diagnosis. Medical records were not obtained for self-reported cases of BCC, because the validity of BCC self-reports was more than 90% in validation studies in our cohorts in early years [13],[14]. The personal history of pathologically confirmed invasive SCC and self-reported BCC was the exposure in this analysis. The study outcome was the occurrence of the first confirmed primary cancer other than NMSC. All other cancer cases were documented by medical records or death certificates, and only confirmed cases were included in the analysis.

Assessment of Covariates

Covariates in this analysis included age (continuous variable), body mass index (BMI) (<21, 21–23, 23–25, 25–27, 27–29, 29–31, >31), physical activity (quintiles), smoking status (never, past 1–14 cigarettes per day, past 15+ cigarettes per day, current 1–14 cigarettes per day, current 15+ cigarettes per day), multi-vitamin use (yes or no), menopause status and hormone replacement therapy use in women (pre-menopause, post-menopause non-user, post-menopause past user, and post-menopause current user), and physical examination in the last 2 y (yes or no). We asked about the location of residence (US states) at birth and at age of 15 and 30. The 50 states (and the District of Columbia) were divided into three ultraviolet (UV) index groups: 5 or less (low UV index); 6 (medium UV index); and 7 or more (high UV index)[15]. We defined participants in these three groups if they resided in the same UV-index region at birth, age of 15 and 30.

Statistical Analysis

Follow-up began in 1984 for the NHS and 1986 for the HPFS when the diagnosis of NMSC was first routinely collected, and follow-up ended in 2008 for both cohorts. Participants who reported a history of cancer (including NMSC) prior to baseline were excluded. Participants contributed person-time from the date of return of the baseline questionnaire (1984 in NHS and 1986 in HPFS) until date of diagnosis of confirmed primary cancer, date of death, or the end of follow-up (May 31, 2008), whichever came first. For those who were lost to follow-up, we censored them at the return date of the last questionnaire. Cox regression analysis with time-dependent covariates was used to determine the relative risks (RRs) and 95% CIs of second primary malignancies associated with a previous NMSC diagnosis. We calculated age-standardized absolute risks (ARs) of second primary malignancies associated with a previous NMSC diagnosis. NMSC diagnosis could change during the follow-up period. For individuals with no personal history of cancer at baseline who went on to be diagnosed with NMSC as a first cancer diagnosis during follow-up, the follow-up period before the NMSC diagnosis contributed person-time to the non-exposure group, and the follow-up period after the NMSC diagnosis contributed person-time to the exposure group. Age was coded as a continuous variable in all the analyses. We showed overall cancer risk with and without melanoma. We performed several secondary analyses. We excluded those diagnosed with other primary cancers within the first 4 y of NMSC diagnosis to minimize the detection bias. We examined BCC and SCC history separately. We performed stratified analysis according to age (≤60 y, >60 y), UV-index of residence at birth, age 15, and age 30 (≤5, = 6, ≥7), smoking status (never smoker, past smoker, current smoker), and BMI (<25, 25–30, ≥30). We coded these factors as dummy variables and tested their interactions with the history of NMSC individually. We tested multiplicative interaction terms by the likelihood ratio test comparing the model with the cross-product terms with the model containing just the main effects of these factors and the history of NMSC along with the same covariates.

We assessed the association between NMSC diagnosis and risk of developing site-specific cancers that were diagnosed in more than 100 patients in each cohort. For individual cancer sites, the Cox models additionally included risk factors specific for some cancer sites. We included additional covariates in the multivariate models for breast, ovarian, endometrial, prostate cancers, and melanoma. The Bonferroni correction for p-value was applied for multiple comparisons for individual cancer sites among men and women, calculated as 0.05/n (n = 28). Statistical analyses were conducted using SAS software (version 9, SAS Institute). All statistical tests were two-sided.

Results

Characteristics of our study population according to a personal history of NMSC in mid-point of the follow-up (1998) are shown in Table 1. Participants with a history of NMSC were more likely to be older and tended to burn and have more severe sunburns. Participants with history of NMSC diagnosis were more likely to have red or blonde hair and to reside in high UV-index states. Other characteristics were similar between the exposure group and the non-exposure group.

Table 1. Characteristics according to personal history of non-melanoma skin cancer in 1998.

doi:10.1371/journal.pmed.1001433.t001

We followed the HPFS participants from 1986 to 2008, for a total of 833,496 person-years. During this period, 1,577 cases of SCC, 10,422 cases of BCC, and 10,590 primary cancer cases other than NMSC were recorded. The mean time for the development of a primary cancer after NMSC was 116±47 mo. We followed the NHS from 1984 to 2008 (2,116,178 person-years) during which 2,322 cases of SCC, 21,781 cases of BCC, and 18,857 primary cancer cases other than NMSC were recorded. The mean time for the development of a primary cancer after NMSC was 156±71 mo.

A personal history of NMSC was associated with a higher risk of other primary cancers in men (RR = 1.15; 95% CI 1.09–1.22, p<0.0001) and women (RR = 1.26; 95% CI 1.21–1.31,p<0.0001) (Table 2). The association attenuated slightly when melanoma was excluded from the outcome in the analysis, but remained significant in men (RR = 1.11; 95% CI 1.05–1.18, p= 0.0007) and in women (RR = 1.20; 95% CI 1.15–1.25, p<0.0001). Age-standardized AR was 176 in men and 182 in women per 100,000 person-years. The association remained significant after we excluded those diagnosed with other primary cancers within the first 4 y of NMSC diagnosis in men (RR = 1.15; 95% CI 1.05–1.25) and women (RR = 1.19; 95% CI 1.11–1.28). In men, the association was significant according to BCC diagnosis (RR = 1.17; 95% CI 1.10–1.24) but not SCC diagnosis (RR = 1.01; 95% CI 0.87–1.17). In women, the association was significant for both BCC (RR = 1.25; 95% CI 1.20–1.30) and SCC diagnosis (RR = 1.24; 95% CI 1.10–1.39). We compared people with personal history of SCC with people with personal history of BCC on their risk of developing subsequent cancer, and no significant differences were found (Table S1). In addition, we have compared SCC in situ group with invasive SCC group and the group of SCC or BCC; the results are shown in Table S2. Compared to those with history of invasive SCC or those with history of SCC or BCC, individuals with history of SCC in situ were less likely to develop subsequent cancers. Such risk reduction was significant among women.

Table 2. Overall and stratified analysis of risks of total subsequent primary cancers according to personal history of non-melanoma skin cancer in men and women.

doi:10.1371/journal.pmed.1001433.t002

No substantial differences were found in the stratified analysis according to age, UV-index, or BMI. When stratified by smoking status, significant associations were found in never-smokers (RR = 1.19; 95% CI 1.08–1.31 in men, and RR = 1.28; 95% CI 1.20–1.38 in women) and past smokers (RR = 1.12; 95% CI 1.03–1.22 in men, and RR = 1.27; 95% CI 1.20–1.35 in women), but not in current smokers (RR = 1.05; 95% CI 0.75–1.46 in men, and RR = 1.10; 95% CI 0.97–1.23 in women). The p-value for interaction was 0.046 for men and women combined.

For individual cancer sites (Table 3), a history of NMSC was associated with an increased risk of prostate cancer in men (RR = 1.11; 95% CI 1.02–1.20, p = 0.01). The age-standardized AR was 137 per 100,000 person-years. The RR was similar for fatal prostate cancer (RR = 1.17; 95% CI 0.89–1.53). A history of NMSC was also associated with an increased risk of melanoma in men (RR = 1.99; 95% CI 1.63–2.43, p<0.0001). The age-standardized AR was 116 per 100,000 person-years. In women, a history of NMSC was associated with an increased risk of breast cancer (RR = 1.19; 95% CI 1.11–1.28, p<0.0001; AR = 87 per 100,000 person-years), lung cancer (RR = 1.32; 95% CI 1.14–1.52, p = 0.0002; AR = 22 per 100,000 person-years), leukemia (RR = 1.30; 95% CI 1.00–1.69, p = 0.05; AR = 7 per 100,000 person-years), kidney cancer (RR = 1.48; 95% CI 1.10–1.99, p = 0.01; AR = 8 per 100,000 person-years), and melanoma (RR = 2.58; 95% CI 2.34 –2.98, p<0.0001; AR = 79 per 100,000 person-years). After taking into account the multiple comparisons for individual cancers (n = 28), the associations with breast cancer, lung cancer in women, and melanoma in both men and women remained significant. We analyzed SCC and BCC history separately for individual cancer sites. We observed different rates for second cancer development according to personal history of SCC and BCC. However, no statistically significant heterogeneity (p for heterogeneity ranged from 0.16 to 0.88) was found for any cancer site between BCC and SCC due to the limited power (Table S3).

Table 3. Risks of subsequent primary cancers at different sites according to personal history of non-melanoma skin cancer in men and women.

doi:10.1371/journal.pmed.1001433.t003

Discussion

To the best of our knowledge, this is the largest prospective study on this topic. In this study, a total of 36,102 cases of NMSC and 29,447 cases of cancers other than NMSC were documented. Among those with a personal history of NMSC, we found a 15% increased risk in men and a 26% increased risk in women of developing a second primary cancer, compared with those who had no such history. A systematic review summarizing previous studies revealed that NMSC is associated with more than 10% increased risk of subsequent primary cancer in registry-based studies and nearly 50% increased risk in cohort studies [16]. Our study has extended previous findings by adding a prospective analysis in two large US cohorts with more than two decades of follow-up. The unique aspects of our study included stratified analyses by other risk factors, disentanglement of surveillance bias, and comprehensive adjustment for potential confounders.

It was speculated that the association between NMSC and subsequent cancer risk may be different among people living in locations with different UV-indexes. Specifically, southern regions have solar UV-B radiation levels that provide sufficient vitamin D to reduce the risk of cancer incidence, and thus inverse associations were more likely to be found. On the contrary, studies that found positive associations were mostly conducted in northern regions where UV-B radiation levels do not provide sufficient vitamin D [17],[18]. In our analysis stratified by UV-index, no substantial differences were found for the associations between NMSC and cancer risk among locations with different UV-indexes. To the extent that some cancers have been suggested to be reduced with higher vitamin D [19], it might be worth noting the fact that while colorectal cancer was not increased in this study, it was not decreased as would be expected if NMSC were a marker for sunlight and thus vitamin D exposure.

Intensified medical surveillance of persons with a history of NMSC is unlikely to explain the increased cancer incidence observed in our study. In our analysis, we adjusted for physical examination in the last 2 y, and the result changed little. After we excluded those diagnosed with other primary cancers within the first 4 y of NMSC diagnosis, the association remained significant. Compared to those with history of invasive SCC or with history of SCC or BCC, individuals with history of SCC in situ were less likely to develop subsequent cancers. These results suggested that the patients who carried NMSC precursors but did not develop skin cancers might be either less genetically susceptible or have lower exposure. In addition, for prostate cancer, the association remained significant for fatal prostate cancer. Furthermore, several cancers that we observed associations with are not ones that would be detected on routine screening. Moreover, at least one study that assessed deaths rather than cancer incidence also found increased cancer mortality in people with history of NMSC [20].

Several studies have observed an increased risk of NMSC after other cancers. In one study, chronic lymphocytic leukemia patients had an increased risk of death due to NMSC (RR = 17.0, 95% CI 14.4–19.8) [21]. In another study, among 14 different sites for first primary malignancies, 11 of these sites including prostate, breast, and leukemia were followed by an increased risk of skin cancer (for SCC, RR of 14.1 for males and 14.6 for females) [22]. However, while treatment of these primary cancers may predispose to subsequent skin cancers, most of the NMSC cases are cured by surgical excision without any systemic chemotherapy, and radiation, and their concomitant side effects, including possible carcinogenicity. In addition, the similarity between the age-adjusted and multivariate-adjusted RRs demonstrated that the observed association between NMSC and subsequent cancers is unlikely to be explained by confounding from smoking, obesity, vitamin use, exercise, or any of the other measured risk factors that we controlled for.

The link between NMSC and risk of other cancers is likely to represent an etiologic association. For melanoma especially, the link may be due to sun exposure. For other cancers, while there are several explanations [23]–[28] of the association between NMSC and the risk of subsequent cancer, studies have found that certain genetic markers underlying skin cancer are also associated with other cancer types [29]. It is biologically plausible that deficiencies of pathways responsible for protecting against cellular transformation in multiple tissues, such as DNA repair or immune responses, may act systemically and play a role in cutaneous and internal carcinogenesis.

Humans have evolved several DNA repair pathways dealing with damage [30]. The nucleotide excision repair (NER) pathway is responsible for the repair of a wide variety of DNA damage that leads to distortion of the DNA helix. Such bulky DNA adducts include UV-induced photoproducts, smoking-related benzo(a)pyrene diolepoxide (BPDE)-DNA adducts, and other DNA damage induced by chemical carcinogens. Reduced capacity of the NER has been shown to confer susceptibility to certain cancers in the general population, including melanoma, BCC, SCC, SCC of head and neck, lung cancer, breast cancer, and bladder cancer[31]–[34]. Personal history of NMSC may be a marker of susceptibility due to reduced DNA repair capacity and it may predict the risk of subsequent cancer development.

The NER activity has been shown to be tissue-specific. For example, relatively low NER efficiency was observed in oral tissues [35]. Both rapidly proliferating tissues (e.g., kidney) and slowly proliferating tissues (e.g., lung) exhibit higher demand for NER capacity upon stimulation to proliferation [36]. The DNA repair system consists of several distinct pathways with many subcomponents, each interacting and overlapping with one another in order to achieve genomic stability and high fidelity. Some tissues, such as breast, lack redundant systems of DNA repair that are present in other tissues [37],[38]. Defects in DNA repair would be expected to have greater impact in such tissues without extensive DNA repair redundancy. In addition, a number of studies have suggested a role of sex hormone (e.g., estrogen and androgen) in the regulation of DNA repair activity in breast and prostate cancers [39]. After correction for multiple comparisons for individual types of cancers, the significant association remained for breast cancer, lung cancer in women, and melanoma in both men and women. Even though the positive associations are biologically plausible, we cannot rule out the possibility of chance findings for each individual cancer site.

In our analysis stratified by smoking status, significant association was found among never and past smokers. Because the NER enzymes recognize bulky DNA adducts including both UV-induced photoproducts and smoking-related BPDE-DNA adducts, the interaction between smoking status and history of NMSC highlights the potential role of the NER pathway in the development of second cancers. However, the effect of inherited insufficient capacity of the NER indicated by history of NMSC is only apparent among non-current smokers and for lung cancer in women. Further mechanistic investigation is warranted.

Sub-optimal immune surveillance could be another common susceptibility factor for both cutaneous and internal cancers. Malignant progression is accompanied by profound immune suppression that interferes with an effective antitumor response and tumor elimination [40]. Impaired immunity has been implicated as a non-site-specific determinant of cancer risk [41]. In addition, UV radiation can also cause immunosuppression. UV exposure adversely affects the skin immune system by diminishing antigen-presenting cell function, inducing immunosuppressive cytokine production, and modulating contact and delayed-type hypersensitivity reactions [42],[43], all of which can reduce the body’s surveillance for tumor cells [44],[45]. UV suppresses immune reactions locally, but can also affect the immune system in a systemic fashion when higher UV doses are given [46],[47]. UV radiation affects immune surveillance by modulating the balance between an effective immune response and immune tolerance of an emerging cancer [41]. We did not observe an association between UV-index and the risk of cancer except for skin cancer in our study, which makes this explanation less likely for our findings.

The identification of BCC cases in this study was based on self-report without pathological confirmation. However, the participants in the two cohorts were nurses and health professionals. The validity of their reports was expected to be high, and it has been proven in our validation studies [13],[14]. In addition, previous studies of BCC in the NHS using the self-reported cases identified both constitutional and sun exposure risk factors as expected, such as lighter pigmentation, less childhood and adolescent tanning tendency, higher tendency to sunburn, and tanning salon attendance [48],[49]. We recently confirmed the MC1R gene as the top BCC risk locus using the NHS and HPFS samples [50]. These data together suggest that the bias due to self-report of BCC is likely to be minimal in our study. Moreover, the potential under-report of BCC diagnosis would be expected to bias observed associations toward the null, and such bias would not explain the positive associations that we found.

The strengths of our study included the prospective cohort design and updated assessment of cancer diagnosis and other risk factors every 2 y, more than two decades of follow-up, and a large number of incident skin cancer cases. We had detailed data on related covariates for stratified analyses and comprehensive adjustment for potential confounders. All the participants were health professionals, minimizing potential confounding by educational attainment or differential access to health care. Nevertheless, we cannot completely exclude residual confounding, and our findings may not assign causality. Although the observed significant associations in breast cancer, lung cancer in women, and melanoma in both men and women remained significant after correction for multiple comparisons, we cannot absolutely rule out chance findings for individual cancer sites, and the underlying mechanism for the associations found in specific cancer sites is not entirely clear. In addition, the significant associations for some individual cancers did not meet the adjusted p-value threshold because of their limited sample size.

We cannot estimate the recurrence rate of NMSC or subsequent cancer risk among people with multiple NMSC because we only recorded the first report of each type of skin cancer in both cohorts. We do not have data for non-whites in this study, and our results cannot be generalized to non-whites owing to the dramatic difference in skin cancer incidence among different races. In summary, we observed a modestly increased risk of other cancers among individuals with a history of NMSC. Because our study was observational, these results should be interpreted cautiously and are insufficient evidence to alter current clinical recommendations. Nevertheless, these data support a need for continued investigation of the potential mechanisms underlying this relationship.

SOURCE:

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001433;jsessionid=55BB9D9B87F79FF1CA7594C56F407F14

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Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease

Posted in Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, tagged Cancer - General, Cancer research, Conditions and Diseases, Exome sequencing, gene sequencing, Ipilimumab, Melanoma, Personalized medicine, skin cancer, treatment, Vemurafenib on April 23, 2013| 3 Comments »

Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease

Author: Ziv Raviv, PhD

Article-7.2.2. Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease

Introduction

Cutaneous melanoma is a type of skin cancer that originates in melanocytes, the cells that are producing melanin. While being the least common type of skin cancer, melanoma is the most aggressive one with invasive characteristics and accounts for the majority of death incidences among skin cancers. Melanoma has an annual rate of 160,000 new cases and 48,000 deaths worldwide. Melanoma affects mainly Caucasians exposed to sun high UV irradiation. Among the genetic factors that characterize the disease, BRAF mutation (V600E) is found in most cases of melanoma (80%). Awareness toward risk factors of melanoma should lead to prevention and early detection*. There are several developmental stages (I-IV) of the disease, starting from local non-invasive melanoma, through invasive and high risk melanoma, up to metastatic melanoma. As with other cancers, the earlier stage melanoma is being detected, the better odds for full recovery are. Treatment is usually involving surgery to remove the local tumor and its margins, and when necessary also to remove the proximal lymph node(s) that drain the tumor. In high stages melanoma, adjuvant therapy is given in the form of chemotherapy (Dacarbazine and Temozolomide) and immunotherapy (IL-2 and IFN). Until recently no useful treatment was available for metastatic melanoma. However, research efforts had led to the development of two new drugs against metastatic melanoma: Vemurafenib (Zelboraf), a B-Raf inhibitor; and Ipilimumab (Yervoy), a monoclonal antibody that blocks the inhibitory signal of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Both drugs are now available for clinical use presenting good results.

Personalized therapy for melanoma

In an attempt to develop personalized therapies for malignant melanoma, a unique strategy has been taken by the group of Prof. Yardena Samuels at the NIH (now situated at the WIS) to identify recurring genetic alterations of metastatic cutaneous melanoma. The researchers approach employed the collections of hundreds of tumors samples taken from metastasized melanoma patients together with matched normal blood tissues samples. The samples are undergoing exome sequencing for the analysis of somatic mutations (namely mutations that evolved during the progress of the disease to the stage of metastatic melanoma, unlike genomic mutations that may have contribute to the formation of the disease). The discrimination of such tumor related somatic mutations is done by comparison to the exome sequencing of the patient’s matched blood cells DNA. In addition, the malignant cells derived from the removed cancer tissue of each patient are extracted to form a cell line and are grown in culture. These cells are easily cultivate in culture with no special media supplements, nor further genetic manipulations such as hTERT are needed, and are extremely aggressive as determined by various cell culture and in vivo tests. The ability to grow these primary tumor-derived cell lines in culture has a great value as a tool for studying and characterizing the biochemical, functional, and clinical aspects of the mutated genes identified.

In one study [1] Samuels and her colleagues performed this sequencing process for mutation analysis for the protein tyrosine kinase (PTK) gene family, as PTKs are frequently mutated in cancer. Using high-throughput gene sequencing to analyze the entire PTK gene family, the researchers have identified 30 somatic mutations affecting the kinase domains of 19 PTKs and subsequently evaluated the entire coding regions of the genes encoding these 19 PTKs for somatic mutations in 79 melanoma samples. The most frequent mutations were found in ERBB4, a member of the EGFR/ErbB family of receptor tyrosine kinase (RTK), were 19% of melanoma patients had such mutations. Seven missense mutations in the ERBB4 gene were found to induce increased kinase activity and transformation capability. Melanoma derived cell lines that were expressing these mutant ERBB4 forms had reduced cell growth after silencing ERBB4 by RNAi or after treatment with the ERBB inhibitor Lapatinib. Lapatinib is already in use in the clinic for the treatment of HER2 (ErbB2) positive breast cancers patients. Following this study, a clinical trial is now conducted with this drug to evaluate its effect in cutaneous metastatic melanoma patients harboring mutations in ERBB4.

In another study of this group [2], the scientists employed the exome sequencing method to analyze the somatic mutations of 734 G protein coupled receptors (GPCRs) in melanoma. GPCRs are regulating various signaling pathways including those that affect cell growth and play also important role in human diseases. This screen revealed that GRM3 gene that encode the metabotropic glutamate receptor 3 (mGluR3), was frequently mutated and that one of its mutations clustered within one position. Mutant GRM3 was found to selectively regulate the phosphorylation of MEK1 leading to increased anchorage-independent cell growth and cellular migration. Tumor derived melanoma cells expressing mutant GRM3 exhibited reduced cell growth and migration upon knockdown of GRM3 by RNAi or by treatment with the selective MEK inhibitor, Selumetinib (AZD-6244), a drug that is being testing in clinical trials. Altogether, the results of this study point to the increased violent characteristics of melanomas bearing mutational GRM3.

In a third study, melanoma samples were examined for somatic mutations in 19 human genes that encode ADAMTS proteins [3]. Some of the ADAMTS genes have been suggested before to have implication in tumorigenesis. ADAMTS18, which was previously found to be a candidate cancer gene, was found in this study to be highly mutated in melanoma. ADAMTS18 mutations were biologically examined and were found to induce an increased proliferation of melanoma cells, as well as increased cell migration and metastasis. Moreover, melanoma cells expressing these mutated ADAMTS18 had reduced cell migration after RNAi-mediated knockdown of ADAMTS18. Thus, these results suggest that genetic alteration of ADAMTS18 plays a major role in melanoma tumorigenesis. Since ADAMTS genes encode extracellular proteins, their accessibility to systematically delivered drugs makes them excellent therapeutic targets.

Conclusive remarks

The above illustrated research approach intends to discover frequent melanoma-specific mutations by employing high-throughput whole exome and genome sequencing means. For the most highly mutated genes identified, the biochemical, functional, and clinical aspects are being characterized to examine their relevancy to the disease outcomes. This approach therefore introduces new opportunities for clinical intervention for the treatment of cutaneous melanoma. In addition to the discovery of novel highly mutated genes, this approach may also help determine which pathways are altered in melanoma and how these genes and pathways interact. Finding melanoma-associated highly mutated genes could lead to personalized therapeutics specifically targeting these altered genes in individual melanomas. Along with the opportunity to develop new agents to treat melanoma, the approach takes advantage of existing anti-cancer drugs, utilizing them to treat these mutated genes melanoma individuals. In addition to their potential for therapeutics, the discovery of highly mutated genes in melanoma patients may lead to the discovery of new markers that may assist the diagnosis of the disease. The implications of these screenings findings on other types of cancer bearing common pathways similar to melanoma should be examined as well. Finally, this elegant approach should be adopted in research efforts of other cancer types.

* Special review will be published further in the cancer prevention section of Pharmaceutical Intelligence

References

1. Prickett TD, Agrawal NS, Wei X, Yates KE, Lin JC, Wunderlich JR, Cronin JC, Cruz P, Rosenberg SA, Samuels Y (2009) Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet 41 (10):1127-1132

2. Prickett TD, Wei X, Cardenas-Navia I, Teer JK, Lin JC, Walia V, Gartner J, Jiang J, Cherukuri PF, Molinolo A, Davies MA, Gershenwald JE, Stemke-Hale K, Rosenberg SA, Margulies EH, Samuels Y (2011) Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma. Nat Genet 43 (11):1119-1126

3. Wei X, Prickett TD, Viloria CG, Molinolo A, Lin JC, Cardenas-Navia I, Cruz P, Rosenberg SA, Davies MA, Gershenwald JE, Lopez-Otin C, Samuels Y (2010) Mutational and functional analysis reveals ADAMTS18 metalloproteinase as a novel driver in melanoma. Mol Cancer Res 8 (11):1513-1525

Related articles on melanoma on this open access online scientific journal:

1. In focus: Melanoma Genetics. Curator: Ritu Saxena, Ph.D.

2. In focus: Melanoma therapeutics. Author and Curator: Ritu Saxena, Ph.D.

3. A New Therapy for Melanoma. Reporter- Larry H Bernstein, M.D.

4. Thymosin alpha1 and melanoma. Author, Editor: Tilda Barliya, Ph.D.

5. Exome sequencing of serous endometrial tumors shows recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Reporter and Curator: Dr. Sudipta Saha, Ph.D.

6. How Genome Sequencing is Revolutionizing Clinical Diagnostics. Reporter: Aviva Lev-Ari, PhD, RN.

7. Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. Curator and Reporter: Stephen J. Williams, Ph.D.

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Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer

Posted in Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, Infectious Disease & New Antibiotic Targets, Interviews with Scientific Leaders, Molecular Genetics & Pharmaceutical, Scientist: Career considerations, Systemic Inflammatory Response Related Disorders, tagged AIDS, autobiography, Aviva Lev-Ari, Biology, Cancer - General, Cell Biology, Conditions and Diseases, DNA, DNA virus, history of science, HIV, National Institutes of Health, NCI, retroviral, retrovirus, RNA, RNA virus, sarcoma, Science and Medicine, Scientific method on April 17, 2013| 3 Comments »

Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer

Curator and Reporter: Stephen J. Williams, PhD

This image has an empty alt attribute; its file name is ArticleID-42.png

WordCloud Image Produced by Adam Tubman

This is the second posting in this series in which I highlight the basic research which led to seminal breakthroughs in the medical field, brought on by the result of basic inquiry, thorough and detailed investigation, meticulously following the scientific method, and eventually leading to development of important medical therapies.

In his autobiography, Virus Hunting: AIDS, Cancer & the Human Retrovirus: A Story of Scientific Discovery, Dr. Robert Gallo, M.D. describes a wonderful story of the history behind, scientific biographies, and chronology of the discoveries which led he and his colleagues (including co-discoverer Dr. Luke Montagnier) to recognize retroviruses (in particular HIV) as the leading culprit for the cause of AIDS and in the etiology of Kaposi’s sarcoma. For anyone who appreciates the history behind scientific discoveries and appreciates learning about the multitude of individual efforts which are the crux of seminal research, this book is a must read.

Recommendations from the back cover include:

“Virus Hunting will be read and reread, for years to come.” —New York Newsday

“Provides a human, revealing look into the arcane, usually secret confines of laboratory science.”

— Martin Delany, Project Inform

..as well as others.

While a fascinating aspect of this book is the description, like fitting pieces of a puzzle, of the important discoveries throughout history which are the necessary foundations for further investigations and discoveries, more important is a telling, personal narrative of the people involved in those initial and subsequent discoveries. In fact, the book has over 396 colleagues, mentors, technicians, students, and even critiques who are given credit, in one form or another, for the ultimate discovery of HIV as a causative agent for the development of AIDS. The book is a literal Who’s Who in Science and shows how important personal collaboration and friendships are in the process of scientific discovery.

In 1972, Dr. Seymour Perry had appointed the young Dr. Robert Gallo as head of a new department, the Human Tumor Cell Biology Branch, renamed the Laboratory of Tumor Cell Biology. The lab was carrying on the work on tRNA that Dr. Gallo had performed in Dr. Sid Perska’s group at NIH. However, with the help of new lab members Dr. David Gillespie, Dr. Flossie Wong-Staal, and Dr. Marjorie Robert-Guroff the lab focused on the search for disease-causing retroviruses, especially in human leukemias. This was, in part, due to conversations with Dr. Robert Huebner and Todaro, who insisted that

“within the genetic makeup of this endogenous retroviral material was, they suggested, a special gene, the oncogene, that was the parent of the cancer-causing protein”

which may explain some of the early work by Rous concerning the Rous sarcoma virus.

Enter in Gallo’s good friend Dr. Bob Ting. Dr. Gallo had known Dr. Ting socially since 1966, shortly after Gallo had arrived at NIH. Dr. Bob Ting was a well-established NCI investigator, who was doing work on DNA and RNA oncogenic viruses of animals. Originally from a large and wealthy family in Hong Kong, Dr. Ting had worked with Nobel Prize winners Salvatore Luria (who worked on phages) and Renato Dulbecco, who, along with his well-known cell culture media, had made the seminal discoveries that led to our knowledge how some DNA viruses can transform normal animal cells into neoplastic-like cells in culture.

Bob Ting gave a talk on these oncogenic viruses and Gallo was very interested in his observations that oncogenic viruses like Rous and Maloney, could transform cells in vitro in a matter of days.

A friendship developed between the two over tennis matches and Chinese food. During this time, Dr. Ting made the important suggestion that they both collaborate and use the viral systems developed by Dulbecco. Ting also introduced him to RNA viruses, Dr. Robert Huebner, and Dr. Howard Temin. It was, in part, due to these associations that Gallo started looking, in earnest, at the possibility of RNA retroviruses in leukemias. Thus, just like the internet today, connections and networking provided new insights into current research, and helped lead the advent of new discoveries, therapies, and scientific disciplines.

Therefore, “after some late-night discussion with Bob Ting, I decided to enter the fray. My own laboratory, … would immediately be set up to compare the properties of reverse transcriptase enzymes from many different animal retroviruses”.

Although the rest is more history, this early friendship, collaboration, and mentoring by Bob Ting had “transformed” Gallo’s research efforts to set him up to make some of the important discoveries eventually leading to the discovery of the role of HIV in AIDS.

A video interviewing Dr. Gallo can be found here:

VIEW VIDEO

https://www.youtube.com/watch?v=ELRlXLGWu4I

A very nice writeup/obituary for Dr. Ting was written by Patricia Sullivan of the Washington Post and is included below.

Robert Ting, 77; Biotech Pioneer

Dr. Robert Ting’s biotech company in Rockville developed the first FDA-approved diagnostic test kits to test for HIV antibodies. (By Gerald Martineau — The Washington Post)

By Patricia Sullivan

Washington Post Staff Writer
Friday, September 22, 2006

Robert C.Y. Ting, 77, a research scientist who started one of the early biotechnology companies in the Washington area, died Sept. 11 of complications after cardiac surgery at the Cleveland Clinic in Cleveland.

Dr. Ting founded Biotech Research Laboratories Inc. in Rockville in 1973, producing cells for government scientists to use in research. Eleven years later, his firm obtained a federal license to develop and produce the first FDA-approved diagnostic test kits for HIV antibody confirmation.

Robert C. Gallo, who co-discovered the HIV virus as the cause of AIDS, called Dr. Ting a pioneer in the field who popularized the term “biotechnology” when he moved from research to entrepreneurship.

“He introduced me to virology, and he did it twice,” said Gallo, director of the Institute of Human Virology in Baltimore. The men had known each other since the 1960s, and while playing tennis one day, Dr. Ting advised the cancer researcher to look at new research in viruses. Later, when Gallo was studying leukemia, Dr. Ting directed him to animal research in leukemia. “First he showed me how viruses change cells. Then he introduced me to retrovirology. . . . I went into retrovirology solely because of those discussions with Bob Ting on tennis courts,” Gallo said.

Dr. Ting, whom Gallo described as a quiet, modest man, was born in Shanghai, the son of a physician to Gen. Chiang Kai-Shek. His family fled the country during the Japanese invasion of China during World War II and moved to Hong Kong. Soon after, he moved to the United States, where he received a bachelor’s degree and in 1956 a master’s degree in genetics from Amherst College.

He received a doctoral degree in microbiology and biochemistry from the University of Illinois in 1960 under Salvador E. Luria, who later won the 1969 Nobel Prize in Medicine and Physiology. Dr. Ting spent the next two years on a postdoctoral fellowship at the California Institute of Technology, working with Renato Dulbecco, who later won the 1975 Nobel Prize in Medicine and Physiology. Their work focused on how viruses cause tumors.

“A lot of molecular biology developed from this,” Dr. Ting told The Washington Post in 1984 from his Rockville office, cluttered with scientific journals, awards and a large blackboard. “There was so much evidence in animal systems [that viruses cause tumors], that the next question was obvious — can you find the equivalent in humans.”

Dr. Ting joined the National Institutes of Health in 1962 as a visiting fellow and then a senior research scientist at the National Cancer Institute. From 1966 to 1968, he was an associate editor for the Journal of the National Cancer Institute.

In 1969, he joined Litton Bionetics Inc. in Rockville as director of experimental oncology, leading a project funded by the institute to search for viruses in human leukemia patients. He became scientific director of the cancer research branch the next year.

With academic, government and private business experience under his belt, Dr. Ting decided to go into business on his own and in 1973 started Biotech Research Laboratories in Rockville. It was a profitable supplier of research services and supplies until 1981, when it went public and produced the HIV diagnostic test kits. It became one of the most successful public biotech companies in the area in the mid-1980s.

The Economic Development Board of Singapore invited him to return to Asia to start a biotech company, which he did in 1985, forming Diagnostic Biotechnology Ltd. He also joined the Institute of Molecular and Cell Biology at the National University of Singapore, which Gallo called “the most prominent Asian academic biotechnology center.”

He returned to the United States in 1998 to join the board of Cell Works Inc. in Baltimore, and became chair and chief executive of a joint venture, Cell Works Asia Limited, in 2000.

Most recently, Dr. Ting was the founding president and chief executive of Profectus Biosciences Inc. of Baltimore, previously known as Maryland BioTherapeutics Inc.

Dr. Ting was past chairman of the F.F. Fraternity, one of the oldest Chinese fraternities in the United States. He was also a member of the Organization of Chinese Americans in the D.C. area since its inception in the early 1970s. He enjoyed tennis, golf, ballroom dancing and international travel. He also was a wine connoisseur.

Survivors include his wife of 44 years, Sylvia Han Ting of Potomac; three children, Anthony Ting of Shaker Heights, Ohio, Andrew Ting of Beverly, Mass., and Jennifer Chow of Potomac; seven sisters; and seven grandchildren.

An obituary written from his son Anthony can be found here:

https://www.amherst.edu/aboutamherst/magazine/in_memory/1953/robertting

Sources:

http://www.amazon.com/Virus-Hunting-Retrovirus-Scientific-Discovery/dp/0465098150

http://www.washingtonpost.com/wp-dyn/content/article/2006/09/21/AR2006092101936.html

Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin

History of medicine, science, and society: 200 Years of the New England Journal of Medicine

Why did Pauling Lose the “Race” to James Watson and Francis Crick? How Crick Describes his Discovery in a Letter to his Son

John Randall’s MRC Research Unit and Rosalind Franklin’s role at Kings College

Interview with the co-discoverer of the structure of DNA: Watson on The Double Helix and his changing view of Rosalind Franklin

Otto Warburg, A Giant of Modern Cellular Biology

Inspiration From Dr. Maureen Cronin’s Achievements in Applying Genomic Sequencing to Cancer Diagnostics

Nanotechnology and HIV/AIDS treatment

HIV vaccine: Caltech puts us One step further

Getting Better: Documentary Videos on Medical Progress — in Surgery, Leukemia, and HIV/AIDS.

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Mitochondrial Dysfunction and Cardiac Disorders

Posted in Atherogenic Processes & Pathology, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, HTN, International Global Work in Pharmaceutical, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Pharmacogenomics, Pharmacotherapy of Cardiovascular Disease, tagged ATP, Cardiovascular disease, Conditions and Diseases, Fatty acid, health, Heart disease, Heart Failure, Hypoxia-inducible factors, Larry H. Bernstein, Mitochondrial DNA, mitochondrial dysfunction, MTA, Muscular dystrophy, Nature Medicine, Simpson on April 14, 2013| 7 Comments »

Mitochondrial Dysfunction and Cardiac Disorders

Curator: Larry H Bernstein, MD, FACP

This article is the THIRD in a four-article Series covering the topic of the Roles of the Mitochondria in Cardiovascular Diseases. They include the following;

Mitochondria and Cardiovascular Disease: A Tribute to Richard Bing, Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/04/14/chapter-5-mitochondria-and-cardiovascular-disease/

Mitochondrial Metabolism and Cardiac Function, Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

Mitochondrial Dysfunction and Cardiac Disorders, Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-dysfunction-and-cardiac-disorders/

Reversal of Cardiac mitochondrial dysfunction, Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/04/14/reversal-of-cardiac-mitochondrial-dysfunction/

Mitochondrial Metabolism in Impaired Cardiac Function

Mitochondrial Dysfunction and the Heart

Chronically elevated plasma free fatty acid levels in heart failure are associated with

decreased metabolic efficiency and cellular insulin resistance.

The mitochondrial theory of aging (MTA) and the free-radical theory of aging (FRTA) are closely related.
They were in fact proposed by the same researcher about 20 years apart. MTA adds

the mitochondria and its production of free radicals
into the concept that free-radicals damage DNA over time.

Tissue hypoxia, resulting from low cardiac output with or independent of endothelial impairment,

increases oxidative stress and leads to apoptosis and mitochondrial DNA damage.

This dysfunctional state causes loss of mitochondrial mass. Therapies aimed at protecting mitochondrial function

have shown promise in patients and animal models with heart failure that will be the subject of Chapter III.

Myocardial function in hypertension

Genetic variation in vitamin D-dependent signaling

is associated with congestive heart failure in human subjects with hypertension.

Functional polymorphisms were selected from five candidate genes:

CYP27B1,
CYP24A1,
VDR,
REN and
ACE.

Using the Marshfield Clinic Personalized Medicine Research Project,

205 subjects with hypertension and congestive heart failure,
206 subjects with hypertension alone and
206 controls (frequency matched by age and gender) were genotyped.

In the context of hypertension, a SNP in CYP27B1 was associated with congestive heart failure

(odds ratio: 2.14 for subjects homozygous for the C allele; 95% CI: 1.05–4.39).

Genetic variation in vitamin D biosynthesis is associated with increased risk of heart failure.

RA Wilke, RU Simpson, BN Mukesh, SV Bhupathi, et al. Genetic variation in CYP27B1 is associated

with congestive heart failure in patients with hypertension. Pharmacogenomics 2009; 10(11): 1789-1797. http://dx.doi.org/10.2217/pgs.09.101

Heart Failure and Coronary Circulation

There is a decrease in resting and peak stress myocardial function in chronic heart failure patients,

with recovery of skeletal muscle phosphocreatine following exercise induced by perhexiline treatment.

This suggested that mitochondrial deﬁciencies, caused by excessive free fatty acids (FFAs)

underlie a common cardiac and skeletal muscle myopathy in heart failure patients.

Tissue hypoxia in chronic heart failure from inadequate circulation in heart failure

increases the oxidative stress in lean body mass and in the heart itself.

The heterodimeric transcription factor hypoxia-inducible factor (HIF)-1

induces changes in the transcription of genes that encode proteins involved in the adaptation to hypoxia.

HIF-1 activity depends on levels of the HIF-1a subunit, which has a short half-life.

HIF-1a increases in rats with experimentally induced myocardial infarction together with elevated levels of

GLUT1 and haemoxygenase-1 in the peri-infarct region of the heart

The cardiac metabolic response to hypoxia is considered to be

a return to a pattern of fetal metabolism, in which
carbohydrates predominate as substrates for energy metabolism.

The reliance on carbohydrate energy source is thought to be a result of the downregulation of PPARa with a decreased activity of

The sarcolemmal fatty acid transporter protein (FATP) levels are also decreased with palmitate oxidation,

transitioning away from fatty acid metabolism proportional to the degree of cardiac impairment.

The hypoxic changes of heart failure drives a switch toward

glycolysis and glucose oxidation
restriction of myocardial fatty acid uptake.

Nevertheless, late in the progression of heart failure, substrate metabolism is insufﬁcient to support cardiac function, because

the hypoxic failing heart is no longer able to oxidize fats and may also be insulin resistant.

The author surmises that mitochondrial dysfunction caused by tissue hypoxia might be mediated by the

proapoptotic protein BCL2/adenovirus E1B 19kDa interacting protein (Bnip)3.

It is strongly upregulated in response to hypoxia. In the isolated, perfused rat heart, Bnip3 expression was

induced after 1h of hypoxia, with Bnip3 integrating into the mitochondria of hypoxic ventricular myocytes.

This resulted in mitochondrial defects associated with

opening of the permeability transition pore, leading to
loss of inner membrane integrity and
loss of mitochondrial mass.

Mitochondrial Dysfunction caused by Bnip3 Precedes Cell Death.

Experimentally induced myocardial ischemia had evidence of contractile dysfunction but preserved viability. A progressive

decline in circulating levels of endothelial progenitor cells was documented 3 months following instrumentation (P<0.001).

Quantitative polymerase chain reaction analysis revealed that

chronic myocardial ischemia produced a biphasic response in both
- hypoxic-inducible factor 1 and
- stromal-derived factor 1 mRNA expression.

While initially unregulated, a gradual decline was observed over time (from day 45 to 90), in

hypoxic-inducible factor 1 and
stromal-derived factor 1 mRNA expression .

On serial assessment, endothelial progenitor cell migration was progressively impaired in response to chemo-attractant gradients of:

vascular endothelial growth factor (10-200 ng/mL)
and stromal cell-derived factor-1 (10-100 ng/mL) .

Decreased circulating levels and migratory dysfunction of bone marrow derived endothelial progenitor cells

were documented in a reproducible clinically relevant model of myocardial ischemia.

Nitric Oxide (NO) in Myocardial Ischemia and Infarct

Nitric oxide (NO) is a free radical with an unpaired electron; it is an important physiologic messenger,

produced by nitric oxide synthases, which catalyze the reaction l-arginine to citrulline and NO.

The constitutive isoforms exists in neuronal and endothelial cells and is calcium dependent. Calcium binds to calmodulin and

the calcium calmodulin complex activates the constitutive NO synthase that releases NO,
relaxing smooth muscle cells through activation of guanylate cyclase and the production cGMP.

Therefore, the NO produced has a negative inotropic effect on the heart and is instrumental in the autoregulation of the coronary circulation.

The inducible form of NO synthase (iNOS), mostly produced in macrophages, is activated by cytokines and endotoxin. It eliminates intracellular pathogens,

damaging cells by inhibiting

ATP production
oxidative phosphorylation
DNA synthesis.

In infection, lipopolysaccharide released from bacterial walls, stimulates production of iNOS. The large amount of NO produced

causes extensive vasodilation and hypotension.

We sought to assess whether oxidation products of

nitric oxide (NO), nitrite (NO2−) and nitrate (NO3−), referred to as NOx,
are released by the heart of patients after acute myocardial infarction (AMI) and
whether NOx can be determined in peripheral blood of these patients.

Previously we reported that in experimental myocardial infarction (rabbits) NOx is released mainly by inflammatory cells

(macrophages) in the myocardium 3 days after onset of ischemia.

NOx is formed in heart muscle from NO; It originates through the activity of the inducible form of nitric oxide synthase (iNOS).

Eight patients with acute anterior MI and an equal number of controls were studied. Coronary venous blood was obtained by

coronary sinus catheterization; NOx concentrations in coronary sinus, in arterial and peripheral venous plasma were measured.

Left ventricular end-diastolic pressure was determined. Measurements were carried out 24, 48 and 72 h after onset of symptoms.

The type and location of coronary arterial lesions were determined by coronary angiography. Plasma NO3− was reduced to NO2−

by nitrate reductase before determination of NO2− concentration by chemiluminescence.

The results provided evidence that in patients with acute anterior MI, the myocardial production of nitrite and nitrate (NOx) was increased,

as well as the coronary arterial–venous difference.

Increased NOx production by the infarcted heart accounted for the increase of NOx concentration in arterial and the peripheral venous plasma.

The peak elevation of NOx occurred on days 2 and 3 after onset of the symptoms, suggesting that NOx production was at least in part the result of

production of NO by inflammatory cells (macrophages) in the heart.

The appearance of oxidative products of NO (NO2− and NO3−) in peripheral blood of patients with acute MI is

the result of their increased release from infarcted heart during the inflammatory phase of myocardial ischemia.

Further studies are needed to define the clinical value of these observations.

K Akiyama, A Kimura, H Suzuki, Y Takeyama, …. R Bing. Production of oxidative products of nitric oxide in infarcted human heart. J Am Coll Cardiol. 1998;32(2):373-379. http://dx.doi.org/10.1016/S0735-1097(98)00270-8

OPA1 Mutation and Late-Onset Cardiomyopathy

No cardiac disorders have been described in patients with OPA1 or similar mutations

involving the fission/fusion genes as seen in inherited maladies like Charcot–Marie–Tooth disease.

Our results indicate that, at least for OPA1, cardiac abnormalities are not completely

manifest until the development of blindness.

The OPA1-mutant mice survived more than 1 year and appeared healthy.

In patients with these diseases, reduced cardiac function may go undetected

secondary to reduced physical activity secondary to loss of vision.

It would be expected that patients with such mutations would have impaired cardiac reserve with

reduced ability to respond to high-stress disease states such as myocardial infarction and sepsis.

The OPA1-mutant mice have reduced cardiac reserve, as shown by

the lack of response to isoproterenol or to ischemia/reperfusion injury,

This suggests that patients with OPA1 and related inherited mitochondrial diseases

should be screened for abnormalities of cardiac function.

Le Chen; T Liu; A Tran; Xiyuan Lu; …AA. Knowlton. OPA1 Mutation and Late-Onset Cardiomyopathy:
Mitochondrial Dysfunction and mtDNA Instability. http://jaha.ahajournals.org/content/1/5/e003012.full

Oxidative Stress and Mitochondria in the Failing Heart

The major problem in tissue hypoxia in the failing heart is oxidative stress. Reactive oxygen species (ROS), including

superoxide,
hydroxyl radicals and
hydrogen peroxide,

are generated by a number of cellular processes, including

mitochondrial electron transport,
NADPH oxidase and
xanthine dehydrogenase/xanthine oxidase.

The low availability of oxygen, the ﬁnal receptor of mitochondrial electron transport (ET), results in

electron accumulation in the ET chain as the complexes become highly reduced.

A number of experimental and clinical studies have suggested that ROS generation is

enhanced in heart failure because of electron leak, and complexes I and II
are implicated as the primary sites of this loss.

Prolonged oxidative stress in cardiac failure results in damage to mitochondrial DNA.

The continued ROS generation and consequent cellular injury leads to functional decline.

Thus, mitochondria are both the sources and targets of a cycle of ROS-mediated injury in the failing heart.

Mice with a cardiac/skeletal muscle speciﬁc deﬁciency in the scavenger enzyme superoxide dismutase

developed progressive congestive heart failure
with defects in mitochondrial respiration.

Oxidative stress in these mice also caused speciﬁc morphological changes in cardiac mitochondria

characterized by decreased ATP levels,
impaired contractility,
dramatically restricted exercise capacity and
decreased survival.

This was in part corrected by treatment with the antioxidant superoxide dismutase mimetic, namely

manganese5,10,15,20-tetrakis-(4-benzoic acid)-porphyrin.

EUK-8, a superoxide dismutase and catalase mimetic improved survival and contractile parameters in a mutant mouse model

of pressure overload-induced oxidative stress and heart failure and in wild-type mice subjected to pressure overload.

In addition, mitochondria show

functional impairment and
morphological disorganization

in the left ventricle of Hypertrophic Cardiomyopathy (HCM) patients without baseline systolic dysfunction.

These mitochondrial changes were associated with impaired myocardial contractile and relaxation reserves.

A strategy to protect the heart against oxidative stress could lie with

the modulation of mitochondrial electron transport itself.

Mild mitochondrial uncoupling may offer a potential cardioprotective effect by decreasing ROS production

preventing electron accumulation at complex III and
the Fe–S centres of complex I, and may therefore

mtDNA, Autophagy, and Heart Failure

Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA.

Mitochondria damaged by external haemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes.

Mitochondrial DNA (mtDNA) that escapes from autophagy cell-autonomously leads to Toll-like receptor (TLR) 9-mediated

inflammatory responses in cardiomyocytes and
is capable of inducing myocarditis and dilated cardiomyopathy.

Cardiac-specific deletion of lysosomal deoxyribonuclease (DNase) II showed no cardiac phenotypes under baseline conditions,

but increased mortality and caused severe myocarditis and dilated cardiomyopathy 10 days after treatment with pressure overload.

Early in the pathogenesis, DNase II-deficient hearts showed

infiltration of inflammatory cells
increased messenger RNA expression of inflammatory cytokines
accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium.

Administration of inhibitory oligodeoxynucleotides against TLR9, which is known to be activated by bacterial DNA6, or ablation of Tlr9

attenuated the development of cardiomyopathy in DNase II-deficient mice.

Furthermore, Tlr9 ablation

improved pressure overload-induced cardiac dysfunction and
inflammation even in mice with wild-type Dnase2a alleles.

These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts.

T Oka, S Hikoso, O Yamaguchi, M Taneike, T Takeda, T Tamai, et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure.

Nature 485, 251–255 (10 May 2012) http://dx.doi.org/10.1038/nature10992

Mitochondrial Dysfunction Increases Expression of Endothelin-1 and Induces Apoptosis

We developed an in vitro model of mitochondrial dysfunction using rotenone, a mitochondrial respiratory chain complex I inhibitor, and studied

preproendothelin-1 gene expression and apoptosis.

Rotenone greatly increased the gene expression of preproendothelin-1 in cardiomyocytes.

This result suggests that the gene expression of preproendothelin-1 is induced by the mitochondrial dysfunction.

Furthermore, treatment of cardiomyocytes with rotenone induced an elevation of caspase-3 activity, and caused a marked

increase in DNA laddering, an indication of apoptosis.

In conclusion, it is suggested that mitochondrial impairment in primary cultured cardiomyocytes induced by rotenone in vitro,

mimics some of the pathophysiological features of heart failure in vivo, and that ET-1 may have a role in myocardial dysfunction
- with impairment of mitochondria in the failing heart.

Yuki, K; Miyauchi, T; Kakinuma, Y; Murakoshi, N; Suzuki, T; et al. Mitochondrial Dysfunction Increases Expression of Endothelin-1 and Induces Apoptosis through Caspase-3 Activation in Rat Cardiomyocytes In Vitro. Journal of Cardiovascular Pharmacology: 2000; 36 VASCULAR EFFECTS: PDF Only http://journals.lww.com/cardiovascularpharm/Abstract/2000/36001/Mitochondrial_Dysfunction_Increases_Expression_of.62.aspx

Summary

This review focused on the evidence accumulated to the effect that mitochondria are key players in

the progression of congestive heart failure (CHF).

Mitochondria are the primary source of energy in the form of adenosine triphosphate that fuels the contractile apparatus,

essential for the mechanical activity and the Starling Effect of the heart.

We evaluate changes in mitochondrial morphology and alterations in the main components of mitochondrial energetics, such as

substrate utilization and
oxidative phosphorylation,

in the context of their contribution to the chronic energy deficit and mechanical dysfunction in HF.

REFERENCES

JM Huss and DP Kelly. Mitochondrial energy metabolism in heart failure: a question of balance.

J. Clin. Invest. 2005: 115(2):547–555. http://dx.doi.org/10.1172/JCI24405

MG Rosca and CL Hoppel. Mitochondria in heart failure. Cardiovascular Research 2010; 88: 40–50. http://dx.doi.org/10.1093/cvr/cvq240

Zachman AL, Page JM, Prabhakar G, Guelcher SA, and Sung HJ, “Elucidation of adhesion-dependent spontaneous apoptosis in macrophages using phase separated PEG/polyurethane films.”
Acta Biomater. 2012 Nov 2. http://dx.doi.org/pii: S1742-7061(12)00530-2. 10.1016/j.actbio.2012.10.038. http://www.ncbi.nlm.nih.gov/pubmed/23128157

K Unno, S Isobe, H Izawa, Xian Wu Cheng, et al. Relation of functional and morphological changes in mitochondria to myocardial contractile and relaxation reserves in asymptomatic to mildly

symptomatic patients with hypertrophic cardiomyopathy. European Heart Journal 2009; 30:1853–1862.

http://dx.doi.org/10.1093/eurheartj/ehp184

Murray AJ, Edwards LM, Clarke K. Mitochondria and heart failure. Curr Opin Clin Nutr Metab Care. 2011 Jan; 14(1):111. http://www.ncbi.nlm.nih.gov/pubmed/18089951

De Haan JB, Crack PJ, Flentjar N, Iannello RC, Hertzog PJ, Kola I. An imbalance in antioxidant defense affects cellular function: the pathophysiological consequences of a reduction in antioxidant defense in the glutathione peroxidase-1 (Gpx1) knockout mouse. Redox Rep. 2003;8(2):69-79. http://dx.doi.org/10.1179/135100003125001378

Tsutsui H, Kinugawa S, Matsushima S.Mitochondrial oxidative stress and dysfunction in myocardial remodelling. Cardiovasc Res. 2009 Feb 15;81(3):449-56. http://dx.doi.org/10.1093/cvr/cvn280pp.449-56

Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

Posted in Advanced Drug Manufacturing Technology, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Health Economics and Outcomes Research, tagged Adverse effect, Cardiomyopathy, Cardiovascular Disorders, Conditions and Diseases, Drug development, drug trial failuress, drug withdrawal costs, Ejection Fraction, health, Induced pluripotent stem cell on April 11, 2013| 5 Comments »

Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

Curator: Larry H Bernstein, MD, FCAP

Introduction

This is the second part of a series on toxicities of therapeutic medications, the first being on the impact on drug development of early phase failure to identify toxicities that are found in late stage trials and result in withdrawal. This portion will go into details of identifying the effects clinically and give some examples. In the future, the design of therapies, the identification of high probability successful genomic targets, and more accurate patient selection will transform the approach to development, clinical trials, and clinical use of pharmaceuticals in patients.

Cardiotoxicity and Cardiomyopathy

refer to: What are cardiotoxicity and cardiomyopathy?

The Scott Hamilton Cares Initiative

Cleveland Clinic

http://chemocare.com/chemotherapy/side-effects/cardiotoxicity-and-cardiomyopathy.aspx

Cardiotoxicity is a condition of heart muscle functional impairment from toxicity as an

adverse secondary effect of taking an essential medication, or
as a result of interactions between prescribed medications that result in heart damage,
usually dose and time related.

If severe, the adverse effect of chemotherapy may lead to cardiomyopathy. While cardiomyopathy might be a result of treatments, such as chemotherapeutic medications, it may also caused by a group of diseases or disorders, leading to

damaged myocardiocytes, and the injury leads to
insufficient cardiac output, referred to as
heart failure.

Cardiomyopathy has many causes, singly or in combination:

viruses – such as,
- coxsackie B,
- human immunodeficiency virus (HIV)
systemic inflammatory disorder
- systemic lupus erythematosis
Amyloidosis – amyloid protein deposits in the myocardium alone, and/or other organs
Infection –
- bacterial (tetanus),
- parasitic (Chaga’s disease)
- Rheumatic fever
high blood pressure
Chronic or long-term alcohol use (B vitamin deficiency)
Endocrine disease, such as hyperthyroidism
Thiamine and Vitamin B deficiency
Radiation therapy
Medications – anthracyclines.

Anthracyclines may be used to treat leukemia, lymphoma, multiple myeloma, breast cancer, and sarcoma. A commonly used anthracycline is called doxorubicin (Adriamycin®).

cardiomyopathy may also result from genetic defects
illegal drugs and toxic substances, cocaine, may also produce serious myocardial damage

With certain drugs, such as doxorubicin, there is a dose at which these cardiotoxic effects on the heart may occur.
An echocardiogram, or a radionuclide ventriculography scan, is performed

prior to initiating a cardiotoxic medication
to determine baseline cardiac function., and
repeated at intervals to monitor heart function while receiving cardiotoxic medications.

The ejection fraction (EF) is a percentage of blood pumped out into the body during each heartbeat. An EF of 50%-75% is considered normal.

The lower the ejection fraction, the more severe the heart failure may be.

This may determine if the cardiotoxic drug has caused cardiomyopathy.

Symptoms of cardiomyopathy:

fatigue
shortness of breath
fever and aching of the joints,
Or, sudden heart failure or sudden cardiac death without any prior symptoms.
- swollen feet and ankles
- distended neck veins
- tachycardia
- dyspnea while reclining

Diagnosis:

history & physical examination
laboratory tests
EKG
Chest x-ray
Echocardiography
Cardiac cath
Angiography

Treatment:

Dexraoxane HCL – doxorubicin
ACE inhibitors
Beta-blockers
Diuretics
Digoxin

Biomolecular Screening for Drug Toxicity

Multiparameter In Vitro Assessment of Compound Effects on Cardiomyocyte Physiology Using iPSC Cells

O Sirenko, C Crittenden, N Callamaras, J Hesley, Yen-Wen Chen, et al.

A sufficient percentage of drugs fail in clinical studies due to cardiac toxicity that the development of new, sensitive in vitro assays that can evaluate potential adverse effects on cardiomyocytes is needed. Cell-based models are more clinically relevant than those used in practice. Human-induced pluripotent stem cell–derived cardiomyocytes are especially attractive because

they express ion channels and
demonstrate spontaneous mechanical and electrical activity
- similar to adult cardiomyocytes.

This study introduces techniques for measuring the impact of pharmacologic compounds on the beating rate of cardiomyocytes with ImageXpress Micro and FLIPR Tetra systems. The assays employ

calcium-sensitive dyes to monitor changes in Ca2+ fluxes

synchronous with cell beating,

This method allows monitoring of the

beat rate
amplitude, and
other parameters.

The system detects

concentration-dependent atypical patterns caused by
hERG inhibitors and other ion channel blockers.

In addition,

both positive and negative chronotropic effects on cardiac rate can be observed and
IC50 values determined.

This methodology is well suited for safety testing and can be used to estimate efficacy and dosing of drug candidates prior to clinical studies.

J Biomol Screen Jan 2013;18(1): 39-53 http://dx.doi.org/10.1177/1087057112457590

Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes.

L Guo, RMC Abrams, JE Babiarz, JD Cohen, S Kameoka, et al.

Early prediction of drug-induced toxicity is needed in the pharmaceutical and biotechnology industries to decrease late-stage drug attrition.

Cardiotoxicity accounts for about one third of safety-based withdrawn pharmaceuticals.

This study reports a high-throughput functional assay, detailing a model that accurately detects

drug-induced cardiac abnormalities.

It employs

induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
Using 96-well plates with interdigitated electrode arrays detect
- assess impedance,
- the rhythmic, synchronous contractions of the iPSC-CMs

Treatment of the iPSC-CMs with 28 different compounds with known cardiac effects resulted in

compound-specific changes in the beat rate and/or
the amplitude of the impedance measurement.

Changes in impedance for the compounds tested were comparable with the results from a related technology,

electric field potential assessment obtained from microelectrode arrays.

Using the results from the set of compounds,

an index of drug-induced arrhythmias was calculated,
which enabled the determination of a drug’s proarrhythmic potential.

This system of interrogating human cardiac function in vitro opens new opportunities for predicting cardiac toxicity and studying cardiac biology.

Toxicol Sci. Sep 2011; 123 (1):281-9 21693436

Determination of the Human Cardiomyocyte mRNA and miRNA Differentiation Network by Fine-Scale Profiling.

JE Babiarz, M Ravon, S Sridhar, P Ravindran, B Swanson, et al.

This study is a detailed comparison of the mRNA and miRNA transcriptomes

across differentiating human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and
biopsies from fetal, adult, and hypertensive human hearts

Gene ontology analysis of the mRNA expression levels of the hiPSCs differentiating into cardiomyocytes
revealed 3 distinct groups of genes:

pluripotent specific,
transitional cardiac specification, and
mature cardiomyocyte specific.

Hierarchical clustering of the mRNA data revealed that the transcriptome of hiPSC cardiomyocytes

stabilizes 20 days after initiation of differentiation.

But analysis of cells continuously cultured for 120 days indicated that

the cardiomyocytes continued to mature toward a more adult-like gene expression pattern.

Analysis of cardiomyocyte-specific miRNAs (miR-1, miR-133a/b, and miR-208a/b) revealed

an miRNA pattern indicative of stem cell to cardiomyocyte specification.

A biostatistitical approach integrated the miRNA and mRNA expression profiles revealing a

cardiomyocyte differentiation miRNA network and
identified putative mRNAs targeted by multiple miRNAs.

Together, these data reveal the

miRNA network in human heart development and

support the notion that overlapping miRNA networks
re-enforce transcriptional control during developmental specification.

Stem Cells Dev. 2012 Jul 20;21 (11):1956-65 22050602

Comparative Gene Expression Profiling in Human Induced Pluripotent Stem Cell Derived Cardiocytes and Human and Cynomolgus Heart Tissue.

D Puppala, LP Collis, SZ Sun, V Bonato, X Chen, B Anson, et al. Compound Safety Prediction.

Cardiotoxicity is one of the leading causes of drug attrition. Current in vitro models insufficiently predict cardiotoxicity. The authors describe

the gene expression profile of human induced pluripotent stem cell derived cardiocytes (iCC)
post-thaw over a period of 42 days in culture and
compare this profile to human fetal and adult as well as
adult cynomolgus nonhuman primate (NHP: Macaca fascicularis) heart tissue.

The results indicate that iCC express relevant cardiac markers such as

ion channels (SCN5A, KCNJ2, CACNA1C, KCNQ1 and KCNH2),
tissue specific structural markers (MYH6, MYLPF, MYBPC3, DES, TNNT2 and TNNI3),
transcription factors (NKX2.5, GATA4 and GATA6), and
lack the expression of stem cell markers (FOXD3, GBX2, NANOG, POU5F1, SOX2, and ZFP42).

A functional evaluation of contractility of the iCC showed

functional and pharmacological correlations with myocytes isolated from adult NHP hearts.

The results suggest that stem cell derived cardiocytes may represent

a novel in vitro model to study human cardiac toxicity with potential ex vivo and in vivo translation.

Toxicol Sci. Sep 14 2012;: 22982684

Characterization of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes:
Bioenergetics and Utilization in Safety Screening.

P Rana, B Anson, S Engle, Y Will. Compound Safety Prediction. Pfizer Global R&D, Groton CT.

Cardiotoxicity remains the number one reason for drug withdrawal from the market and FDA issued black box warnings; thus

demonstrating the need for more predictive preclinical safety screening,
especially early in the drug discovery process.

Whereas hERG screening has become routine to mitigate proarrhythmic risk,

the development of in vitro assays predicting additional on- and off-target biochemical toxicities
will benefit from cellular models exhibiting true cardiomyocyte characteristics
- such as, native tissue-like mitochondrial activity.

An hypothesis was tested for using human stem cell derived tissue cells by using a combination of

flux analysis,
gene and protein expression, and
toxicity-profiling techniques
- to characterize mitochondrial function
- in induced pluripotent stem cell (iPSC)-derived human cardiomyocytes
  - in the presence of differing carbon sources
  - over extended periods in cell culture.

Functional analyses demonstrate that iPSC-derived cardiomyocytes:

1) are capable of utilizing anaerobic or aerobic respiration depending upon the available carbon substrate,

2) are bioenergetically closest to adult heart tissue cells when cultured in galactose or galactose supplemented with fatty acids, and

3) show a dose dependent toxicity profile to a variety of kinase inhibitors with known clinical cardiac liabilities.

Furthermore, gene and protein expression analyses revealed that in comparison to adult cardiac tissue,

iPSCs-derived cardiomyocytes possess a qualitatively similar expression pattern of mitochondrial genes,
an up-regulation of apoptotic and antioxidant genes, and
a mitochondrial transcription pattern that is similar across different carbon substrates
despite showing changes in protein levels and functional bioenergetic adaptation.

Toxicol Sci. 2012 Jul 27;: 22843568

Decreasing cardiac chamber sizes and associated heart dysfunction in COPD – role of hyperinflation.

H Watz, B Waschki, T Meyer, G Kretschmar, A Kirsten, M Claussen, H Magnussen

This study examined the relationship of

lung function with heart size and heart dysfunction and
associated consequences for 6-minute walk distance (6MWD)
- in patients with COPD of different severity.

METHODS: 138 patients with COPD (GOLD I-IV)

the size of all cardiac chambers,
left ventricular diastolic dysfunction (relaxation and filling), and
global right ventricular dysfunction (Tei-index)
- were measured by echocardiography .
lung function (spirometry, bodyplethysmography, diffusion capacity) and
6MWD …. were measured.

RESULTS: Size of all cardiac chambers decreased with GOLD stages. Overall,
moderate relationships existed between

variables of lung function and cardiac chamber sizes.

Static hyperinflation (inspiratory-to-total lung capacity ratio [IC/TLC],
functional residual capacity, and residual volume)

showed stronger associations with

cardiac chamber sizes than
airway obstruction or diffusion capacity.

IC/TLC ratio correlated best with cardiac chamber sizes and was

an independent predictor of cardiac chamber sizes
- after adjustment for body surface area.

Patients with an IC/TLC ratio <!–= 0.25 had a significantly–>

impaired left ventricular diastolic filling pattern and
a significantly impaired Tei-index
- compared to patients with an IC/TLC ratio > 0.25.

An impaired left ventricular diastolic filling pattern was independently associated with

a reduced 6MWD.

An increasing severity of COPD is associated with a decreasing heart size.

Hyperinflation in patients with COPD might have an important role with respect to

heart size and
cardiac dysfunction

Chest. Feb 26 2010;: 20190002 Cit:4

Cardiovascular Events After Clarithromycin Use in Lower Respiratory Tract Infections
Analysis of Two Prospective Cohort Studies

S Schembri, PA Williamson, PM Short, A Singanayagam, A Akram, et al. British Medical Journal

Acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia are common causes of admission to a hospital.

Antibiotics, including clarithromycin, are commonly prescribed during acute exacerbations of chronic obstructive pulmonary disease, especially

in the presence of increased breathlessness,
sputum volume, and
purulence.

Use of macrolide antibiotics in community acquired pneumonia has been consistently associated with improved short term mortality in observational studies,
and national and international guidelines therefore recommend their use in combination with β lactams for patients admitted to hospital.

Widespread use of macrolide antibiotics has been accompanied by concerns about adverse effects on cardiovascular morbidity and mortality.
A retrospective study of erythromycin use in 1,249,943 patients identified an increase in deaths from cardiovascular disease.
Azithromycin was shown to have a similar association with increased cardiovascular deaths

during the time of administration.

CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients with Ischemic Heart Disease trial) was a double blind, placebo controlled trial
showing that a two week course of clarithromycin administered to patients with coronary heart disease

increased cardiovascular and all cause mortality

The increased mortality rate (clear of pulmonary infection)

persisted for three years after discontinuation of the drug.

A recent meta-analysis of 17 trials of antibiotics in coronary heart disease showed

increased long term mortality after macrolides, primarily due
to increased deaths from cardiovascular disease.

However, no studies have examined the long term effect of clarithromycin on cardiovascular events and mortality in patients

after acute exacerbations of chronic obstructive pulmonary disease or community acquired pneumonia.

Therefore, this prospective cohort study was undertaken to examine the association of clarithromycin with cardiovascular events

in the setting of acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia.

Population.

1343 patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease
and 1631 patients admitted with community acquired pneumonia.

Main Outcome Measures.

Hazard ratios for cardiovascular events at one year (defined as hospital admissions with

acute coronary syndrome, decompensated cardiac failure, serious arrhythmia, or sudden cardiac death) and
admissions for acute coronary syndrome (acute ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina).

Secondary outcomes were all cause and cardiovascular mortality at one year.

Results.

268 cardiovascular events occurred in the acute exacerbations of chronic obstructive pulmonary disease cohort and
171 in the community acquired pneumonia cohort over one year.

After multivariable adjustment, clarithromycin use in acute exacerbations of chronic obstructive pulmonary disease

was associated with an increased risk of cardiovascular events and acute coronary syndrome—
hazard ratios 1.50 (95% confidence interval 1.13 to 1.97) and 1.67 (1.04 to 2.68).

After multivariable adjustment, clarithromycin use in community acquired pneumonia

was associated with increased risk of cardiovascular events (hazard ratio 1.68, 1.18 to 2.38)
but not acute coronary syndrome (1.65, 0.97 to 2.80).

This association was found between clarithromycin use in acute exacerbations of COPD and

cardiovascular mortality (adjusted hazard ratio 1.52, 1.02 to 2.26)
but not all cause mortality (1.16, 0.90 to 1.51) .

No association was found between clarithromycin use in community acquired pneumonia and all cause mortality or cardiovascular mortality.
Use of β lactam antibiotics or doxycycline was not associated with increased cardiovascular events in patients with

acute exacerbations of chronic obstructive pulmonary disease, suggesting an effect specific to clarithromycin.

Timing of Cardiovascular Events

The study found no significantly increased risk of cardiovascular events while patients were taking clarithromycin in the COPD cohort
(hazard ratio 1.73, 0.71 to 4.25), but

an increased risk was present after the clarithromycin course ended (1.41, 1.05 to 1.89).

In the community acquired pneumonia cohort, the hazard ratio for association between clarithromycin use and cardiovascular events
was 1.84 (0.75 to 4.51) during clarithromycin use and 1.66 (1.14 to 2.43) after the antibiotic was stopped.

Association With Duration of Antibiotic Use

Longer courses of clarithromycin were associated with more cardiovascular events. The median duration of treatment was seven days in both cohorts.
Less than three days of clarithromycin treatment was not associated with cardiovascular events in the chronic obstructive pulmonary disease cohort
(hazard ratio 0.89, 0.50 to 1.57) or the community acquired pneumonia cohort (0.63, 0.15-2.65), compared with patients who did not receive clarithromycin.

Effect of Age and Cardiovascular Risk Status

The hazard ratios of the effect of clarithromycin on cardiovascular events in such patients were

1.35 (0.94 to 1.95) in those with a high cardiovascular risk and 0.88 (0.20 to 3.96) in those with a low risk.

The lowest hazard ratios for cardiovascular events were in patients aged 60 or below (1.01, 0.36 to 2.91).
The hazard ratio was 1.47 (1.01 to 2.14) for patients aged 60-79, and a higher risk was associated with

clarithromycin use in patients aged over 80 (hazard ratio 1.68, 1.05 to 2.69).

Use of Other Antibiotics

Use of β lactam or doxycycline was not associated with increased cardiovascular events

(hazard ratios 1.06 (0.83 to 1.37) and 0.96 (0.61 to 1.51), respectively)

in the chronic obstructive pulmonary disease cohort compared with patients not receiving antibiotics.

Possible Explanations for Findings

There was a strong association between prolonged (more than seven days) courses of clarithromycin and

cardiovascular events,
- which strengthens the case for a true biological cause.

The association between duration of antibiotic treatment and cardiovascular events

could also represent residual confounding by severity of illness.

How do the results point to the effect on outcome after cessation of the drug? The authors support an ischaemic mechanism.
Clarithromycin may activate macrophages, leading to an inflammatory cascade resulting in more vulnerable plaques that

over time may lead to acute coronary syndromes or sudden cardiac death by plaque rupture.

Conclusion

Prolonged courses of clarithromycin (more than seven days) may be associated with

increased risk of cardiovascular events,
especially in patients with a pre-existing history of coronary heart disease.

This may be of particular importance given recent data supporting long term macrolide use

to prevent exacerbations of chronic obstructive pulmonary disease.

Biomarkers Role in Drug Development

Biomarkers: An indispensible addition to the drug development toolkit

Biomarkers are becoming an essential part of clinical development. In this white paper, Thomson Reuters explores
the role of biomarkers as evaluative tools in improving clinical research and the challenges this presents.
The potential of biomarkers to

improve decision making,
accelerate drug development and
reduce development costs

is discussed with insights into a faster alternative to the conventional drug development approach and the promise of

safer drugs,
in greater numbers,
approved more quickly.

The attrition rate for drugs in clinical development is high: the percentage of tested products

entering phase I trials that eventually gain regulatory approval has been estimated at a paltry 8%.

Many of these failures happen late in clinical trials, with the consequence that expenditure in clinical drug development is increasing.
One study calculated that the cost of developing a drug increased by over 50% between 2002 and 2007. The related concern is that
very few drugs are making it out of the clinical research pipeline.
In 2007, the FDA approved just 17 new molecular entities and 2 biologic licenses, the lowest number since 1983.

The problem is mainly due to a gap in the industry’s ability to predict a drug candidate’s performance early, and with a large degree of certainty.
The convention in clinical research has been to measure the performance of novel therapies using clinical outcomes. This approach is
laborious, inexact and, as the US Food and Drug Administration (FDA ) puts it, decades old.

Why and what kinds of biomarkers do we determine are ESSENTIAL?

Biomarkers — a measure of

a normal biological process in the body,
a pathological process, or
the response of the body to a therapy —

may offer information about

the mechanism of action of the drug,
its efficacy, its safety and
its metabolic profile.

They feature heavily in the FDA ’s Critical Path Opportunities List for their potential

to speed the development and approval of medical products.
Moreover, they can predict drug efficacy more quickly than conventional clinical endpoints.

The first three examples are measures of drug efficacy and treatment response, but are not indicators of TOXICITY.

In 1960, researchers discovered that some patients with chronic myelogenous leukemia (CML), a form of adult leukemia

in which there is a proliferation of myeloid cells in the bone marrow,
have a specific genetic change associated with their cancer, a shortened version of chromosome.

The Philadelphia chromosome is caused by a translocation between chromosomes 9 and 22. The consequence of this genetic swap

is the creation of the BCR-ABL ‘oncogene’;
this cancer-causing gene produces a protein with elevated tyrosine kinase activity
that induces the onset of leukemia.

Researchers were able to use the Philadelphia chromosome as a biomarker

to indicate which patients would benefit from drug candidates (tyrosine-kinase inhibitors)
- specifically targeting the rogue protein.

The drug imatinib (Gleevec) is a Tyr kinase inhibitor and

decreases the proliferation of Philadelphia chromosome+ cells,
slowing the progression of the disease.

Specific mutations in the BCR–ABL gene were biomarkers that predicted resistance to imatinib,

leading to the development of newer tyrosine-kinase inhibitors dasatinib and nilotinib.

In the late 1980’s, scientists discovered that HIV viral load could be used as a marker of disease progression
Viral load was used to show that patients receiving combination therapy had

a higher reduction in viral load than those on monotherapy.

Eventually, the viral load biomarker was used in the development and assessment of Highly Active Antiretroviral Therapy (HAART)
treatment regimens taken by many people living with HIV today.

The HER-2 gene and receptor was also discovered in the mid 1980’s. Between 20–30% of breast cancer patients show an

over-expression of the HER-2 receptor on their cancer cells (usually postmenopausal).

This biomarker indicates a higher risk of adverse outcomes, but it gave clinicians a new target for novel therapies, and

the antibody trastuzumab (Herceptin) was developed
to target HER-2 receptors in these ‘overexpressing’ patients.

Preventing Drug Development Disasters

The need for biomarkers to guide clinical research is perhaps best highlighted in the stories of recent drug development failures.
Between 1995 and 2005, at least 34 drugs were withdrawn from the market, mainly as a result of hepatotoxic or cardiotoxic effects.

Many of us are familiar with the withdrawal in 2004 of the anti-inflammatory drug rofecoxib (Vioxx) due to concerns about its

increased risk of heart attack and stroke, and more recently with
the extremely serious adverse effects in the phase I clinical trial and subsequent failure of the monoclonal antibody, TGN1412.

TG N1412, a ‘superagonist’, produced by the firm TeGenero, stimulates an immune response. While originally intended to treat B cell
chronic lymphocytic leukemia and rheumatoid arthritis, it had been tested pre-clinically with no toxic or pro-inflammatory effects.
In 2006, six healthy male volunteers took part in a phase I clinical trial to test the safety of the candidate. Within 90 minutes of receiving the drug,

all six men were experiencing the beginnings of a ‘cytokine storm’, a term that describes
a cascade of proinflammatory cytokine release
leading to organ failure due to hypotension.

Although all the men survived, they required weeks of hospitalization. The cost of a failure, such as TGN1412,

in terms of patient health and lost resources is huge.

The TGN1412 trial failure highlighted a need for improved preclinical safety testing. It has been suggested that had procedures using safety biomarkers to

guide dosing and predict the toxicity of this drug been used, the disaster may not have occurred.

Biomarkers today

Today you “would not even conceive” of developing a new drug without simultaneously looking for biomarkers for

efficacy,
safety, and
to measure the pharmacodynamics of the drug,

says Dr Jeffrey Ross, Head of Pathology at the Albany Medical Center in New York, involved in the original work on HER-2.

The field of oncology is leading the way in the use of biomarkers in drug development. “Clinical trials are designed upon biomarker assays,”
“abstracts of phase II and III cancer trials talk about what biomarkers were selected.

In vivo biomarkers,
imaging biomarkers,
blood and tissue based biomarkers,

One example of a biomarker in use in oncology is circulating tumor cells (CTCs), a biomarker present in the blood of cancer patients.
At the moment, CTCs are used in the development of anti-cancer drugs as

an objective and direct measurement of the response of the cancer to a novel agent.

The way that clinical trials had been done previously was to enroll all patients

with a given disease independent of gene or phenotypic makers.
By selecting a population with the particular gene which is predicted
to be important for response to a novel therapeutic, then
- a smaller clinical trial should be sufficient to see whether it works or not.

The chemotherapy drug irinotecan (Camptosar) is an example of personalized medicine,

using a biomarker to guide both clinical practice and subsequent clinical trials.

Irinotecan is used to treat advanced colorectal cancer. Once administered, irinotecan is

activated to the metabolite SN-38, and then
eventually inactivated in the body by the UGT1A1 enzyme.

In 2005, the US Food and Drug Administration added a warning to the label of the drug, stating that patients

homozygous for a particular a version of the UGT1A1 gene — the UGT1A1*28 allele,
associated with decreased UGT1A1 enzyme activity —
- should be given a reduced dose.

Because patients with this allele clear the drug less quickly from their body than the rest of the population,

they effectively receive a greater exposure to the drug from the same dose.

As a consequence, they are at higher risk of potentially life-threatening side effects such as neutropenia (a decrease in white blood cells) and diarrhea.
The toxicity of irinotecan has long been a concern, and this biomarker now allows clinicians to better identify those patients who are at high risk of

serious side-effects (about 10% of the population are homozygous for UGT1A1*28).

And while this pharmacogenomics information has helped improve the clinical use and efficacy of irinotecan, it has also fed back into

the development of other drugs; this new understanding prompted the use of the UGT1A1 biomarker to guide other studies,
including several new irinotecan and oxaliplatin-based chemotherapy regimens.

Using preclinical biomarkers as evidence of efficacy

biomarkers can accelerate research by substituting for clinical symptoms as a measure of efficacy.
biomarkers can also replace clinical symptoms when it comes to measuring drug safety
an efficacy biomarker plus a safety biomarker will define not just whether a drug will work, but also what kind of dose might be relevant in humans

Improving efficacy in cardiology

Consider the role of inflammatory marker C-reactive-protein (CRP) in cardiovascular disease. CRP is released by inflamed atherosclerotic plaques in the arteries
of individuals with coronary heart disease, and increased levels of CRP are associated with a greater risk of plaque rupture, but also of a silent heart attack.
CRP is being used as a biomarker to measure drug efficacy, in particular whether rosuvastatin (Crestor)

reduces the risk of cardiovascular morbidity and mortality
in apparently healthy individuals with low LDL-cholesterol levels but elevated CRP.

The JUPITER study (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) was halted in March 2008

due to firm evidence that the drug is indeed more beneficial than placebo and
improves the prognosis of individuals with high CRP levels.

A related biomarker of cardiovascular risk called neopterin. Just as CRP is produced by inflamed atherosclerotic plaques at risk of rupture,
neopterin is produced by activated macrophages in this inflammatory process. Circulating neopterin levels are higher in patients with ACS and may be
a marker of coronary disease activity. In addition, “Neopterin could also potentially be a marker of drug efficacy because
if you reduce the number of active macrophages in the plaque or the circulation, the levels of neopterin also decrease,” says Dr Juan Carlos Kaski,
Professor of Cardiovascular Science and Director of the Cardiovascular Biology Research Centre at St George’s University of London.

Other uses of biomarkers

These types of biomarkers can be used to drive critical ‘go/no go’ decision in drug development

Mechanistic or ‘target’ biomarkers can be used in pre-clinical or phase I trials to measure the pharmacological effect of the drug, i.e.

whether the drug interacts with its receptor, enzyme, or protein target,
whether it is distributed to the site where it needs to act,whether there is some
- form of downstream pharmacology, and
the dose ranges in which the drug is pharmacologically active.

Drugs such as 5-HT4 receptor agonists (e.g. cisapride, mosapride), used in gastro-esophageal reflux disease (GERD), stimulate

the secretion of aldosterone as a side-effect.

Although aldosterone is not linked to GERD (and can’t be used as a biomarker of the disease), the hormone can be used

as a mechanistic biomarker in drug development to assess whether
- novel 5-HT4 agonists in development have a pharmacological effect.

Discovering new biomarkers

The fundamental issue we have to deal with, both with target selection and developing better biomarkers,

is a better understanding of pathophysiology.

The clinical need is huge, not least in diseases like chronic obstructive pulmonary disease (COPD), an illness about which we know very little.

“COPD has very few markers to indicate severity and disease progression,” says Dr Trevor Hansel, Medical Director of the National Heart &
Lung Institute Clinical Studies Unit in London. Many pharmaceutical companies have begun to invest in ‘omics’ —

genomics,
proteomics,
metabonomics —

to begin to sort through this mountain of molecules and characterize biomarkers based on a molecular understanding of disease.

The ‘omics’ approach enables

the detection of small changes in tissue composition through protein profiling technologies such as
mass spectrometry and gel electrophoresis.

Essentially, it is about capturing a molecular profile from a clinical sample and converting this into

information about a clinical condition — for example the stage of disease or
what players are involved in the disease pathways.

“We will be able to look at diseases and catagorize them based on

biochemical or physiological findings, rather than just on symptoms” … David Roblin, Pfizer

Companion Diagnostics and the Drug–Diagnostic Codevelopment Model

Jan Trøst Jørgensen Drug Development Research Nov 2012; 73(7):390-397. http://dx.doi.org/10.1002/ddr.21029

The concept of using a predictive or selective diagnostic assay in relation to drug development goes back to the 1970s when

the selective estrogen receptor modulator, tamoxifen (AstraZeneca) was developed for metastatic breast cancer.

Clinical data showed that the estrogen receptor status correlated well with the clinical outcome when the patients were treated with tamoxifen.

It is only within the last decade that this model has gained widespread acceptance. The drug and the diagnostic are interdependent, and
if the development project proves successful, the companion diagnostic assay (CoDx) will end up determining the conditions for the use of the drug.

This gatekeeper role obviously requires that the CoDx assays adhere to the same strict rules and regulations that are known from the development of drugs.
For any CoDx assay, it must be documented that it is robust and reliable and that it possesses clinical utility. The article focus on some of the most important
aspects of the CoDx development process with emphasis on the clinical validation and clinical utility but also other critical issues, such as,

the biomarker selection process,
determination of the cut-off value, and
the analytical validation.

Detecting Potential Toxicity in Mitochondria

Brad Larson, Principal Scientist; Peter Banks, Scientific Director; BioTek Instruments, Winooski, Vt.

Mitochondrial dysfunction may be

inherited,
arise spontaneously, or
develop as a result of drug toxicity.

Mitochondrial toxicity as a result of pharmaceutical use may damage key organs, such as the liver and heart. For example,

nefazodone—a depression treatment—was withdrawn from the U.S. market after it was shown to

significantly inhibit mitochondrial respiration in liver cells, leading to liver failure. Troglitazone, an anti-diabetic and anti-inflammatory,

was withdrawn from all markets after research concluded that it caused acute mitochondrial membrane depolarization, also leading to liver failure.

Drug recalls are costly to a manufacturer’s bottom line and reputation, and more importantly, can be harmful or even fatal to users. As drug

discovery continues to evolve, much lead compound research now includes careful review of its interaction and potential toxicity with mitochondria.

Cytotoxicity and ATP production are measured in cancerous and normal hepatocytes using a known inducer of cellular necrosis. (All figures: BioTek Instruments)

Cell-based mitochondrial assays in microplate format may include

mitochondrial membrane potential,
total energy metabolism,
oxygen consumption, and
metabolic activity;

and offer a truer environment for mitochondrial function in the presence of drug compounds compared to isolated mitochondria-based tests.
Combining more than one assay in a multiplex format increases the amount of data per well while decreasing data variability arising from running the assays separately.

The aggregated data also provides a more encompassing analysis of the drug’s effect on mitochondria than a single test.

http://www.dddmag.com/articles/2012/08/detecting-potential-toxicity-mitochondria

Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR) (pharmaceuticalintelligence.com)
Amyloidosis with Cardiomyopathy (pharmaceuticalintelligence.com)
Beta-Blockers, Left and Right Ventricular Function, and In-Vivo Calcium Influx in Muscular Dystrophy Cardiomyopathy (plosone.org)
Cellular Dynamics Announces Presentations at the Society of Toxicology’s 52nd Annual Meeting … (biomedreports.com)
Doctors Not Informed of Drug Side Effects During Sales Visits (healthland.time.com)
Inverted takotsubo cardiomyopathy (doctorrw.blogspot.com)
Accurate Identification and Treatment of Emergent Cardiac Events
(http://pharmaceuticalintelligence.com/2013/03/15/accurate-identification-and-treatment-of-emergent-cardiac-events/)
Predicting Drug Toxicity for Acute Cardiac Events (http://pharmaceuticalintelligence.com/2013/03/15/predicting-drug-toxicity-for-acute-cardiac-events/)

Human cardiac muscle (Photo credit: Carolina Biological Supply Company)

English: Non-sustained run of ventricular tachycardia on telemonitoring from a patient with chemotherapy-induced cardiomyopathy. (Photo credit: Wikipedia)

English: Doxorubicin 3D model Русский: Трёхмерная модель молекулы доксорубицина (Photo credit: Wikipedia)

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Amyloidosis with Cardiomyopathy

Posted in Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, International Global Work in Pharmaceutical, Liver & Digestive Diseases Research, Medical and Population Genetics, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Pharmacotherapy and Cell Activity, Pharmacotherapy of Cardiovascular Disease, Proteomics, Systemic Inflammatory Response Related Disorders, tagged AL amyloidosis, Amyloidosis, Conditions and Diseases, Familial Amyloid, FAP, health, Transthyretin, Transthyretin-related hereditary amyloidosis, TTR, United States on March 31, 2013| 11 Comments »

Amyloidosis with Cardiomyopathy

Author: Larry H Bernstein, MD, FACP

Introduction

Amyloidosis describes the various clinical syndromes that occur as a result of damage by amyloid deposits in tissues and organs throughout the body. Systemic amyloidosis is a relatively rare multisystem disease caused by the deposition of misfolded protein in various tissues and organs. The term amyloid describes the deposition in the extracellular space of certain proteins in a highly characteristic, insoluble fibrillar form. The disease entity is a disorder of misfolded or misassembled proteins. There is extracellular amyloid fiber laid down as cross β-sheets disrupting organ function, which may affect the pancreas, kidney, autonomic nervous system, the heart, and in one form causes carpal tunnel syndrome.

It may present to almost any specialty, and diagnosis is frequently delayed. Cardiac involvement is a leading cause of morbidity and mortality, especially in primary light chain (AL) amyloidosis and in both wild-type and hereditary transthyretin amyloidosis. The heart is also occasionally involved in acquired serum amyloid A type (AA) amyloidosis and other rare hereditary types. Clinical phenotype varies greatly between different types of amyloidosis, and even the cardiac presentation has a great spectrum. The incidence of amyloidosis is uncertain, but it is thought that the most frequently diagnosed AL amyloidosis has an annual incidence of 6 to 10 cases per million population in the United Kingdom and United States.

The molecular basis for this particular phenomenon came with the extensive work done on multiple myeloma, antibody structure, and light chains. In 1950, the discovery of a familial amyloid polyneuropathy was described in Portugal, and there were similar diseases in Sweden and Japan. There were 72 known variants of transthyretin (TTR) in 1995, and now there are 100. In addition, the occurance of different TTR associated variants with and without (amyloid) is found is Brazil, UK, US, Israel, Spain, France, Germany, Denmark, and Africa. The table of variants, organ damage, and geographic location is too large to place on this document. If we refer to amyloid cardiomyopathy, it is exclusively a primary amyloidopathy, not secondary to light chain disorders or an inflammatory disease. If we consider amyloidosis, we also have to consider family history, organ dysfunction, and we have to make a distinction between primary cardiac involvement, autonomic nervous system instability, and the two coexisting. Familial amyloid polyneuropathy (FAP) is an extremely debilitating and progressive disease that is only treatable by liver transplantation. Primary amyloid cardiomyopathy has been treated by heart transplant. The qualifying statement here is, it depends.

Primary and Secondary Amyloidoses

Amyloid was originally described by pathologists based on microscopy. Amyloidoses are a systemic primary or secondary disease. There are distinctions to be made based on location and type. The clinical significance of amyloid disease varies enormously, ranging from incidental asymptomatic deposits to localized disease through to rapidly fatal systemic forms that can affect multiple vital organs.

Common causes of secondary amyloidosis are – light chain production (AL) as in plasma cell dyscrasia, amyloid A (AA), senile systemic amyloidosis (diagnosed rarely in life). The systemic amyloidoses are designated by a capital A (for amyloid) followed by the abbreviation for the chemical identity of the fibril protein. Thus, TTR amyloidosis is abbreviated ATTR, and immunoglobulin light chain type amyloidosis is abbreviated AL. Both normal-sequence TTR and variant-sequence TTR form amyloidosis. Normal-sequence TTR forms cardiac amyloidosis in elderly people, termed senile cardiac amyloidosis (SCA). When it was recognized that SCA is often accompanied by microscopic deposits in many other organs, the alternative name senile systemic amyloidosis (SSA) was proposed. Both terms are now used.

Currently available therapy is focused on reducing the supply of the respective amyloid fibril precursor protein and supportive medical care, which together have greatly improved survival. Chemotherapy and anti-inflammatory treatment for the disorders that underlie AL and AA amyloidosis are guided by serial measurements of the respective circulating amyloid precursor proteins, i.e. serial serum free light chains in AL and serum amyloid A protein in AA type.

Quality of life and prognosis of some forms of hereditary systemic amyloidosis can be improved by liver and other organ transplants. Various new therapies, ranging from silencing RNA, protein stabilizers to monoclonal antibodies, aimed at inhibiting fibril precursor supply, fibril formation or the persistence of amyloid deposits, are in development; some are already in clinical phase.

Ann Clin Biochem May 2012; 49(3 ): 229-241 http://acb.2011.011225v1 49/3/229

What is transthyretin (TTR)?

TTR is a tetramer of 4 127 amino acid subunits synthesized by the liver that circulates as a transporter of thyroxin, and with retinol-binding protein, transports vitamin A. It was originally defined by the migration in electrophoresis more anodal to albumin, hence, prealbumin. It is present in cerebrospinal fluid, secreted by the choroid plexus. The TTR monomer contains 8 antiparallel beta pleated sheet domains. TTR can be found in plasma and in cerebrospinal fluid and is synthesized by the choroid plexus of the brain and, to a lesser degree, by the retina. Its gene is located on the long arm of chromosome 18 and contains 4 exons and 3 introns.

The concentration in serum can be expected to be above 20 mg/dL in a health adult, but the protein decreases by 1 mg/dL/day postoperatively, and it decreases with acute or chronic renal failure, pneumonia or sepsis, rising again with the onset of anabolism. Patients in the pulmonary intensive care unit have TTR levels that remain low for 7-10 days, but followup data for the remainder of the hospital stay or in relationship to readmission in the six months after release from hospital care was not part of the study.

A decrease in TTR is associated with the systemic inflammatory response, whereby, the liver reprioritizes the synthesis of proteins with an increase in acute phase reactants (APRs), namely, C-reactive protein (CRP) and a-1 acid glycoprotein, and decreased albumin and TTR. The inflammatory condition maintains a euthyroid status with decreased TTR because of the availability of free thyroxine in equilibrium with the lower binding protein. This has been referred to sick euthyroid status. The role in thyroxine transport is not insignificant, as chronic protein malnutrition is associated with hypothyroidism, as originally described by Prof. Yves Ingenbleek, Univ. Louis Pateur, Starsbourg, Fr. in Senegalese children with Kwashiorkor. However, the importance of TTR as a unique biomarker is not to be downgraded because of what is often refered to as “an inverted APR”.

Transthyretin was discovered to be a good reflection of the “lean body mass”, by Vernon Young, MIT, and Ingenbleek, as a result of 3 decades of study. The ratio of S:N being 1:20 in plant proteins and 1:12.5 in animal sources, is closely related to methylation reactions and sustained deficiency of S intake results in elevated homocysteine level.

What is FAP?

Familial amyloid polyneuropathy (FAP), also called transthyretin-related hereditary amyloidosis, transthyretin amyloidosis or Corino de Andrade’s disease, is an autosomal dominant neurodegenerative disease. It is a form of amyloidosis, and was first identified and described by Portuguese neurologist Mário Corino da Costa Andrade, in the 1950s.FAP is distinct from senile systemic amyloidosis (SAS), which is not inherited, and which was determined to be the primary cause of death for 70% of supercentenarians who have been autopsied.

Familial amyloid polyneuropathy (FAP) is an extremely debilitating and progressive disease that is only treatable by liver transplantation. Primary amyloid cardiomyopathy has been treated by heart transplant. The qualifying statement here is, it depends. Those patients with TTR-amyloidopathy have a specific gene substitution in the TTR gene. Consequently, there is circulation TTR, but it is not effectively involved in thyroxine transport.

Characteristics.

Usually manifesting itself between 20 and 40 years of age, it is characterized by pain, paresthesia, muscular weakness and autonomic dysfunction. In its terminal state, the kidneys and the heart are affected. FAP is characterized by the systemic deposition of amyloidogenic variants of the transthyretin protein, especially in the peripheral nervous system, causing a progressive sensory and motor polyneuropathy. The age at symptom onset, pattern of organ involvement, and disease course vary, but most mutations are associated with cardiac and/or nerve involvement. The gastrointestinal tract, vitreous, lungs, and carpal ligament are also frequently affected. When the peripheral nerves are prominently affected, the disease is termed familial amyloidotic polyneuropathy (FAP). When the heart is involved heavily but the nerves are not, the disease is called familial amyloid cardiomyopathy (FAC). Regardless of which organ is primarily targeted, the general term is simply amyloidosis-transthyretin type, abbreviated ATTR.

Genetics.

TTR mutations accelerate the process of TTR amyloid formation and are the most important risk factor for the development of clinically significant ATTR. More than 85 amyloidogenic TTR variants cause systemic familial amyloidosis. The variant TTR is mostly produced by the liver. Amyloidogenic TTR mutations destabilize TTR monomers or tetramers, allowing the molecule to more easily attain an amyloidogenic intermediate conformation. The tetramer has to dissociate into misfolded monomers to aggregate into a variety of structures including amyloid fibrils. Because most patients are heterozygotes, they deposit both mutant and wild type TTR subnits.
Familial amyloid polyneuropathy has an autosomal dominant pattern of inheritance. FAP is caused by a mutation of the TTR gene, located on human chromosome 18q12.1-11.2. A replacement of valine by methionine at position 30 (TTR V30M) is the mutation most commonly found in FAP.
The disease in the TTR V30M kindreds was termed FAP because early symptoms arose from peripheral neuropathy, but these patients actually have systemic amyloidosis, with widespread deposits often involving the heart, gastrointestinal tract, eye, and other organs.
TTR V122I: This variant, carried by 3.9% of African Americans and over 5% of the population in some areas of West Africa, increases the risk of late-onset (after age 60 years) cardiac amyloidosis. It appears to be the most common amyloid-associated TTR variant worldwide. Affected patients usually do not have peripheral neuropathy.
TTR T60A: This variant causes late-onset systemic amyloidosis with cardiac, and sometimes neuropathic, involvement. This variant originated in northwest Ireland and is found in Irish and Irish American patients.
TTR L58H: Typically affecting the carpal ligament and nerves of the upper extremities, this variant originated in Germany. It has spread throughout the United States but is most common in the mid-Atlantic region.
TTR G6S: This is the most common TTR variant, but it appears to be a neutral polymorphism not associated with amyloidosis. It is carried by about 10% of people of white European descent.

Cardiac transthyretin (TTR) amyloidosis

Cardiac amyloidosis of transthyretin fibril protein (ATTR) type is an infiltrative cardiomyopathy characterised by ventricular wall thickening and diastolic heart failure. More than 27 different precursor proteins have the propensity to form amyloid fibrils. The particular precursor protein that misfolds to form amyloid fibrils defines the amyloid type and predicts the patient’s clinical course. Several types of amyloid can infiltrate the heart, resulting in progressive diastolic and systolic dysfunction, congestive heart failure, and death. Increased access to cardiovascular magnetic resonance imaging has led to a marked increase in referrals to St George’s University of London, London (Dr. Jason Dungu) of Caucasian patients with wild-type ATTR (senile systemic) amyloidosis and Afro-Caribbean patients with the hereditary ATTR V122I type. Both subtypes present predominantly as isolated cardiomyopathy. The differential diagnosis includes cardiac amyloid light-chain (AL) amyloidosis, which has a poorer prognosis and can be amenable to chemotherapy.

Clinical Presentation

Cardiac amyloidosis, irrespective of type, presents as a restrictive cardiomyopathy characterized by progressive diastolic and subsequently systolic biventricular dysfunction and arrhythmia.1 Key “red flags” to possible systemic amyloidosis include nephrotic syndrome, autonomic neuropathy (eg, postural hypotension, diarrhea), soft-tissue infiltrations (eg, macroglossia, carpal tunnel syndrome, respiratory disease), bleeding (eg, cutaneous, such as periorbital, gastrointestinal), malnutrition/cachexia and genetic predisposition (eg, family history, ethnicity). Initial presentations may be cardiac, with progressive exercise intolerance and heart failure. Other organ involvement, particularly in AL amyloidosis, may cloud the cardiac presentation (eg, nephrotic syndrome, autonomic neuropathy, pulmonary or bronchial involvement). Pulmonary edema is not common early in the disease process, but pleural and pericardial effusions and atrial arrhythmias are often seen. Syncope is common and a poor prognostic sign. It is typically exertional or postprandial as part of restrictive cardiomyopathy, sensitivity to intravascular fluid depletion from loop diuretics combined with autonomic neuropathy, or conduction tissue involvement (atrioventricular or sinoatrial nodes) or ventricular arrhythmia. The latter may rarely cause recurrent syncope. Disproportionate septal amyloid accumulation mimicking hypertrophic cardiomyopathy with dynamic left ventricular (LV) outflow tract obstruction is rare but well documented. Myocardial ischemia can result from amyloid deposits within the microvasculature. Atrial thrombus is common, particularly in AL amyloidosis

Diagnosis and Treatment

imaging – Cardiovascular Magnetic Resonance in Cardiac Amyloidosis*.

Cardiac amyloidosis can be diagnostically challenging. Cardiovascular magnetic resonance (CMR) can assess abnormal myocardial interstitium. In cardiac amyloidosis, CMR shows a characteristic pattern of global subendocardial late enhancement coupled with abnormal myocardial and blood-pool gadolinium kinetics. The findings agree with the transmural histological distribution of amyloid protein and the cardiac amyloid load.

*AM Maceira; J Joshi; SK Prasad; J Charles Moon, et al. Royal Brompton Hospital, London;

The diagnosis of amyloidosis requires histological identification of amyloid deposits. Congo Red staining renders amyloid deposits salmon pink by light microscopy, with a characteristic apple green birefringence under polarized light conditions. Additional immunohistochemical staining for precursor proteins identifies the type of amyloidosis. Ultimately, immunogold electron microscopy and mass spectrometry confer the greatest sensitivity and specificity for amyloid typing.

Treatment of cardiac amyloidosis is dictated by the amyloid type and degree of involvement. Consequently, early recognition and accurate classification are essential.

Novel diagnostic and surveillance approaches using imaging (echocardiography, cardiovascular magnetic resonance), biomarkers (brain natriuretic peptide [BNP], high-sensitivity troponin), new histological typing techniques, and current and future treatments, including approaches directly targeting the amyloid deposits.

Etiology

Amyloidosis is caused by the extracellular deposition of autologous protein in an abnormal insoluble β-pleated sheet fibrillary conformation—that is, as amyloid fibrils. More than 30 proteins are known to be able to form amyloid fibrils in vivo, which cause disease by progressively damaging the structure and function of affected tissues. Amyloid deposits also contain minor nonfibrillary constituents, including serum amyloid P component (SAP), apolipoprotein E, connective tissue components (glycosaminoglycans, collagen), and basement membrane components (fibronectin, laminin). Amyloid deposits can be massive, and cardiac or other tissues may become substantially replaced. Amyloid fibrils bind Congo red stain, yielding the pathognomonic apple-green birefringence under cross-polarized light microscopy that remains the gold standard for identifying amyloid deposits.

Heart 2012;98:1546-1554 http://dx.doi.org/10.1136/heartjnl-2012-301924

AL Amyloidosis

AL amyloidosis is caused by deposition of fibrils composed of monoclonal immunoglobulin light chains and is associated with clonal plasma cell or other B-cell dyscrasias. The spectrum and pattern of organ involvement is very wide, but cardiac involvement occurs in half of cases and is sometimes the only presenting feature. Cardiac AL amyloidosis may be rapidly progressive. Low QRS voltages, particularly in the limb leads, are common. Thickening of the LV wall is typically mild to moderate and is rarely >18 mm even in advanced disease. Cardiac AL amyloid deposition is accompanied by marked elevation of the biomarkers BNP and cardiac troponin, even at an early stage. Involvement of the heart is the commonest cause of death in AL amyloidosis and is a major determinant of prognosis; without cardiac involvement, patients with AL amyloidosis have a median survival of around 4 years, but the prognosis among affected patients with markedly elevated BNP and cardiac troponin (Mayo stage III disease) is on the order of 8 months.

Hereditary Amyloidoses

Mutations in several genes, such as transthyretin, fibrinogen, apolipoprotein A1, and apolipoprotein A2 can be responsible for hereditary amyloidosis, but by far the most common cause is variant ATTR amyloidosis (variant ATTR) caused by mutations in the transthyretin gene causing neuropathy and, often, cardiac involvement.

TTR gene mutation

The most common is the Val122Ile mutation. In a large autopsy study that included individuals with cardiac amyloidosis, the TTR Val122Ile allele was present in 3.9% of all African Americans and 23% of African Americans with cardiac amyloidosis. Penetrance of the mutation is not truly known and is associated with a late-onset cardiomyopathy that is indistinguishable from senile cardiac amyloidosis.

Pathology, Presentation, and Management of Amyloidoses

More than 100 genetic variants of TTR are associated with amyloidosis. Most present as the clinical syndrome of progressive peripheral and autonomic neuropathy. Unlike wild-type ATTR or variant ATTR Val122Ile, the features of other variant ATTR include vitreous amyloid deposits or, rarely, deposits in other organs. Cardiac involvement in variant ATTR varies by mutations and can be the presenting or indeed the only clinical feature. For example, cardiac involvement is rare in variant ATTR associated with Val30Met (a common variant in Portugal or Sweden), but it is almost universal and develops early in individuals with variant ATTR due to Thr60Ala mutation (a mutation common in Ireland).

Senile Systemic Amyloidosis (Wild-Type ATTR)

Wild-type TTR amyloid deposits are found at autopsy in about 25% of individuals >80 years of age. The prevalence of wild-type TTR deposits leading to the clinical syndrome of wild-type ATTR cardiac amyloidosis is unknown. Wild-type ATTR is a predominantly cardiac disease, and the only other significant extracardiac feature is a history of carpal tunnel syndrome, often preceding heart failure by 3 to 5 years. Extracardiac involvement is most unusual.

Both wild-type ATTR and ATTR due to Val122Ile are diseases of the >60-year age group and are often misdiagnosed as hypertensive heart disease. Wild-type ATTR has a strong male predominance, and the natural history remains poorly understood, but studies suggest a median survival of about 7 years from presentation. Recent developments in cardiac magnetic resonance (CMR), which have greatly improved detection of cardiac amyloid during life, suggest that wild-type ATTR is more common than previously thought: It accounted for 0.5% of all patients seen at the UK amyloidosis center until 2001 but now accounts for 7% of 1100 cases with amyloidosis seen since the end of 2009. There appears to be an association between wild-type ATTR and history of myocardial infarctions, G/G (Val/Val) exon 24 polymorphism in the alpha2-macroglobulin (alpha2M), and the H2 haplotype of the tau gene36; the association of tau with Alzheimer’s disease raises interesting questions as both are amyloid-associated diseases of aging.

Figure 1 http://jaha.ahajournals.org/content/1/2/e000364/F1.small.gif

ECG of a patient with cardiac AL amyloidosis showing small QRS voltages (defined as ≤6 mm height), predominantly in the limb leads and pseudoinfarction pattern in the anterior leads.

Echocardiography is characteristic. Typical findings include concentric ventricular thickening with right ventricular involvement, poor biventricular long-axis function with normal/near-normal ejection fraction and valvular thickening (particularly in wild-type or variant ATTR). Diastolic dysfunction is the earliest echocardiographic abnormality and may occur before cardiac symptoms develop. Biatrial dilatation in presence of biventricular, valvular, and interatrial septal thickening 53 is a useful clue to the diagnosis.

Figure 2 http://jaha.ahajournals.org/content/1/2/e000364/F2.medium.gif

Transthoracic echocardiogram with speckle tracking. The red and yellow lines represent longitudinal motion in the basal segments, whereas the purple and green lines represent apical motion. This shows loss of longitudinal ventricular contraction at the base compared to apex.

Biomarkers.

High-sensitivity troponin is abnormal in >90% of cardiac AL patients, and the combination of BNP/NT-proBNP plus troponin measurements is used to stage and risk-stratify patients with AL amyloidosis at diagnosis. Very interestingly, the concentration of BNP/NT-proBNP in AL amyloidosis may fall dramatically within weeks after chemotherapy that substantially reduces the production of amyloidogenic light chains. The basis for this very rapid phenomenon, which is not mirrored by changes on echocardiography or CMR, remains uncertain, but a substantial fall is associated with improved outcomes.

Cardiac Magnetic Resonance.

CMR provides functional and morphological information on cardiac amyloid in a similar way to echocardiography, though the latter is superior for evaluating and quantifying diastolic abnormalities. An advantage of CMR is in myocardial tissue characterization. Amyloidotic myocardium reveals subtle precontrast abnormalities (T1, T2), but extravascular contrast agents based on chelated gadolinium provide the key information.

Figure 3 http://jaha.ahajournals.org/content/1/2/e000364/F3.small.gif

CMR with the classic amyloid global, subendocardial late gadolinium enhancement pattern in the left ventricle with blood and mid-/epimyocardium nulling together.

Recently, the technique of equilibrium contrast CMR has demonstrated much higher extracellular myocardial volume in cardiac amyloid than any other measured disease. It is anticipated that accurate measurements of the expanded interstitium in amyloidosis will prove useful in serial quantification of cardiac amyloid burden.

Figure 4 http://jaha.ahajournals.org/content/1/2/e000364/F4.small.gif

Sequential static images from a CMR TI scout sequence. As the inversion time (TI) increases, myocardium nulls first (arrow in image 3), followed by blood afterwards (arrow in image 6), implying that there is more gadolinium contrast in the myocardium than blood—a degree of interstitial expansion such that the “myocrit” is smaller than the hematocrit.

Tissue biopsy.

To confirm amyloidosis, including familial TTR amyloidosis, the demonstration of amyloid deposition on biopsied tissues is essential. With Congo red staining, amyloid deposits show a characteristic yellow-green birefringence under polarized light. Tissues suitable for biopsy include: subcutaneous fatty tissue of the abdominal wall, skin, gastric or rectal mucosa, sural nerve, and peritendinous fat from specimens obtained at carpal tunnel surgery. Sensitivity of endoscopic biopsy of gastrointestinal mucosa is around 85%; biopsy of the sural nerve is less sensitive. It is ideal to show that these amyloid deposits are specifically immunolabeled by anti-TTR antibodies.

Serum variant TTR protein.

TTR protein normally circulates in serum or plasma as a soluble protein having a tetrameric structure [Kelly 1998, Rochet & Lansbury 2000]. Normal plasma TTR concentration is 20-40 mg/dL (0.20-0.40 mg/mL). Pathogenic mutations in TTR cause conformational change in the TTR protein molecule, disrupting the stability of the TTR tetramer, which is then more easily dissociated into pro-amyloidogenic monomers.

After immunoprecipitation with anti-TTR antibody, serum variant TTR protein can be detected by mass spectrometry. Approximately 90% of TTR variants so far identified are confirmed by this method. Mass shift associated with each variant TTR protein is indicated.

Molecular genetic testing.

TTR is the only gene in which mutations are known to cause familial TTR amyloidosis.
Identified in many individuals of different ethnic backgrounds; found in large clusters in Portugal, Sweden, and Japan.
The gene has four exons; and all the hitherto-identified mutations are in exons 2, 3, or 4.

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory.

Molecular genetic testing of TTR by sequence analysis (may be preceded by targeted mutation analysis)
Although deletion/duplication testing is available clinically, no exonic or whole-gene deletions or duplications involving TTR have been reported to cause familial transthyretin amyloidosis.
However, with newly available deletion/duplication testing methods, it is theoretically possible that such mutations may be identified in affected individuals in whom prior testing by sequence analysis of the entire coding region was negative.
Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Familial euthyroid hyperthyroxinemia is caused by normal allelic variants in TTR, including Gly6Ser, Ala109Thr, Ala109Val, and Thr119Met (see Table 5) [Nakazato 1998, Benson 2001, Saraiva 2001]. The TTR protein binds approximately 15% of serum thyroxine. These mutations increase total serum thyroxine concentration because of their increased affinity for thyroxine, however, they increase neither free thyroxine nor free triiodothyronine. Therefore, individuals with these sequence variants develop no clinical symptoms (i.e., they are euthyroid).

Senile systemic amyloidosis (SSA; previously called senile cardiac amyloidosis) results from the pathologic deposition of wild-type TTR, predominantly in the heart. Pathologic deposits are also seen in the lungs, blood vessels, and the renal medulla of the kidneys [Westermark et al 2003]. SSA affects mainly the elderly but is rarely diagnosed during life.

Sensorimotor neuropathy and autonomic neuropathy progress over ten to 20 years. Various types of cardiac conduction block frequently appear. Cachexia is a common feature at the late stage of the disease. Affected individuals usually die of cardiac failure, renal failure, or infection.

Cardiac amyloidosis.

Cardiac amyloidosis, mainly characterized by progressive cardiomyopathy, has been reported with more than two thirds of TTR mutations. In some families with specific TTR mutations, such as Asp18Asn, Val20Ile, Pro24Ser, Ala45Thr, Ala45Ser, His56Arg, Gly57Arg, Ile68Leu, Ala81Thr, Ala81Val, His88Arg, Glu92Lys, Arg103Ser, Leu111Met, or Val122Ile, cardiomyopathy without peripheral neuropathy is a main feature of the disease.

Cardiac amyloidosis is usually late onset. Most individuals develop cardiac symptoms after age 50 years; cardiac amyloidosis generally presents with restrictive cardiomyopathy. The typical electrocardiogram shows a pseudoinfarction pattern with prominent Q wave in leads II, III, aVF, and V1-V3, presumably resulting from dense amyloid deposition in the anterobasal or anteroseptal wall of the left ventricle. The echocardiogram reveals left ventricular hypertrophy with preserved systolic function. The thickened walls present “a granular sparkling appearance.”

Among the mutations responsible for cardiac amyloidosis, Val122Ile is notable for its prevalence in African Americans. Approximately 3.0%-3.9% of African Americans are heterozygous for Val122Ile . The high frequency of Val122Ile partly explains the observation that in individuals in the US older than age 60 years, cardiac amyloidosis is four times more common among blacks than whites.

Leptomeningeal (oculoleptomeningeal) amyloidosis.

Amyloid deposition is seen in the pial and arachnoid membrane, as well as in the walls of vessels in the subarachnoid space associated with TTR mutations including Leu12Pro, Asp18Gly, Ala25Thr, Val30Gly, Ala36Pro, Gly53Glu, Gly53Ala, Phe64Ser, Tyr69His, or Tyr114Cys. Individuals with leptomeningeal amyloidosis show CNS signs and symptoms including: dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage. When associated with vitreous amyloid deposits, leptomeningeal amyloidosis is known as familial oculolepto-meningeal amyloidosis (FOLMA). In leptomeningeal amyloidosis protein concentration in the cerebrospinal fluid is usually high, and gadolinium-enhanced MRI typically shows extensive enhancement of the surface of the brain, ventricles, and spinal cord.

Genotype-Phenotype Correlations.

In subsets of families with the Val30Met mutation, considerable variation in phenotypic manifestations and age of onset is observed. It is hypothesized that genetic modifiers and non-genetic factors contribute to the pathogenesis and progression of familial TTR amyloidosis. The vast majority of individuals with familial TTR amyloidosis are heterozygous for a TTR mutation. It has been clinically and experimentally demonstrated that the normal allelic variant c.416C>T (Thr119Met) has a protective effect on amyloidogenesis in individuals who have the Val30Met mutation.

Cardiac amyloidosis is caused by Asp18Asn, Val20Ile, Pro24Ser, Ala45Thr, Ala45Ser, His56Arg, Gly57Arg, Ile68Leu, Ala81Thr, Ala81Val, His88Arg, Glu92Lys, Arg103Ser, Leu111Met, or Val122Ile. Peripheral and autonomic neuropathy are absent or less evident in persons with these mutations.

Leptomeningeal amyloidosis is associated with Leu12Pro, Asp18Gly, Ala25Thr, Val30Gly, Ala36Pro, Gly53Glu, Gly53Ala, Phe64Ser, Tyr69His, or Tyr114Cys.

Penetrance.

It is generally accepted that the penetrance is much higher in individuals in endemic foci than outside of endemic foci. In Portugal, cumulative disease risk in individuals with the Val30Met mutation is estimated at 80% by age 50 and 91% by age 70 years, whereas the risk in French heterozygotes is 14% by age 50 and 50% by age 70 years. In Sweden, the penetrance is much lower: 1.7% by age 30, 5% by age 40, 11% by age 50, 22% by age 60, 36% by age 70, 52% by age 80, and 69% by age 90, respectively.

Nomenclature

The neuropathy associated with TTR mutations, now called familial TTR amyloidosis, was formerly referred to as one of the following:

Familial amyloid polyneuropathy type I (or the Portuguese-Swedish-Japanese type)
Familial amyloid polyneuropathy type II (or the Indiana/Swiss or Maryland/German type)

Prevalence

The Val30Met mutation, found worldwide, is the most widely studied TTR variant and is responsible for the well-known large foci of individuals with TTR amyloid polyneuropathy in Portugal, Sweden, and Japan. Numerous families with various non-Val30Met mutations have also been identified worldwide.

Small transthyretin (TTR) ligands as possible therapeutic agents in TTR amyloidoses.

Almeida MR, Gales L, Damas AM, Cardoso I, Saraiva MJ. Porto, Portugal.

Curr Drug Targets CNS Neurol Disord. 2005 Oct;4(5):587-96.

In transthyretin (TTR) amyloidosis TTR variants deposit as amyloid fibrils giving origin, in most cases, to peripheral polyneuropathy, cardiomyopathy, carpal tunnel syndrome and/or amyloid deposition in the eye. The amino acid substitutions in the TTR variants destabilize the tetramer, which may dissociate into non native monomeric intermediates that aggregate and polymerize in amyloid fibrils that further elongate. Since this is a multi-step process there is the possibility to impair TTR amyloid fibril formation at different stages of the process namely by tetramer stabilization, inhibition of fibril formation or fibril disruption. Based on the proposed mechanism for TTR amyloid fibril formation we discuss the action of some of the proposed TTR stabilizers such as derivatives of some NSAIDs (diflunisal, diclofenac, flufenamic acid, and derivatives) and the action of amyloid disrupters such as 4′-iodo-4′-deoxydoxorubicin (I-DOX) and tetracyclines. Among all these compounds, TTR stabilizers seem to be the most interesting since they would impair very early the process of amyloid formation and could also have a prophylactic effect.

Clusterin regulates transthyretin amyloidosis.

Lee KW, Lee DH, Son H, Kim YS, Park JY, et al. Gyeongnam National University, South Korea

Biochem Biophys Res Commun 2009;388(2):256-60. http://dx.doi.org/10.1016/j.bbrc.2009.07.166.

Clusterin has recently been proposed to play a role as an extracellular molecular chaperone, affecting the fibril formation of amyloidogenic proteins. The ability of clusterin to influence amyloid fibril formation prompted us to investigate whether clusterin is capable of inhibiting TTR amyloidosis. Here, we report that clusterin strongly interacts with wild-type TTR and TTR variants V30M and L55P under acidic conditions, and blocks the amyloid fibril formation of TTR variants. In particular, the amyloid fibril formation of V30M TTR in the presence of clusterin is reduced to level similar to wild-type TTR. We also demonstrated that clusterin is an effective inhibitor of L55P TTR amyloidosis, the most aggressive form of TTR diseases. The mechanism by which clusterin inhibits TTR amyloidosis appears to be through stabilization of TTR tetrameric structure.

Prognosis.

Cardiac amyloidosis in general has a poor prognosis, but this differs according to amyloid type and availability and response to therapy. Treatment may be classified as follows: supportive therapy (ie, modified heart-failure treatment including device therapy); therapies that suppress production of the respective amyloid fibril precursor protein (eg, chemotherapy in AL amyloidosis); and novel strategies to inhibit amyloid fibril formation or to directly target the amyloid deposits or stabilize the precursor protein (especially in ATTR with drugs such as tafamidis or diflunisal). Cardiac transplantation, although rarely feasible, can be very successful in carefully selected patients.

Reducing Amyloid Fibril Precursor Protein Production

Treatment of amyloidosis is currently based on the concept of reducing the supply of the respective amyloid fibril precursor protein. In AL amyloidosis, therapy is directed toward the clonal plasma cells using either cyclical combination chemotherapy or high-dose therapy with autologous stem cell transplantation.

The newer treatment options include bortezomib (a proteosome inhibitor)105 and the newer immunomodulatory drugs lenalidomide and pomalidomide. Bortezomib combinations appear to be especially efficient in amyloidosis with high rates of near-complete clonal responses, which appear to translate into early cardiac responses.106–108 Phase II (bortezomib in combination with cyclophosphamide or doxorubicin) and phase III (bortezomib, melphalan, and dexamethasone compared to melphalan and dexamethasone as front-line treatment) trials are underway.

AA amyloidosis is the only other type of amyloidosis in which production of the fibril precursor protein can be effectively suppressed by currently available therapies. Anti-inflammatory therapies, such as anti-tumor necrosis factor agents in rheumatoid arthritis, can substantially suppress serum amyloid A protein production, but very little experience has been obtained regarding cardiac involvement, which is very rare in this particular type of amyloidosis.

TTR is produced almost exclusively in the liver, and TTR amyloidosis has lately become a focus for novel drug developments aimed at reducing production of TTR through silencing RNA and antisense oligonucleotide therapies. ALN-TTR01, a systemically delivered silencing RNA therapeutic, is already in phase I clinical trial. Liver transplantation has been used as a treatment for variant ATTR for 20 years, to remove genetically variant TTR from the plasma. Although this is a successful approach in ATTR Val30Met, it has had disappointing results in patients with other ATTR variants, which often involve the heart. The procedure commonly results in progressive cardiac amyloidosis through ongoing accumulation of wild-type TTR on the existing template of variant TTR amyloid. The role of liver transplantation in non-Val30Met–associated hereditary TTR amyloidosis thus remains very uncertain.

Inhibition of Amyloid Formation

Amyloid fibril formation involves massive conformational transformation of the respective precursor protein into a completely different form with predominant β-sheet structure. The hypothesis that this conversion might be inhibited by stabilizing the fibril precursor protein through specific binding to a pharmaceutical has lately been explored in TTR amyloidosis. A key step in TTR amyloid fibril formation is the dissociation of the normal TTR tetramer into monomeric species that can autoaggregate in a misfolded form. In vitro studies identified that diflunisal, a now little used nonsteroidal anti-inflammatory analgesic, is bound by TTR in plasma, and that this enhances the stability of the normal soluble structure of the protein. Studies of diflunisal in ATTR are in progress. Tafamidis is a new compound without anti-inflammatory analgesic properties that has a similar mechanism of action. Tafamidis has just been licensed for neuropathic ATTR, but its role in cardiac amyloidosis remains uncertain, and clinical trial results are eagerly awaited. Higher-affinity “superstabilizers” are also in development.

Conclusion

Cardiac amyloidosis remains challenging to diagnose and to treat. Key “red flags” that should raise suspicion include clinical features indicating multisystem disease and concentric LV thickening on echocardiography in the absence of increased voltage on ECG; the pattern of gadolinium enhancement on CMR appears to be very characteristic. Confirmation of amyloid type is now possible in most cases through a combination of immunohistochemistry, DNA analysis, and proteomics. A variety of novel specific therapies are on the near horizon, with potential to both inhibit new amyloid formation and enhance clearance of existing deposits.

Circulation 2012; 126:1286-1300 http://dx.doi.org/10.1161/CIRCULATIONAHA.111.078915

Future Prospects

Jeffery W. Kelly, the former Dean of Graduate Studies (2000-2008) and Vice President of Academic Affairs (2000-2006), currently is the Chairman of Molecular and Experimental Medicine and the Lita Annenberg Hazen Professor of Chemistry within the Skaggs Institute of Chemical Biology at The Scripps Research Institute in La Jolla, California.

The work on folding proteins by the Kelly Group focuses on

[1] understanding protein misfolding and aggregation and on developing both chemical

[2] and biological strategies

[3] to ameliorate diseases caused by protein misfolding and/or aggregation.

Besides studying the structural and energetic basis behind protein folding, his laboratory also studies the etiology of neurodegenerative diseases linked to protein aggregation, including Alzheimer’s disease, Parkinson’s Disease, and the familial gelsolin and transthyretin-based amyloidoses–publishing over 250 peer-reviewed papers in this area to date. He has also provided insight into genetic diseases associated with loss of protein function, such as lysosomal storage diseases.

Kelly has cofounded three biotechnology companies, FoldRx Pharmaceuticals (with Susan Lindquist), now owned by Pfizer, Proteostasis Therapeutics, Inc. (with Andrew Dillin and Richard Morimoto) (a private corporation) and Misfolding Diagnostics (with Xin Jiang and Justin Chapman; a private corporation). The Kelly laboratory discovered the first regulatory agency-approved drug that slows the progression of a human amyloid disease using a structure-based design approach. This drug, now called Tafamidis or Vyndaqel, slowed the progression of familial amyloid polyneuropathy in an 18 month placebo controlled trial and in an 18 month extension study sponsored by FoldRx Pharmaceuticals (acquired by Pfizer in 2010). Vyndaqel or Tafamidis was approved for the treatment of Familial amyloid Polyneuropathy by the European Medicines Agency in late 2011. Kelly also discovered that diflunisal kinetically stabilizes transthyretin, enabling a placebo controlled clinical trial with it to ameliorate familial amyloid polyneuropathy–the results of which will be announced in 2013. Proteostasis Therapeutics, Inc. is developing first-in-class drugs that adapt the proteostasis network to ameliorate both loss-of-function misfolding diseases and gain-of-toxic function diseases linked to protein aggregation.

In addition to discovering the first drug that slows the progression of a human amyloid disease, the Kelly Laboratory is credited with demonstrating that transthyretin conformational changes alone are sufficient for amyloidogenesis, discovering the first example of functional amyloid in mammals, making major contributions toward understanding β-sheet folding, discovering the “enhanced aromatic sequon”–sequences that are more efficiently glycosylated by cells and sequences which stabilize the proteins that they are incorporated into as a consequence of N-glycosylation and was corresponding author on and contributed some of the key experimental data demonstrating that altering cellular proteostasis capacity has the potential to alleviate protein misfolding and aggregation diseases.

http://www.scripps.edu/kelly/research.php?a=l&cid=3&lsc=t&lscid=23

http://www.scripps.edu/kelly/images/tsri_logo.gif

http://www.scripps.edu/kelly/photos/fig01.jpg

Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: a focus on the transthyretin amyloidoses. Johnson SM, Wiseman RL, Sekijima Y, Green NS, Adamski-Werner SL, Kelly JW. http://www.ncbi.nlm.nih.gov/pubmed/16359163

Small molecule-mediated protein stabilization inside or outside of the cell is a promising strategy to treat protein misfolding/misassembly diseases. Herein we focus on the transthyretin (TTR) amyloidoses and demonstrate that preferential ligand binding to and stabilization of the native state over the dissociative transition state raises the kinetic barrier of dissociation (rate-limiting for amyloidogenesis), slowing and in many cases preventing TTR amyloid fibril formation. Since T119M-TTR subunit incorporation into tetramers otherwise composed of disease-associated subunits also imparts kinetic stability on the tetramer and ameliorates amyloidosis in humans, it is likely that small molecule-mediated native state kinetic stabilization will also alleviate TTR amyloidoses.

Energetic characteristics of the new transthyretin variant A25T may explain its atypical central nervous system pathology.

Sekijima Y, Hammarström P, Matsumura M, Shimizu Y, Iwata M, Tokuda T, Ikeda S, Kelly JW.

Lab Invest. 2003 Mar;83(3):409-17. http://www.ncbi.nlm.nih.gov/pubmed/12649341

Transthyretin (TTR) is a tetrameric protein that must misfold to form amyloid fibrils. Misfolding includes rate-limiting tetramer dissociation, followed by fast tertiary structural changes that enable aggregation. Amyloidogenesis of wild-type (WT) TTR causes a late-onset cardiac disease called senile systemic amyloidosis. The aggregation of one of > 80 TTR variants leads to familial amyloidosis encompassing a collection of disorders characterized by peripheral neuropathy and/or cardiomyopathy. Prominent central nervous system (CNS) impairment is rare in TTR amyloidosis. Herein, we identify a new A25T TTR variant in a Japanese patient who presented with CNS amyloidosis at age 42 and peripheral neuropathy at age 44. The A25T variant is the most destabilized and fastest dissociating TTR tetramer published to date, yet, surprising, disease onset is in the fifth decade. Quantification of A25T TTR in the serum of this heterozygote reveals low levels relative to WT, suggesting that protein concentration influences disease phenotype. Another recently characterized TTR CNS variant (D18G TTR) exhibits strictly analogous characteristics, suggesting that instability coupled with low serum concentrations is the signature of CNS pathology and protects against early-onset systemic amyloidosis. The low A25T serum concentration may be explained either by impaired secretion from the liver or by increased clearance, both scenarios consistent with A25T’s low kinetic and thermodynamic stability. Liver transplantation is the only known treatment for familial amyloid polyneuropathy. This is a form of gene therapy that removes the variant protein from serum preventing systemic amyloidosis. Unfortunately, the choroid plexus would have to be resected to remove A25T from the CSF-the source of the CNS TTR amyloid. Herein we demonstrate that small-molecule tetramer stabilizers represent an attractive therapeutic strategy to inhibit A25T misfolding and CNS amyloidosis. Specifically, 2-[(3,5-dichlorophenyl)amino]benzoic acid is an excellent inhibitor of A25T TTR amyloidosis in vitro.

Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics

Per Hammarström*, R. Luke Wiseman*, Evan T. Powers, Jeffery W. Kelly†

Science 31 Jan 2003; 299(5607):713-716 http://dx.doi.org/10.1126/science.1079589

Genetic evidence suggests that inhibition of amyloid fibril formation by small molecules should be effective against amyloid diseases. Known amyloid inhibitors appear to function by shifting the aggregation equilibrium away from the amyloid state. Here, we describe a series of transthyretin amyloidosis inhibitors that functioned by increasing the kinetic barrier associated with misfolding, preventing amyloidogenesis by stabilizing the native state. The trans-suppressor mutation, threonine 119 → methionine 119, which is known to ameliorate familial amyloid disease, also functioned through kinetic stabilization, implying that this small-molecule strategy should be effective in treating amyloid diseases.

R104H may suppress transthyretin amyloidogenesis by thermodynamic stabilization, but not by the kinetic mechanism characterizing T119 interallelic trans-suppression.

Sekijima Y, Dendle MT, Wiseman RL, White JT, D’Haeze W, Kelly JW.

Amyloid. Jun 2006;13(2):57-66. http://www.ncbi.nlm.nih.gov/pubmed/16911959

The tetrameric protein transthyretin (TTR) forms amyloid fibrils upon dissociation and subsequent monomer misfolding, enabling misassembly. Remarkably, the aggregation of one of over 100 destabilized TTR variants leads to familial amyloid disease. It is known that trans-suppression mediated by the incorporation of T119M subunits into tetramers otherwise composed of the most common familial variant V30M, ameliorates disease by substantially slowing the rate of tetramer dissociation, a mechanism referred to as kinetic stabilization of the native state. R104H TTR has been reported to be non-pathogenic, and recently, this variant has been invoked as a trans-suppressor of amyloid fibril formation. Here, we demonstrate that the trans-suppression mechanism of R104H does not involve kinetic stabilization of the tetrameric structure, instead its modest trans-suppression most likely results from the thermodynamic stabilization of the tetrameric TTR structure. Thermodynamic stabilization increases the fraction of tetramer at the expense of the misfolding competent monomer decreasing the ability of TTR to aggregate into amyloid fibrils. As a consequence of this stabilization mechanism, R104H may be capable of protecting patients with modestly destabilizing mutations against amyloidosis by slightly lowering the overall population of monomeric protein that can misfold and form amyloid.

Impact of Regional Left Ventricular Function on Outcome for Patients with AL Amyloidosis (plosone.org)
Inhibition of TTR Aggregation-Induced Cell Death – A New Role for Serum Amyloid P Component (plosone.org)
Amyloid imaging shows promise for detecting cardiac amyloidosis (medicalxpress.com)
Detecting Cardiac Amyloidosis Using Amyloid Imaging (medicalnewstoday.com)

Amyloidosis, Node, Congo Red. The amyloid deposits are strongly congophilic when viewed before white light. (Photo credit: Wikipedia)

Amyloidosis (Photo credit: Boonyarit Cheunsuchon)

English: Intermed. mag. (H&E). Image:Cardiac amyloidosis high mag he.jpg (Photo credit: Wikipedia)

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Treatment for Infective Endocarditis

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Cardiac & Vascular Repair Tools Subsegment, Coagulation Therapy and Internal Bleeding, Health Economics and Outcomes Research, Infectious Disease & New Antibiotic Targets, Medical Devices R&D and Inventions, Mitral Valve: Repair and Replacement, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Systemic Inflammatory Response Related Disorders, tagged Antibacterial, Cardiovascular Disorders, Conditions and Diseases, health, Heart Failure, Heart valve, Infective endocarditis, NEJM, Staphylococcus, surgery, The New England Journal of Medicine on March 30, 2013| Leave a Comment »

Treatment for Infective Endocarditis

Curator: Larry H Bernstein, MD, FACP

UPDATED on 3/4/2019

WATCH VIDEO

https://consultqd.clevelandclinic.org/tricuspid-valve-reconstruction-for-infective-endocarditis-operative-highlights-video/amp/?__twitter_impression=true

Tricuspid Valve Reconstruction for Infective Endocarditis: Operative Highlights (Video)

There are no easy solutions for acute infective tricuspid valve endocarditis in IV drug users, as the risk of prosthetic endocarditis in this population is high. Complete valve resection without replacement is feasible but leads to progressive right-sided heart failure. Reconstruction of the tricuspid valve with autologous pericardium is an alternative option, as demonstrated in the video case study below.

A 29-year-old female drug abuser with fever, hemoptysis and MRSA bacteremia was started on IV antibiotics. She looked frail and had prominent jugular venous pressure as well as 95 percent saturation on 2 liters of nasal cannula oxygen. She was not on inotropes and had a pulmonary artery pressure of 40/20 mmHg with a good cardiac index. Chest CT showed a large left pleural effusion with associated atelectasis of the left lung. The right lung had manifestations of septic emboli and a smaller pleural effusion.

A Cleveland Clinic surgical team led by cardiothoracic surgeon Faisal Bakaeen, MD, proceeded to excise the patient’s extensive infected and devitalized tissue around the tricuspid valve, leaving only a portion of the anterior leaflet to serve as a reference for reconstruction using autologous pericardium. Dr. Bakaeen walks us through the essential surgical steps — and their underlying rationale — in the narrated operative video below.

SOURCE

https://consultqd.clevelandclinic.org/tricuspid-valve-reconstruction-for-infective-endocarditis-operative-highlights-video/amp/?__twitter_impression=true

An article that appeared in NEJM compares early surgery versus conventional treatment for infective endocarditis.
Early Surgery versus Conventional Treatment for Infective Endocarditis
Duk-Hyun Kang, Yong-Jin Kim, Sung-Han Kim, Byung Joo Sun, et al.

N Engl J Med June 28, 2012; 366:2466-2473. http://doi.org/10.1056/NEJMoa1112843

Background and Purpose: While current guidelines advocate surgical management for complicated left-sided infective endocarditis and early surgery for patients with infective endocarditis and congestive heart failure, the indications for surgical intervention to prevent systemic embolism remain unclear. Surgery is favored by experience with complete excision of infected tissue and valve repair, and low operative mortality, but it does not remove concerns about residual active infection, which results in two sets of guidelines, the 2006 ACC-AHA for class IIa indication only for recurrent emboli and persistent vegetation, and the 2009 ESC guidelines for class IIb indication for very large, isolated vegetations. The Early Surgery versus Conventional Treatment in Infective Endocarditis (EASE) trial was conducted to determine whether early surgical intervention woulddecrease rate of death or embolic events.

Patient Enrollment: The study enrolled 76 consecutive patients, 18 years of age or older, with left-sided, native-valve infective endocarditis and a high risk of embolism. For all patients with suspected infective endocarditis, blood cultures were obtained and transthoracic echocardiography was performed within 24 hours after hospitalization. Patients were only eligible for enrollment if they had received a diagnosis of definite infective endocarditis and had severe mitral valve or aortic valve disease and vegetation with a diameter greater than 10 mm. Patients were excluded if they had moderate-to-severe congestive heart failure, infective endocarditis complicated by heart block, annular or aortic abscess, destructive penetrating lesions requiring urgent surgery, or fungal endocarditis, or were over 80 years age, or coexisting major embolic stroke with a risk of hemorrhagic transformation at the time of diagnosis, and a serious coexisting condition. Patients were also excluded if they had infective endocarditis involving a prosthetic valve, right-sided vegetations, or small vegetations (diameter, ≤10 mm) or had been referred from another hospital more than 7 days after the diagnosis of infective endocarditis.
The protocol specified that patients who were assigned to the early-surgery group should undergo surgery within 48 hours after randomization. Patients assigned to the conventional-treatment group were treated according to the AHA guidelines, and surgery was performed only if complications requiring urgent surgery developed during medical treatment or if symptoms persisted after the completion of antibiotic therapy. Details of the study procedures are provided in the Supplementary Appendix, available at NEJM.org.

Study End Points: The primary end point was a composite of in-hospital death or clinical embolic events that occurred within 6 weeks after randomization. An embolic event was defined as a systemic embolism fulfilling both prespecified criteria: the acute onset of clinical symptoms or signs of embolism and the occurrence of new lesions, as confirmed by follow-up imaging studies. Prespecified secondary end points, at 6 months of follow-up, included death from any cause, embolic events, recurrence of infective endocarditis, and repeat hospitalization due to the development of congestive heart failure.

Clinical and Echocardiographic Characteristics of the Patients at Baseline, According to Treatment Group:

The mean age of the patients was 47 years, and 67% were men. The mitral valve was involved in 45 patients, the aortic valve in 22, and both valves in 9. Severe mitral regurgitation was observed in 45 patients, severe aortic regurgitation in 23, severe aortic stenosis in 3, severe mitral regurgitation and stenosis in 1, and both severe mitral regurgitation and aortic regurgitation in 4. The median diameter of vegetation was 12 mm (interquartile range, 11 to 17). All patients met the Duke criteria for definite endocarditis; the most common pathogens in both groups were viridans streptococci (in 30% of all patients), other streptococci (in 30%), and Staphylococcus aureus (in 11%). Characteristics of Antibiotic Therapy, According to Treatment Group: There were no significant between-group differences in terms of control of the underlying infection, the antibiotic regimen used, or the duration of antibiotic therapy.

Surgical Procedures: All patients in the early-surgery group underwent valve surgery within 48 hours after randomization; the median time between randomization and surgery was 24 hours (interquartile range, 7 to 45). Of the 22 patients with involvement of the mitral valve, 8 patients underwent mitral-valve repair and 14 underwent mitral-valve replacement with a mechanical valve. Of the 15 patients with involvement of the aortic valve or both the mitral and aortic valves, 14 underwent mechanical-valve replacement and 1 underwent valve replacement with a biologic prosthesis. Concomitant coronary-artery bypass grafting at the time of valve surgery was performed in 2 patients (5%).

Conventional Therapy: Of the 39 patients assigned to the conventional-treatment group, 30 (77%) underwent surgery during the initial hospitalization (27 patients) or during follow-up (3). The surgical procedures included 11 mitral-valve repairs, 6 mitral-valve replacements (with 5 patients receiving a mechanical valve and 1 a biologic prosthesis), 11 aortic-valve replacements (with 9 patients receiving a mechanical valve and 2 a biologic prosthesis), and 2 combined aortic-valve replacements (with 1 patient receiving a mechanical valve and 1 a biologic prosthesis) and mitral-valve repairs. In 8 patients (21%), indications for urgent surgery developed during hospitalization (median time to surgery after randomization, 6.5 days [interquartile range, 6 to 10]). Elective surgery was performed in an additional 22 patients owing to symptoms or left ventricular dysfunction more than 2 weeks after randomization. Surgical results are shown in the Supplementary Appendix.

Primary End Point: The primary end point of in-hospital death or embolic events within the first 6 weeks after randomization occurred in one patient (3%) in the early-surgery group, as compared with nine (23%) in the conventional-treatment group (hazard ratio, 0.10; 95% confidence interval [CI], 0.01 to 0.82; P=0.03). In the early-surgery group, one patient died in the hospital and no patients had embolic events; in the conventional-treatment group, one patient died in the hospital and eight patients had embolic events (Table 3TABLE 3).
http://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/2012/nejm_2012.366.issue-26/nejmoa1112843/production/images/small/nejmoa1112843_t3.gif

At 6 weeks after randomization, the rate of embolism was 0% in the early-surgery group, as compared with 21% in the conventional-treatment group (P=0.005). No patient in either group had an embolic event or was hospitalized for congestive heart failure during follow-up. Recurrence of infective endocarditis within 6 months after discharge was not observed in any patient in the early-surgery group but was reported in 1 patient in the conventional-treatment group. Among the 11 patients (28%) in the conventional-treatment group who were treated medically and discharged without undergoing surgery, 1 (3%) died suddenly, 7 (18%) had symptoms related to severe valve disease or recurrence of infective endocarditis (3 of whom underwent surgery during follow-up), and 3 (8%) had no symptoms or embolic events (Table S3 in the Supplementary Appendix).
There was no significant difference between the early-surgery and conventional-treatment groups in all-cause mortality at 6 months (3% and 5%, respectively; hazard ratio, 0.51; 95% CI, 0.05 to 5.66; P=0.59) (Figure 2AFIGURE 2).
http://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/2012/nejm_2012.366.issue-26/nejmoa1112843/production/images/small/nejmoa1112843_f2.gif
Kaplan–Meier Curves for the Cumulative Probabilities of Death and of the Composite End Point at 6 Months, According to Treatment Group.

At 6 months, the rate of the composite of death from any cause, embolic events, recurrence of infective endocarditis, or repeat hospitalization due to the development of congestive heart failure was 3% in the early-surgery group, as compared with 28% in the conventional-treatment group (hazard ratio, 0.08; 95% CI, 0.01 to 0.65; P=0.02). The estimated actuarial rate of end points was significantly lower in the early-surgery group than in the conventional-treatment group (P=0.009 by the log-rank test) (Figure 2B).

Conclusion: Early surgery performed within 48 hours after diagnosis reduced the composite primary end point of death from any cause or embolic events by effectively reducing the risk of systemic embolism. Moreover, these improvements in clinical outcomes were achieved without an increase in operative mortality or recurrence of infective endocarditis.

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Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel-Aviv

Posted in Cancer Prevention: Research & Programs, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, tagged American Cancer Society, Cancer - General, Centers for Disease Control and Prevention, cond, Conditions and Diseases, cost efficient cancer diagnosis, Tel Aviv Sourasky Medical Center on March 25, 2013| 7 Comments »

Cancer Screening Programs at Sourasky Medical Center’s Cancer Prevention Center in Tel-Aviv

Author: Ziv Raviv, PhD

Article-7.1.4. Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel Aviv

Cancer is one of the leading causes of death in the World. Major efforts are devoted for its eradication. There are several strategies to fighting cancer. Considerable research efforts were allocated over the last 50 years to elucidate the genetic factors causing cancer and the molecular mechanisms governing its biology for the purpose of developing anti-cancer treatments. It is important to note that cancer is a disease that environmental and life style factors play crucial role in its development.

It is accepted in the Medical community that the earlier the cancer has being detected, the greater are the odds for better prognosis and often the attainment of complete remission. Thus, it is important that more efforts should be addressed into prevention and early detection programs. Several medical centers and research institutes have set up prevention programs, among them is the integrated cancer prevention center (ICPC) of Tel-Aviv Sourasky medical center (TASMC) directed by Prof. Nadir Arber. A comprehensive cancer screening is applied by specialist physicians aimed at identification of potential cancer patients. The Screening program is supported by an integrated research laboratory, that develops and implements innovative technologies and approaches for early detection and therapy of cancer.

ICPC program is considered to be unique in the World. The Screening involves a comprehensive examination, on the spot, for the early detection of at least 11 different most common cancers taking advantage of up-to-date contemporary as well as innovative tests, which are carried out under the same roof and require a single visit taking only few hours, where results are given within few weeks. That is instead of doing separate examinations for the detection of each cancer type, a process when performed through the ordinary health care pathway could consume much of the patient time and involves several bureaucratic levels.

The cancers being tested for by the center include among others:

Skin
Colon
Breast
Lung
Ovarian
Prostate

Respectively, the screenings performed include careful body and skin examination, imaging, blood tests for cancer markers accompanied with standard clinical tests, as well as personal interview evaluating the family history and risk factors of the client. However, it is important to note that the ICPC is not restricted only to patients with known family history of cancer incidents and/or with high risk factors, rather, ICPC is providing its services to any person whom would like to be examined if having cancer. The goal of ICPC is indeed to create the atmosphere among the general public to give attitude to this screening as it is a standard process of body checkup that should be performed periodically on a regular basis. The visit at ICPC clinic consumes relatively small effort from the patient in terms of time and costs. In addition, the persons arriving to ICPC are receiving dietary as well as life style counseling. If cancer or a pre-cancerous condition is been discovered, the client is being referred for further evaluation of treatment options. Personalized approach is applied that includes performing a personal questionnaire and interview before screening as mentioned above, as well as ongoing documentation and follow-ups that are initiated after the results are obtained and shared with the patient.

The cost of this sequence of checkups and tests is seemingly expensive, and there is an impression that this is a “rich people only clinic”, too expensive for the average pocket. Yet, when thinking carefully the costs are rather low, only few hundreds of American dollars, a price which is definitely low comparing to the costs of some of these tests, and as Prof. Arber stated: “the cost is not higher than that one pays for his annual car service, so why not giving the same attention to your own body as given to your car.” The fees being paid by the patients for the screening and genetic testing are not covering the costs. However, in the long run, it is believed that this approach is worthwhile if taking in consideration the costs benefits of cancer early detection, of reducing hospitalization days and medicines prescription. Therefore, a governmental intervention should take place in the form of subsidizing the costs of the cancer screening. In addition, the various health care insurance plans should cover at least in part the fees required to be paid by the patient for this screening, thus, making the visit to the cancer prevention center affordable to every citizen.

ICPC reported that, around 10 percent of people following the screening protocol, were found to be carrying premature tumors, emphasizing the importance of the existence of such a preventive center. Now it is remained to evaluate if the program is being accepted broadly by the general public. PR is needed in order to support public awareness to this program. It is important to note that aside from rising public responsiveness for the existence of ICPC, overcoming psychological barriers is another issue that requires attention on as many people do not like to “know what the future holds” especially when it comes to diseases.

ICPC, a cancer prevention center located within a major hospital, integrates specialized medical doctors with state of the art facilities, performing comprehensive tests for cancer detection in an intensive one-day visit, is unique and very important for performing a good cancer prevention program. The ICPC and other similar prevention centers (see references) should give example for other medical centers around the globe willing to adopt the approach of cancer prevention in the ongoing battle against cancer. The more centers as such will exist, the greater are the chances for early Cancer detection and increase the potential of significantly reducing the rate of cancer incidences worldwide.

REFERENCES:

http://www.tasmc.org.il/sites/en/internalmed/ICPC/Pages/ICPC.aspx

MD Anderson Cancer Prevention Center

St. Joseph Hospital cancer programs Related article on this Open Access Online Scientific Journal, include the following:

http://pharmaceuticalintelligence.com/2013/03/07/the-importance-of-cancer-prevention-programs-new-perceptions-for-fighting-cancer/

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Posts Tagged ‘Conditions and Diseases’

Pros and Cons of Drug Stabilizers for Arterial Elasticity as an Alternative or Adjunct to Diuretics and Vasodilators in the Management of Hypertension.

Conceptual development of the subject is presented in the following nine parts:

1. Physiology of Circulation and Role of Arterial Elasticity

2. Isolated Systolic Hypertension caused by Arterial Stiffening may be inadequately treated by Diuretics or Vasodilatation Antihypertensive Medications

3. Physiology of Circulation and Compensatory Mechanism of Arterial Elasticity

Reduced volume (diuretics)

Increased vascular space (vasodilation)

Reduced pulsatile force (beta blockers)

Angiotensin-converting enzyme (ACE) inhibitors

Angiotensin II receptor blockers

Compensatory Effects in the Physiology of Circulation

Cardiac Circulation Dynamics

Aging and Vasculature Diminished Elasticity

Aging and Myocardial Diminished Contractility and Ejection Fraction

Increased Arterial Elasticity – Potential Risk to Myocardium

4. Vascular Compliance – The Potential of Noval Therapies

Novel Mechanism for Disease Etiology for the Cardiac Phenotype: Modulation of Nuclear and Cytoskeletal Actin Polymerization.

Genetic Therapy to Conductivity Disease

Regenerative Medicine for Vasculature Function Protection

5. Stabilizing BP Variability is the next Big Target in Hypertension Management

Hypertension caused by Arterial Stiffening is Ineffectively Treated by Diuretics and Vasodilatation Antihypertensives

The Goal of Stabilizing BP variability

June 29, 2010 Lisa Nainggolan

6. Mathematical Modeling: Arterial stiffening provides sufficient explanation for primary hypertension

7. Classification of Blood Pressure and Hypertensive Treatment:

Best Practice of Care in the US

8. Genetic Risk for High Blood Pressure

Blood Pressure Single-Nucleotide Polymorphisms and Coronary Artery Sisease (page 995)

Masked Hypertension in Diabetes Mellitus (page 964)

Genetic Risk Score for Blood Pressure (page 987)

Related Articles on Genetics and Blood Pressure

9. Is it Hypertension or Physical Inactivity: Cardiovascular Risk and Mortality – New results in 3/2013.

Estimating the effect of long-term physical activity on cardiovascular disease and mortality: evidence from the Framingham Heart Study

Abstract

Summary – PENDING

Other related articles were published on this Open Access Online Scientific Journal including the following:

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Ultrasound-based Screening for Ovarian Cancer

Abstract

Objectives

Methods

Results

Conclusions

Other research papers related to the management of Prostate cancer were published on this Scientific Web site:

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Risk of a Second Primary Cancer after Non-melanoma Skin Cancer in White Men and Women: A Prospective Cohort Study

Abstract

Background

Methods and Findings

Conclusion

Editors’ Summary

Background

Why Was This Study Done?

What Did the Researchers Do and Find?

What Do These Findings Mean?

Additional Information

Introduction

Methods

Ethics Statement

Study Population

Identification of NMSC and Other Primary Cancers

Assessment of Covariates

Statistical Analysis

Results

Discussion

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Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease

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Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer

Other articles/postings related to this topic and HIV on this site includes:

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Mitochondrial Dysfunction and Cardiac Disorders

Mitochondrial Metabolism in Impaired Cardiac Function

Mitochondrial Dysfunction and the Heart

Characterization of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes:
Bioenergetics and Utilization in Safety Screening.

Cardiovascular Events After Clarithromycin Use in Lower Respiratory Tract Infections
Analysis of Two Prospective Cohort Studies