Feeds:
Posts
Comments

Posts Tagged ‘vasodilation’


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  (Eadyn relates volume variation (VVS) to pressure variation (PPV): Eadyn=PPV/SVV
    • PPV(%) = 100% × (PPmax − PPmin)/[(PPmax + PPmin)/2)]
      • where PPmax and PPmin are the maximum and minimum pulse pressures determined during a single  respiratory cycle
    • SVV(%) = 100% × [(SVmax − SVmin)/SVmean]
      • where SVmax and SVmin  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

3. Physiology of Circulation and Compensatory Mechanism of Arterial Elasticity

Antihypertensive agents have focused on the following approaches:

  1. 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.
  2. 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.0503723102http://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

https://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

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

and

https://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.

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

and

https://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

https://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.

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

and

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

and

https://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:

https://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.

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

and

https://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

Chin Yee Ho,

Diana E. Jaalouk,

Maria K. Vartiainen

Jan Lammerding

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 LmnaN195K/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 LmnaN195K/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

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

  • Regenerative Medicine for Vasculature Function Protection

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

and

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

and

https://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  

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. PettersenScott M. BugenhagenJavaid NaumanDaniel A. BeardStig 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

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.

Related Articles on Genetics and Blood Pressure

Genetic Predisposition to Higher Blood Pressure Increases Coronary Artery Disease Risk

  • Wolfgang Lieb,
  • Henning Jansen,
  • Christina Loley,
  • Michael J. Pencina,
  • Christopher P. Nelson,
  • Christopher Newton-Cheh,
  • Sekar Kathiresan,
  • Muredach P. Reilly,
  • Themistocles L. Assimes,
  • Eric Boerwinkle,
  • Alistair S. Hall,
  • Christian Hengstenberg,
  • Reijo Laaksonen,
  • Ruth McPherson,
  • Unnur Thorsteinsdottir,
  • Andreas Ziegler,
  • Annette Peters,
  • John R. Thompson,
  • Inke R. König,
  • Jeanette Erdmann,
  • Nilesh J. Samani,
  • Ramachandran S. Vasan,
  • andHeribert Schunkert
  • , on behalf of CARDIoGRAM

Hypertension. 2013;61:995-1001, published online before print March 11 2013,doi:10.1161/HYPERTENSIONAHA.111.00275

Masked Hypertension in Diabetes Mellitus: Treatment Implications for Clinical Practice

  • Stanley S. Franklin,
  • Lutgarde Thijs,
  • Yan Li,
  • Tine W. Hansen,
  • José Boggia,
  • Yanping Liu,
  • Kei Asayama,
  • Kristina Björklund-Bodegård,
  • Takayoshi Ohkubo,
  • Jørgen Jeppesen,
  • Christian Torp-Pedersen,
  • Eamon Dolan,
  • Tatiana Kuznetsova,
  • Katarzyna Stolarz-Skrzypek,
  • Valérie Tikhonoff,
  • Sofia Malyutina,
  • Edoardo Casiglia,
  • Yuri Nikitin,
  • Lars Lind,
  • Edgardo Sandoya,
  • Kalina Kawecka-Jaszcz,
  • Jan Filipovský,
  • Yutaka Imai,
  • Jiguang Wang,
  • Hans Ibsen,
  • Eoin O’Brien,
  • and Jan A. Staessen
  • , on behalf of the International Database on Ambulatory blood pressure in relation to Cardiovascular Outcomes (IDACO) Investigators

Hypertension. 2013;61:964-971, published online before print March 11 2013,doi:10.1161/HYPERTENSIONAHA.111.00289

A Blood Pressure Genetic Risk Score Is a Significant Predictor of Incident Cardiovascular Events in 32 669 Individuals

  • Aki S. Havulinna,
  • Johannes Kettunen,
  • Olavi Ukkola,
  • Clive Osmond,
  • Johan G. Eriksson,
  • Y. Antero Kesäniemi,
  • Antti Jula,
  • Leena Peltonen,
  • Kimmo Kontula,
  • Veikko Salomaa,
  • and Christopher Newton-Cheh

Hypertension. 2013;61:987-994, published online before print March 18 2013,doi:10.1161/HYPERTENSIONAHA.111.00649

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

  1. Susan M Shortreed1,2,
  2. Anna Peeters1,3,
  3. Andrew B Forbes1

+Author Affiliations


  1. 1Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia

  2. 2Biostatistics Unit, Group Health Research Institute, Seattle, Washington, USA

  3. 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
1. Kannel WB, Gordan T (1978) Evaluation of cardiovascular risk in the elderly: the Framingham study. Bull N Y Acad Med 54:573–591.
2. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D (1999) Is pulse pressure useful in predicting risk for coronary heart disease?: The Framingham Heart Study. Circulation 100:354–360.
3. Mitchell GF et al. (2010) Hemodynamic Correlates of Blood Pressure Across the Adult Age Spectrum: Noninvasive Evaluation in the Framingham Heart Study. Circulation 122:1379–1386.
4. Khattar RS, Swales JD, Dore C, Senior R, Lahiri A (2001) Effect of Aging on the Prognostic Significance of Ambulatory Systolic, Diastolic, and Pulse Pressure in Essential Hypertension. Circulation 104:783–789.
5. Franklin SS et al. (1997) Hemodynamic patterns of age-related changes in blood pressure: the Framingham Heart Study. Circulation 96:308.
6. Guyenet PG (2006) The sympathetic control of blood pressure. Nat Rev Neurosci 7:335–346.
7. Monahan KD (2007) Effect of aging on baroreflex function in humans. Am J Physiol Regul Integr Comp Physiol 293:R3–R12.
8. Zieman SJ (2005) Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness. Arterioscler Thromb Vasc Biol 25:932–943.
9. McVeigh GE, Bank AJ, Cohn JN (2007) Arterial compliance. Cardiovasc Med:1811–1831.
10. Guyton AC (1991) Blood pressure control–special role of the kidneys and body fluids. Science 252:1813–1816.
11. Smith BW, Chase JG, Nokes RI, Shaw GM, Wake G (2004) Minimal haemodynamic system model including ventricular interaction and valve dynamics. Med Eng Phys 26:131–139.
12. Smith BW, Geoffrey Chase J, Shaw GM, Nokes RI (2005) Experimentally verified minimal cardiovascular system model for rapid diagnostic assistance. Control Eng Pract 13:1183–1193.13. Bugenhagen SM, Cowley AW, Beard DA (2010) Identifying physiological origins of baroreflex dysfunction in salt-sensitive hypertension in the Dahl SS rat. Physiol Genomics 42:23–41.14. Beard DA et al. (2012) Multiscale Modeling and Data Integration in the Virtual Physiological Rat Project. Ann Biomed Eng.15. King AL (1946) Pressure-Volume Relation for Cylindrical Tubes with Elastomeric Walls: The Human Aorta. J Appl Phys 17:501.16. Dayan P, Abbott LF (2001) Theoretical Neuroscience: Computational and Mathematical Modeling of Neural Systems (Computational Neuroscience) (The MIT Press). 1st Ed.17. Andresen MC, Krauhs JM, Brown AM (1978) Relationship of aortic wall and baroreceptor properties during development in normotensive and spontaneously hypertensive rats. Circ Res 43:728–738.18. Hallock P, Benson IC (1937) Studies on the elastic properties of human isolated aorta. J Clin Invest 16:595–602.19. Coffman TM (2011) Under pressure: the search for the essential mechanisms of hypertension. Nat Med 17:1402–1409.20. Proctor DN et al. (1998) Influence of age and gender on cardiac output-V O 2 relationships during submaximal cycle ergometry. J Appl Physiol 84:599–605.21. Fagard R, Thijs L, AMERY A (1993) Age and the Hemodynamic Response to Posture and Exercise. Am J Geriatr Cardiol 2:23–40.22. Stratton JR, Levy WC, Cerqueira MD, Schwartz RS, Abrass IB (1994) Cardiovascular responses to exercise. Effects of aging and exercise training in healthy men. Circulation 89:1648–1655.23. Holmen J et al. (2003) The Nord-Trøndelag Health Study 1995–97 (HUNT 2): objectives, contents, methods and participation. Norsk epidemiologi 13:19–32.24. Chobanian AV et al. (2003) The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 289:2560–2572.25. Cowley AW, LIARD JF, Guyton AC (1973) Role of the Baroreceptor Reflex in Daily Control of Arterial Blood Pressure and Other Variables in Dogs. Circ Res 32:564–576.26. Schreihofer AM, Sved AF (1992) Nucleus tractus solitarius and control of blood pressure in chronic sinoaortic denervated rats. Am J Physiol 263:R258–66.27. Ito S, Sved AF (1997) Influence of GABA in the nucleus of the solitary tract on blood pressure in baroreceptor-denervated rats. Am J Physiol Regul Integr Comp Physiol 273:R1657–R1662.28. Thrasher TN (2004) Baroreceptors, baroreceptor unloading, and the long-term control of blood pressure. Am J Physiol Regul Integr Comp Physiol 288:R819– R827.29. Monahan KD et al. (2001) Age-associated changes in cardiovagal baroreflex sensitivity are related to central arterial compliance. Am J Physiol Heart Circ Physiol 281:H284–H289.30. Malpas S (2009) Editorial comment: Montani versus Osborn exchange of views. Experimental Physiology 94:381–382.31. Mori T et al. (2008) High Perfusion Pressure Accelerates Renal Injury in Salt-Sensitive Hypertension. Journal of the American Society of Nephrology 19:1472–1482.32. Beard DA, Mescam M (2012) Mechanisms of pressure-diuresis and pressurenatriuresis in Dahl salt-resistant and Dahl salt-sensitive rats. BMC Physiol 12:6.33. Iliescu R, Irwin ED, Georgakopoulos D, Lohmeier TE (2012) Renal Responses to Chronic Suppression of Central Sympathetic Outflow. Hypertension 60:749–756.34. Krum H et al. (2009) Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 373:1275–1281.35. Mahfoud F et al. (2012) Renal Hemodynamics and Renal Function After Catheter-Based Renal Sympathetic Denervation in Patients With Resistant Hypertension. Hypertension 60:419–424.36. Vink EE, Blankestijn PJ (2012) Evidence and Consequences of the Central Role of the Kidneys in the Pathophysiology of Sympathetic Hyperactivity. Front Physio 3.37. Cowley A Jr (1992) Long-term control of arterial blood pressure. Physiol Rev 72:231–300.38. Mancia G, Ludbrook J, Ferrari A, Gregorini L, Zanchetti A (1978) Baroreceptor reflexes in human hypertension. Circ Res 43:170–177.39. Kaess BM et al. (2012) Aortic stiffness, blood pressure progression, and incident hypertension. JAMA 308:875–881.

40. Kirkwood TBL (1977) Evolution of ageing. Nature 270:301–304.

41. Nakayama Y et al. (2001) Heart Rate-Independent Vagal Effect on End-Systolic Elastance of the Canine Left Ventricle Under Various Levels of Sympathetic Tone. Circulation 104:2277–2279.

42. Cohen A (1991) A Padé approximant to the inverse Langevin function. Rheologic Acta 30:270–273.

43. Brown AM, Saum WR, Tuley FH (1976) A comparison of aortic baroreceptor discharge in normotensive and spontaneously hypertensive rats. Circ Res 39:488–496.

44. Smith H (2011) in Texts in Applied Mathematics, Texts in Applied Mathematics. (Springer New York, New York, NY), pp 119–130.

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

Pearlman, JD and A. Lev-Ari 5/24/2013 Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

https://pharmaceuticalintelligence.com/2013/05/24/imaging-biomarker-for-arterial-stiffness-pathways-in-pharmacotherapy-for-hypertension-and-hypercholesterolemia-management/

Lev-Ari, A. 5/17/2013 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

https://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

Bernstein, HL and A. Lev-Ari 5/15/2013 Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems

https://pharmaceuticalintelligence.com/2013/05/15/diagnosis-of-cardiovascular-disease-treatment-and-prevention-current-predicted-cost-of-care-and-the-promise-of-individualized-medicine-using-clinical-decision-support-systems-2/

Pearlman, JD and A. Lev-Ari 5/7/2013 On Devices and On Algorithms: Arrhythmia after Cardiac Surgery Prediction and ECG Prediction of Paroxysmal Atrial Fibrillation Onset

https://pharmaceuticalintelligence.com/2013/05/07/on-devices-and-on-algorithms-arrhythmia-after-cardiac-surgery-prediction-and-ecg-prediction-of-paroxysmal-atrial-fibrillation-onset/

Pearlman, JD and A. Lev-Ari 5/4/2013 Cardiovascular Diseases: Decision Support Systems for Disease Management Decision Making

https://pharmaceuticalintelligence.com/2013/05/04/cardiovascular-diseases-decision-support-systems-for-disease-management-decision-making/

Larry H Bernstein, MD, FACP, 12/10/2012

Genomics & Genetics of Cardiovascular DiseaseDiagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FACP, 3/7/2013

Mitochondrial Dysfunction and Cardiac Disorders

Curator: Larry H Bernstein, MD, FACP

Aviva Lev-Ari, PhD, RN, 4/7/2013

 

Read Full Post »


Reporter: Aviva Lev-Ari, PhD, RN

Combinatorial Pharmacogenetic Interactions of Bucindolol and β1, α2C Adrenergic Receptor Polymorphisms

 

UPDATED ON 9/4/2019

Beta-Blockers Increase Survival for HF Patients With Renal Impairment

Call for use of the agents in those with heart failure with reduced ejection fraction

 

Christopher M. O’Connor1*, Mona Fiuzat1, Peter E. Carson2, Inder S. Anand3, Jonathan F. Plehn4, Stephen S. Gottlieb5, Marc A. Silver6, JoAnn Lindenfeld7, Alan B. Miller8, Michel White9, Ryan Walsh7, Penny Nelson7, Allen Medway7, Gordon Davis10, Alastair D. Robertson7, J. David Port7,10, James Carr10, Guinevere A. Murphy10,Laura C. Lazzeroni11, William T. Abraham12, Stephen B. Liggett13, Michael R. Bristow7,10

1 Division of Cardiology, Duke University Medical Center/Duke Clinical Research Institute, Durham, North Carolina, United States of America,2 Division of Cardiology, Department of Veterans Affairs, Washington, District of Columbia, United States of America, 3 Division of Cardiology, Department of Veterans Affairs, Minneapolis, Minnesota, United States of America, 4 National Heart, Lung, and Blood Institute, National Institutes of Health, Washington, District of Columbia, United States of America, 5 Department of Medicine, University of Maryland, Baltimore, Maryland, United States of America, 6 Heart and Vascular Institute, Advocate Christ Medical Center, Oak Lawn, Illinois, United States of America, 7 Division of Cardiology/Cardiovascular Institute, University of Colorado School of Medicine, Aurora, Colorado, United States of America, 8 Division of Cardiology, University of Florida Health Sciences Center, Jacksonville, Florida, United States of America, 9 Research Center, Montreal Heart Institute, Montreal, Quebec, Canada, 10 ARCA biopharma, Broomfield, Colorado, United States of America, 11 Department of Psychiatry and Behavioral United States of America, Sciences and of Pediatrics, Stanford University, Stanford, California, United States of America, 12 Ohio State University, Columbus, Ohio, United States of America, 13 Center for Personalized Medicine and Genomics, University of South Florida, Morsani College of Medicine, Tampa, Florida, United States of America

Competing interests: Drs Bristow, Carr, Murphy, and Port and Mr Davis are employees of and own stock or stock options in ARCA biopharma, Inc., which owns the rights to bucindolol. Drs Fiuzat, Liggett, Lindenfeld, and Robertson are consultants of ARCA biopharma. Also, Drs Fiuzat and Liggett own stock or stock options in ARCA biopharma. Drs O’Connor, Carson, Anand, Plehn, Gottlieb, Silver, Miller, White, Lazzeroni, and Abraham and Mr Walsh, Ms Nelson, and Mr Medway have no conflicts to report. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.* E-mail: christophe.oconnor@duke.edu

Background

Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a β-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (β1 adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α2C AR Ins [wild-type (Wt)] 322–325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology.

Methodology

In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of β1389 and α2C322–325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for β1389 AR variants was measured in human explanted left ventricles.

Principal Findings

The combination of β1389 Arg+α2C322–325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in β1389 Arg homozygotes+α2C322–325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in β1389 Arg vs. Gly ARs, which converts α2CDel minor allele-associated NE lowering from a therapeutic liability to a benefit.

Conclusions

On combination, the two sets of AR polymorphisms

1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and

2) identified subpopulations with enhanced (β1389 Arg homozygotes), intermediate (β1389 Gly carriers+α2C322–325 Wt homozygotes), and no (β1389 Gly carriers+α2C322–325 Del carriers) efficacy.

thumbnail

Figure 1:

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0044324

Limitations

There are some limitations to this study. First, although the substudy was prospectively designed and hypothesis-driven, the pharmacogenetic data were generated and analyzed after the trial’s main results were analyzed and published [5]. However, the investigators generating the pharmacogenetic data remained blinded to the treatment code and to clinical outcomes throughout. Second, approximately two-thirds of the patients were enrolled into the DNA substudy after being randomized into the parent trial. This “late entry” phenomenon has been extensively analyzed, by both L-truncation [12] and, most recently, propensity score statistical methods (unpublished observations). The effect of late entry into the DNA substudy is only to lower event rates for all clinical endpoints, without affecting genotype-specific treatment effects.

Conclusions

The combinatorial interaction of two sets of AR polymorphisms that influence bucindolol’s drug action resulted in unanticipated effects on HF clinical responses, non-additivity in efficacy enhancement for the major allele homozygotes, and additive effects for minor allele carrier-associated efficacy loss. An explanation for these disparate results was provided by the effects of the α2C322–325 minor (Del) allele on facilitating bucindolol’s NE-lowering properties, where excessive NE lowering abolished efficacy when the β1389 Gly minor allele and low NE affinity AR were present but did not alter or even enhance efficacy in the presence of the major allele homozygous β1389 Arg genotype, which encodes ARs with a NE affinity of ~100-fold more than 389 Gly ARs.

Combinatorial genotyping led to improvement in pharmacogenetic differentiation of drug response compared with monotype genotyping. The use of β1389 Arg/Gly and α2C322–325 Wt/Del genotype combinations accomplishes the goal of pharmacogenetics to identify response outliers from both ends of the therapeutic spectrum. Compared with the use of β1389 Arg/Gly or α2C322–325 Wt/Del monotypes, the differential efficacy gained by the use of genotype combinations was increased by respective amounts of 54% and 94%. The new identification of a completely unresponsive genotype, supported by biologic plausibility and bolstered by data consistency across multiple clinical endpoints, is especially important inasmuch as a major goal of pharmacogenetics is to identify patients with no likelihood of benefit who can then be spared drug side effects [21]. Other β-blockers that have been used to treat HF do not have these pharmacogenetic interactions [22][23], but rather exhibit response heterogeneity through other, unknown mechanisms[8]. Thus, the ability to predict drug response through pre-treatment pharmacogenetic testing should improve therapeutic response to this drug class but will need to be confirmed by prospective studies.

Finally, the unexpected results of this study, (i.e., the additive loss of efficacy by minor allele combinations in the absence of additive gain of efficacy by major allele homozygotes) emphasizes that combinations of response-altering polymorphisms may behave in unpredictable ways and in-silico predictions of combinatorial genetic effects will need to be supported by empirical data.

References

  1. [No authors listed] (1999) The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 353: 9–13. FIND THIS ARTICLE ONLINE
  2. Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, et al. (2005) Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 26: 215–225. FIND THIS ARTICLE ONLINE
  3. [No authors listed] (1999) Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353: 2001–2007.FIND THIS ARTICLE ONLINE
  4. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, et al. (2001) Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 344: 1651–1658. FIND THIS ARTICLE ONLINE
  5. The Beta Blocker Evaluation of Survival Trial Investigators (2001) A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 344: 1659–1667. FIND THIS ARTICLE ONLINE
  6. Domanski MJ, Krause-Steinrauf H, Massie BM, Deedwania P, Follmann D, et al. (2003) A comparative analysis of the results from 4 trials of beta-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS. J Card Fail 9: 354–363. FIND THIS ARTICLE ONLINE
  7. O’Connor CM, Fiuzat M, Caron MF, Deedwania P, Follmann D, et al. (2011) Influence of global region on outcomes in large heart failure β-blocker trials. J Am Coll Cardiol 58: 915–922. FIND THIS ARTICLE ONLINE
  8. Metra M, Bristow MR (2010) Beta-blocker therapy in chronic heart failure. In: Mann DL, ed. Heart Failure: A companion to Braunwald’s Heart Disease.
  9. Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB (2002) Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med 347: 1135–1142. FIND THIS ARTICLE ONLINE
  10. Mialet Perez J, Rathz DA, Petrashevskaya NN, Hahn HS, Wagoner LE, et al. (2003) Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat Med 9: 1300–1305. FIND THIS ARTICLE ONLINE
  11. Liggett SB, Mialet-Perez J, Thaneemit-Chen S, Weber SA, Greene SM, et al. (2006) A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc Natl Acad Sci U S A 103: 11288–11293. FIND THIS ARTICLE ONLINE
  12. Bristow MR, Murphy GA, Krause-Steinrauf H, Anderson JL, Carlquist JF, et al. (2010) An α2C-adrenergic receptor polymorphism alters the norepinephrine lowering effects and therapeutic response of the beta blocker bucindolol in chronic heart failure. Circ Heart Fail 3: 21–28. FIND THIS ARTICLE ONLINE
  13. Mason DA, Moore JD, Green SA, Liggett SB (1999) A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem 274: 12670–12674. FIND THIS ARTICLE ONLINE
  14. Sandilands AJ, O’Shaughnessy KM, Brown MJ (2003) Greater inotropic and cyclic AMP responses evoked by noradrenaline through Arg389 β1-adrenoceptors versus Gly389 β1-adrenoceptors in isolated human atrial myocardium. Br J Pharmacol 138: 386–392. FIND THIS ARTICLE ONLINE
  15. Hein L, Altman JD, Kobilka BK (1999) Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission. Nature 402: 181–184. FIND THIS ARTICLE ONLINE
  16. Small KM, Forbes SL, Rahman FF, Bridges KM, Liggett SB (2000) A four amino acid deletion polymorphism in the third intracellular loop of the human alpha 2C-adrenergic receptor confers impaired coupling to multiple effectors. J Biol Chem 275: 23059–23064. FIND THIS ARTICLE ONLINE
  17. Evans WE, Relling MV (2004) Moving towards individualized medicine with pharmacogenomics. Nature 429: 464–468. FIND THIS ARTICLE ONLINE
  18. Sadee W, Dai Z (2005) Pharmacogenetics/genomics and personalized medicine. Hum Mol Genet 14 (Spec No.2) R207–R214. FIND THIS ARTICLE ONLINE
  19. Hershberger RE, Wynn JR, Sundberg L, Bristow MR (1990) Mechanism of action of bucindolol in human ventricular myocardium. J Cardiovasc Pharm 15: 959–967. doi: 10.1097/00005344-199006000-00014FIND THIS ARTICLE ONLINE
  20. Bristow MR, Krause-Steinrauf H, Nuzzo R, Liang CS, Lindenfeld J, et al. (2004) Effect of baseline or changes in adrenergic activity on clinical outcomes in the beta-blocker evaluation of survival trial (BEST). Circulation 110: 1437–1442. FIND THIS ARTICLE ONLINE
  21. Woodcock J, Lesko LJ (2009) Pharmacogenetics–tailoring treatment for the outliers. N Engl J Med 360: 811–813. FIND THIS ARTICLE ONLINE
  22. White HL, de Boer RA, Maqbool A, Greenwood D, van Veldhuisen DJ, et al. (2003) An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study. Eur J Heart Fail 5: 463–468. FIND THIS ARTICLE ONLINE
  23. Sehnert AJ, Daniels SE, Elashoff M, Wingrove JA, Burrow CR, et al. (2008) Lack of association between beta adrenergic receptor genotype and survival in heart failure patients treated with carvedilol or metoprolol. J Am Coll Cardiol 52: 644–651. FIND THIS ARTICLE ONLINE
Source:

BROOMFIELD, Colo. (TheStreet) — Wacky, inexplicable things sometimes happen to biotech stocks. Like Friday, when ARCA Biopharma (ABIO) shares more than tripled after the small drug company was granted a new U.S. patent for its experimental heart failure drug.

Arca shares rose an astonishing $5.57, or 210%, to close Friday at $8.22. Calculated another way, one U.S. patent for Arca added $40 million in market value.

Not bad, especially considering Friday’s announcement wasn’t particularly new. Arca issued a press release in January announcing the U.S. Patent and Trademark Office had informed the company that the patent was coming. Friday’s press release simply confirmed that the patent had been issued.

In case you’re wondering, Arca shares rose just 17 cents as a result of the January press release.

So, what’s made Arca rocket Friday when it barely budged in January on the same patent news?

Like I said, some things in biotech defy logic. Fundamentals had nothing to do it, clearly. Instead, Friday’s move was more likely a function of momentum traders finding an easy plaything in Arca, which sports a tiny float of just 4.4 million shares.

More than 49 million Arca shares traded hands Friday, or seven times the number of shares outstanding.

It was little noticed Friday, but Arca actually disclosed some bad news regarding the development of its heart failure drug bucindolol. Arca and the U.S. Food and Drug Administration have still not come to agreement on a Special Protocol Assessment for a proposed phase III study of bucindolol. Arca said Friday it had to submit revisions to the design of the study, which will now enroll 3,200 heart failure patients, up from 3,000 patients previously.

Arca needs FDA sign off on the bucindolol trial design, after which the company needs to raise money to conduct the trial. Arca says it can likely start the pivotal bucindolol study one year after both those things happen. The company expects the study to take two years to complete once fully enrolled.

As of December 31, Arca had $7.8 million in its coffers.

http://www.thestreet.com/story/10712682/1/arca-biopharma-patent-deja-vu-biobuzz.html

In a study sponsored by ARCA Biopharma ($ABIO) and carried out by a number of U.S. universities, a pharmacogenetic test predicted which patients would respond to the company’s beta blocker and vasodilator bucindolol (Gencaro), in development for the treatment of chronic heart failure. The level of clinical activity of this oral drug depends on two changes in two genes.

The researchers screened more than a thousand of the patients with congestive heart failure who took part in the Beta-Blocker Evaluation of Survival Trial (BEST) and were given either bucindolol or dummy pills. Based on the patients’ clinical results and genetic profile, the team created a “genetic scorecard.” The results were published in PLoS ONE.

A biomarker for bucindolol will not only speed it through development but could also be used to point out those patients who will (and won’t) respond to which drug, sparing those patients who won’t respond the risk of potential side effects.

According to Stephen B. Liggett of the University of South Florida and founder of ARCA Biopharma, the researchers were able to use the two-gene test to “identify individuals with heart failure who will not respond to bucindolol and those who have an especially favorable treatment response. We also identified those who will have an intermediate level of response. The results showed that the choice of the best drug for a given patient, made the first time without a trial-and-error period, can be accomplished using this two-gene test.”

Bucindolol has been designated as a fast track development program for the reduction of cardiovascular mortality and cardiovascular hospitalizations in a genotype-defined heart failure population.

http://www.fiercebiomarkers.com/press-releases/two-gene-test-predicts-which-patients-heart-failure-respond-best-beta-block?utm_medium=nl&utm_source=internal

October 17, 2012

Two-gene test predicts which patients with heart failure respond best to beta-blocker drug, study finds
Personalized medicine research at University of South Florida strikes early for heart genes

Tampa, FL – A landmark paper identifying genetic signatures that predict which patients will respond to a life-saving drug for treating congestive heart failure has been published by a research team co-led by Stephen B. Liggett, MD, of the University of South Florida.

The study, drawing upon a randomized placebo-controlled trial for the beta blocker bucindolol, appears this month in the  international online journal PLoS ONE.  In addition to Dr. Liggett, whose laboratory discovered and characterized the two genetic variations, Christopher O’Connor, MD, of Duke University Medical Center, and Michael Bristow, MD, PhD, of ARCA biopharma and the University of Colorado Anschutz Medical Campus, were leading members of the research team.
The analysis led to a “genetic scorecard” for patients with congestive heart failure, a serious condition in which the heart can’t pump enough blood to meet the body’s needs, said Dr. Liggett, the study’s co-principal investigator and the new vice dean for research and vice dean for personalized medicine and genomics at the USF Morsani College of Medicine.
“We have been studying the molecular basis of heart failure in the laboratory with a goal of finding genetic variations in a patient’s DNA that alter how drugs work,” Dr. Liggett said.  “We took this knowledge from the lab to patients and found that we can indeed, using a two-gene test, identify individuals with heart failure who will not respond to bucindolol and those who have an especially favorable treatment response. We also identified those who will have an intermediate level of response.” The research has implications for clinical practice, because the genetic test could theoretically be used to target the beta blocker to patients the drug is likely to help. Equally important, its use could be avoided in patients with no likelihood of benefit, who could then be spared potential drug side effects.  Prospective studies are needed to confirm that bucindolol would be a better treatment than other classes of beta blockers for a subset of patients with health failure.

Dr. Liggett collaborated with medical centers across the United States, including the NASDAq-listed biotech company ARCA biopharma, which he co-founded in Denver, CO.   This genetic sub-study involved 1,040 patients who participated in the Beta-Blocker Evaluation of Survival Trial (BEST).  The researchers analyzed mortality, hospital admissions for heart failure exacerbations and other clinical outcome indicators of drug performance.

“The results showed that the choice of the best drug for a given patient, made the first time without a trial-and-error period, can be accomplished using this two-gene test,” Dr. Liggett said.

The genetic test discovered by the Liggett team requires less than 1/100th of a teaspoon of blood drawn from a patient, from which DNA is isolated.  DNA is highly stable when frozen, so a single blood draw will suffice for many decades, Dr. Liggett said. And since a patient’s DNA does not change over their lifetime, as new discoveries are made and other tests need to be run, it would not be necessary to give another blood sample, he added.

This is part of the strategy for the USF Center for Personalized Medicine and Genomics. The discovery of genetic variations in diseases can be targeted to predict three new types of information: who will get a disease, how the disease will progress, and the best drug to use for treatment.

“In the not too distant future, such tests will become routine, and patient outcomes, and the efficiency and cost of medical care will be impacted in positive ways.  We also will move toward an era where we embrace the fact that one drug does not fit all,” Dr. Liggett said.  “If we can identify by straightforward tests which drug is best for which patient, drugs that work with certain smaller populations can be brought to the market, filling a somewhat empty pipeline of new drugs.”

This approach is applicable to most diseases, Dr. Liggett said, but the USF Center has initially concentrated on heart disease, because it is a leading cause of deaths, hospitalizations and lost productivity in the Tampa Bay region and Florida.  Dr. Liggett is a recent recruit to the USF Health Morsani College of Medicine, coming from the University of Maryland School of Medicine.  His work at USF has been supported by several National Institutes of Health grants and $2 million in funding from Hillsborough County.

Heart failure is characterized by an inability of the heart muscle to pump blood, resulting in dysfunction of multiple organs caused by poor blood and oxygen flow throughout the body.  An estimated 6 million Americans are living with heart failure, and more than half a million new cases are diagnosed each year.  About 50 percent of patients diagnosed with heart failure die within five years.  The economic burden of heart failure in the United States is estimated at $40 billion a year.

Article citation:
Christopher M. O’Connor, Mona Fiuzat, Peter E. Carson, Inder S. Anand, Jonathan F. Plehn, Stephen S. Gottlieb, Marc A. Silver, JoAnn Lindenfeld, Alan B. Miller, Michel White, Ryan Walsh, Penny Nelson, Allen Medway, Gordon Davis, Alastair D. Robertson, J. David Port, James Carr, Guinevere A. Murphy, Laura C. Lazzeroni, William T. Abraham, Stephen B. Liggett and Michael Bristow, “Combinatorial Pharmacogenetic Interactions of Bucindolol and β1, α2C Adrenergic Receptor Polymorphisms,” PLoS ONE   7(10): e44324. doi:10.1371/journal.pone.0044324

-USF Health-

USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a global research university ranked 50th in the nation by the National Science Foundation for both federal and total research expenditures among all U.S. universities.

Media contact:
Anne DeLotto Baier, USF Health Communications
(813) 974-3303 or abaier@health.usf.edu

Read more: Two-gene test predicts which patients with heart failure respond best to beta-blocker drug, study finds – FierceBiomarkers http://www.fiercebiomarkers.com/press-releases/two-gene-test-predicts-which-patients-heart-failure-respond-best-beta-block#ixzz29ZLX92k6
http://www.fiercebiomarkers.com/signup?sourceform=Viral-Tynt-FierceBiomarkers-FierceBiomarkers

Read Full Post »