Hypertension: Hegele RA

Khan NA, Hemmelgarn B, Herman RJ, Bell CM, Mahon JL, Leiter LA, Rabkin SW, Hill MD, Padwal R, Touyz RM, Larochelle P, Feldman RD, Schiffrin EL, Campbell NR, Moe G, Prasad R, Arnold MO, Campbell TS, Milot A, Stone JA, Jones C, Ogilvie RI, Hamet P, Fodor G, Carruthers G, Burns KD, Ruzicka M, DeChamplain J, Pylypchuk G, Petrella R, Boulanger JM, Trudeau L, Hegele RA, Woo V, McFarlane P, Vallée M, Howlett J, Bacon SL, Lindsay P, Gilbert RE, Lewanczuk RZ, Tobe S, Anonymous00150. · Division of General Internal Medicine, University of British Columbia, Vancouver, Canada. · Can J Cardiol. · Pubmed #19417859 No free full text.

Abstract: OBJECTIVE: To update the evidence-based recommendations for the prevention and management of hypertension in adults for 2009. OPTIONS AND OUTCOMES: For lifestyle and pharmacological interventions, evidence from randomized controlled trials and systematic reviews of trials was preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. Progression of kidney dysfunction was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease. EVIDENCE: A Cochrane collaboration librarian conducted an independent MEDLINE search from 2007 to August 2008 to update the 2008 recommendations. To identify additional published studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS: For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to less than 2300 mg (100 mmol)/day (and 1500 mg to 2300 mg [65 mmol to 100 mmol]/day in hypertensive patients); perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m(2) to 24.9 kg/m(2)) and waist circumference (smaller than 102 cm for men and smaller than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a diet that is reduced in saturated fat and cholesterol, and that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and consider stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on by the patient's global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to lower than 140/90 mmHg in all patients, and to lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin- converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor antagonists (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as the initial treatment of hypertension if the systolic blood pressure is 20 mmHg above the target or if the diastolic blood pressure is 10 mmHg above the target. The combination of ACE inhibitors and ARBs should not be used. Other agents appropriate for first-line therapy for isolated systolic hypertension include long- acting dihydropyridine CCBs or ARBs. In patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered. VALIDATION: All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

Khan NA, Hemmelgarn B, Padwal R, Larochelle P, Mahon JL, Lewanczuk RZ, McAlister FA, Rabkin SW, Hill MD, Feldman RD, Schiffrin EL, Campbell NR, Logan AG, Arnold M, Moe G, Campbell TS, Milot A, Stone JA, Jones C, Leiter LA, Ogilvie RI, Herman RJ, Hamet P, Fodor G, Carruthers G, Culleton B, Burns KD, Ruzicka M, deChamplain J, Pylypchuk G, Gledhill N, Petrella R, Boulanger JM, Trudeau L, Hegele RA, Woo V, McFarlane P, Touyz RM, Tobe SW, Anonymous00039. · Division of General Internal Medicine, University of British Columbia, Vancouver, British Columbia. · Can J Cardiol. · Pubmed #17534460 links to  free full text

Abstract: OBJECTIVE: To provide updated, evidence-based recommendations for the prevention and management of hypertension in adults. OPTIONS AND OUTCOMES: For lifestyle and pharmacological interventions, evidence was reviewed from randomized controlled trials and systematic reviews of trials. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. For treatment of patients with kidney disease, the progression of kidney dysfunction was also accepted as a clinically relevant primary outcome. EVIDENCE: A Cochrane collaboration librarian conducted an independent MEDLINE search from 2005 to August 2006 to update the 2006 Canadian Hypertension Education Program recommendations. In addition, reference lists were scanned and experts were contacted to identify additional published studies. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS: Dietary lifestyle modifications for prevention of hypertension, in addition to a well-balanced diet, include a dietary sodium intake of less than 100 mmol/day. In hypertensive patients, the dietary sodium intake should be limited to 65 mmol/day to 100 mmol/day. Other lifestyle modifications for both normotensive and hypertensive patients include: performing 30 min to 60 min of aerobic exercise four to seven days per week; maintaining a healthy body weight (body mass index of 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm in men and less than 88 cm in women); limiting alcohol consumption to no more than 14 units per week in men or nine units per week in women; following a diet reduced in saturated fat and cholesterol, and one that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and considering stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should take into account each individual's global atherosclerotic risk, target organ damage and any comorbid conditions: blood pressure should be lowered to lower than 140/90 mmHg in all patients and lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients require more than one agent to achieve these blood pressure targets. In adults without compelling indications for other agents, initial therapy should include thiazide diuretics; other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin-converting enzyme (ACE) inhibitors (except in black patients), long-acting calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs) or beta-blockers (in those younger than 60 years of age). First-line therapy for isolated systolic hypertension includes long-acting dihydropyridine CCBs or ARBs. Certain comorbid conditions provide compelling indications for first-line use of other agents: in patients with angina, recent myocardial infarction, or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor plus diuretic combination is preferred; in patients with nondiabetic chronic kidney disease, ACE inhibitors are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered. VALIDATION: All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

Khan NA, Hemmelgarn B, Herman RJ, Rabkin SW, McAlister FA, Bell CM, Touyz RM, Padwal R, Leiter LA, Mahon JL, Hill MD, Larochelle P, Feldman RD, Schiffrin EL, Campbell NR, Arnold MO, Moe G, Campbell TS, Milot A, Stone JA, Jones C, Ogilvie RI, Hamet P, Fodor G, Carruthers G, Burns KD, Ruzicka M, dechamplain J, Pylypchuk G, Petrella R, Boulanger JM, Trudeau L, Hegele RA, Woo V, McFarlane P, Vallée M, Howlett J, Katzmarzyk P, Tobe S, Lewanczuk RZ, Anonymous00046. · Division of General Internal Medicine, University of British Columbia, Vancouver, Canada. · Can J Cardiol. · Pubmed #18548143 links to  free full text

Abstract: OBJECTIVE: To update the evidence-based recommendations for the prevention and management of hypertension in adults. OPTIONS AND OUTCOMES: For lifestyle and pharmacological interventions, evidence was preferentially reviewed from randomized controlled trials and systematic reviews of trials. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. Progression of kidney dysfunction was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease. EVIDENCE: A Cochrane collaboration librarian conducted an independent MEDLINE search from 2006 to August 2007 to update the 2007 recommendations. To identify additional published studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS: For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium intake to less than 100 mmol/day (and 65 mmol/day to 100 mmol/day in hypertensive patients); perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m(2) to 24.9 kg/m(2)) and waist circumference (smaller than 102 cm for men and smaller than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a diet that is reduced in saturated fat and cholesterol, and one that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and consider stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on by the patient's global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to lower than 140/90 mmHg in all patients, and to lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin-converting enzyme (ACE) inhibitors (in nonblack patients), long-acting calcium channel blockers (CCBs), angiotensin receptor antagonists (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered for initial treatment of hypertension if systolic blood pressure is 20 mmHg above target or if diastolic blood pressure is 10 mmHg above target. Other agents appropriate for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine CCBs or ARBs. In patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension but who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered. Validation: All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

Joy T, Hegele RA. · Robarts Research Institute, 406 - 100 Perth Drive, London, Ontario, N6A 5K8, Canada. · Curr Atheroscler Rep. · Pubmed #18489847 No free full text.

Abstract: Metabolic syndrome (MetS) is a common complex trait consisting of the clustering of abdominal obesity, hypertension, dyslipidemia, and dysglycemia. MetS is found in about 25% of the population in the United States and is associated with increased risk for type 2 diabetes and cardiovascular disease. Despite research into possible genetic influences for MetS, no consistently reproducible genetic markers have been obtained, partially due to lack of agreement on the definition of the phenotype. Because phenotypic precision is essential for genomic interrogation, the evolving discipline of clinical phenomics, which uses objective and systematic acquisition of phenotypic data (ie, "deep phenotyping"), may help evaluate the genetic influences of MetS. This article reviews evidence that MetS has a genetic component and the potential applicability of clinical phenomics for the genetic evaluation of MetS using the example of hierarchical cluster analysis of phenotypic components of lipodystrophy syndromes, which serve as monogenic models of MetS.

Joy T, Lahiry P, Pollex RL, Hegele RA. · No affiliation provided · Curr Diab Rep. · Pubmed #18445357 No free full text.

Abstract: Metabolic syndrome (MetS) is a common phenotype, affecting about 24% of the US population. It is associated with an increased risk for type 2 diabetes and cardiovascular disease. Although there is no universally accepted definition for MetS, affected individuals commonly have a cluster of features, including abdominal obesity, hypertension, dyslipidemia, and dysglycemia. Recently, there has been extensive interest in potential genetic contributions to MetS. At present, no single gene or cluster of genes has been consistently replicated for MetS among different populations, likely due to the complex interplay between gene and environment necessary for expression of this phenotype. We review recent studies regarding the genetic contributions to MetS.

Moride Y, Hegele RA, Langer A, McPherson R, Miller DB, Rinfret S. · Faculty of Pharmacy, Université de Montreal, Montréal, Quebec. · Can J Cardiol. · Pubmed #18401470 links to  free full text

Abstract: Peer-reviewed, evidence-based recommendations for statin use in primary prevention of cardiovascular events are limited. A narrative review of published randomized controlled trials and meta-analyses was conducted to critically appraise the benefits and risks of statins in primary prevention. Statins effectively reduce plasma concentrations of low-density lipoprotein cholesterol, and reduce the risk of cardiovascular events and death. The greatest benefits are observed in high-risk subjects, such as patients with diabetes or hypertension. Serious cardiovascular events should not be included among serious adverse events because they are efficacy outcomes and are dependent on the baseline risk of patients. Rates of specific serious adverse events, such as cancer and rhabdomyolysis, seem to be similar between the statin and control arms of the clinical trials examined. Thus, the benefits of statins in primary prevention outweigh the risks, particularly among high-risk patients. However, the benefit-risk ratio would likely be optimized through interventions designed to increase persistence and adherence in a real-life setting.

Joy T, Cao H, Black G, Malik R, Charlton-Menys V, Hegele RA, Durrington PN. · Department of Vascular Biology and Medicine, Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada. · Orphanet J Rare Dis. · Pubmed #18154657 links to  free full text

Abstract: BACKGROUND: Alstrom syndrome (AS) is a rare autosomal recessive disease characterized by multiorgan dysfunction. The key features are childhood obesity, blindness due to congenital retinal dystrophy, and sensorineural hearing loss. Associated endocrinologic features include hyperinsulinemia, early-onset type 2 diabetes, and hypertriglyceridemia. Thus, AS shares several features with the common metabolic syndrome, namely obesity, hyperinsulinemia, and hypertriglyceridemia. Mutations in the ALMS1 gene have been found to be causative for AS with a total of 79 disease-causing mutations having been described. CASE PRESENTATION: We describe the case of a 27-year old female from an English (Caucasian) kindred. She had been initially referred for hypertriglyceridemia, but demonstrated other features suggestive of AS, including blindness, obesity, type 2 diabetes, renal dysfunction, and hypertension. DNA analysis revealed that she is a compound heterozygote with two novel mutations in the ALMS1 gene - H3882Y and V424I. Examination of her family revealed that her phenotypically unaffected mother and younger sister also had heterozygous mutations in the ALMS1 gene. In addition to presenting these novel molecular findings for AS, we review the clinical and genetic features of AS in the context of our case. CONCLUSION: Two novel mutations in the ALMS1 gene causative for AS have been reported here, thereby increasing the number of reported mutations to 81 and providing a wider basis for mutational screening among affected individuals.

Yuan G, Hegele RA. · Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8. · J Cardiometab Syndr. · Pubmed #17684446 No free full text.

Abstract: A well-worn medical aphorism states that "when you hear hoof beats, think of a horse and not a zebra." When applying this principle to the cardiometabolic syndrome (CMS), the horse would be represented by the prevalent CMS phenotype that affects approximately 30% of individuals in Westernized societies, while the zebra is represented by very rare conditions--such as lipodystrophy syndromes--that share some features with the more prevalent CMS. For instance, familial partial lipodystrophy types 2 and 3 result from heterozygous mutations in LMNA, encoding nuclear lamin A/C, and in PPARG, encoding peroxisome proliferator-activated receptor (PPAR)-gamma, respectively. Patients with either subtype of partial lipodystrophy exhibit an increased ratio of central to peripheral fat stores, dysglycemia, dyslipidemia, and hypertension, with predisposition for developing insulin-resistant diabetes and atherosclerosis end points. Sometimes, however, the zebra serves as a model that can help us understand the horse, so that the rare partial lipodystrophies might offer some insight into pathogenesis and treatment of the more prevalent CMS.

Monajemi H, Stroes E, Hegele RA, Fliers E. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. · Clin Endocrinol (Oxf). · Pubmed #17561981 No free full text.

Abstract: Lipodystrophies represent a heterogeneous group of diseases characterized by an abnormal subcutaneous fat distribution, the extent of which can vary from localized, to partial, to generalized lipoatrophy. Whereas partial and generalized lipodystrophies are each associated with metabolic abnormalities, the localized form is not. These metabolic changes include insulin resistance with type 2 diabetes, acanthosis nigricans, dyslipidaemia predominantly consisting of hypertriglyceridaemia (associated with the onset of pancreatitis) and depressed HDL cholesterol, liver steatosis and hypertension. Affected women are often hirsute and this can be associated with the presence of polycystic ovarian syndrome (PCOS). Most of these clinical features are present to some extent in patients with the common metabolic syndrome. As the prevalence of metabolic syndrome far outweighs that of lipodystrophy, the diagnosis of this rare disorder may often be overlooked with the affected patient diagnosed as merely being 'yet' another case of metabolic syndrome. In this article, we draw attention to the importance of recognizing patients with lipodystrophy who present with metabolic abnormalities, as both the diagnostic as well as the therapeutic approach of these patients differ profoundly from patients with the metabolic syndrome.

Pollex RL, Hegele RA. · Vascular Biology Group, Robarts Research Institute, London, ON, Canada. · Nat Clin Pract Cardiovasc Med. · Pubmed #16932765 No free full text.

Abstract: The metabolic syndrome is a commonly encountered clinical phenotype presenting as concurrent metabolic abnormalities, including central obesity, dysglycemia, dyslipidemia, and hypertension. Several definitions exist, and it is debated whether or not the clustered risk factors impart a higher cardiovascular risk than the simple sum of the individual components. Nevertheless, the concept of a metabolic syndrome has proven helpful in emphasizing the importance of obesity, insulin resistance and related traits in relation to cardiovascular disease risk. Furthermore, the metabolic syndrome as defined by the National Cholesterol Education Program appears to have a component of heritability, which suggests a genetic basis. Indeed, patients with certain rare single-gene disorders express clusters of abnormalities commonly seen in the metabolic syndrome. Moreover, studies indicate that common genetic variants are associated with the development of this syndrome, although the associations are quite weak and replication of findings has been poor. As with most complex traits, it is premature to propose molecular genetic testing for diagnosis, treatment or both. Unresolved issues include the roles of gene-environment interactions, ethnicity, and sex. In this review, we look at the currently available evidence for common genes that predispose to the development of the metabolic syndrome.

Al-Shali KZ, Hegele RA. · Robarts Research Institute and University of Western Ontario, London, Canada. · Arterioscler Thromb Vasc Biol. · Pubmed #15205220 links to  free full text

Abstract: Laminopathies are genetic diseases that encompass a wide spectrum of phenotypes with diverse tissue pathologies and result mainly from mutations in the LMNA gene encoding nuclear lamin A/C. Some laminopathies affect the cardiovascular system, and a few (namely, Dunnigan-type familial partial lipodystrophy [FPLD2] and Hutchinson-Gilford progeria syndrome [HGPS]) feature atherosclerosis as a key component. The premature atherosclerosis of FPLD2 is probably related to characteristic proatherogenic metabolic disturbances such as dyslipidemia, hyperinsulinemia, hypertension, and diabetes. In contrast, the premature atherosclerosis of HGPS occurs with less exposure to metabolic proatherogenic traits and probably reflects the generalized process of accelerated aging in HGPS. Although some common polymorphisms of LMNA have been associated with traits related to atherosclerosis, the monogenic diseases FPLD2 and HGPS are more likely to provide clues about new pathways for the general process of atherosclerosis. Dunnigan-type familial partial lipodystrophy and Hutchinson-Gilford progeria syndrome are laminopathies caused by mutation in LMNA that feature atherosclerosis, which is related to proatherogenic metabolic disturbances and to the generalized process of accelerated aging, respectively. These monogenic diseases may provide clues about new pathways for atherogenesis.

Spence JD, Hegele RA. · Stroke Prevention & Atherosclerosis Research Centre, 1400 Western Rd., London, ON, Canada N6G 2V2. · Curr Drug Targets Cardiovasc Haematol Disord. · Pubmed #15180485 No free full text.

Abstract: The reasons to measure atherosclerosis include 1) risk stratification and prediction; 2) evaluation of patient response to interventions; and 3) identification of novel genetic, cellular and molecular determinants of risk. Atherosclerosis can be quantified non-invasively using the increasingly reliable and precise modalities described in this issue, which include ultrasound and magnetic resonance imaging. While each modality assesses "atherosclerosis", the particular morphological entities captured may reflect different aspects of atherogenesis with different biological determinants. For instance, among carotid ultrasound determinations, intima-media thickness (IMT) may reflect medial hypertrophy from hypertension, while plaque volume and stenosis and calcium deposition may additionally reflect foam cell proliferation, scarring and/or thrombosis. Clarifying the biological and clinical correlates of images may guide the choice of modality for specific applications. In addition, these tools are presently used to assess structures at a single time point. However, using them to follow temporal changes may further enhance their value. In this regard, certain modalities, such as ultrasound assessment of carotid plaque area or volume, may be more sensitive than others, such as assessment of IMT, for detecting temporal changes in atherosclerosis. Combining modalities--and adding new biomarkers of disease--may be necessary to grasp the full complex vascular phenotypic picture--"phenomics"--of both individual subjects and groups of patients. In evaluating new determinants and novel therapies, it will be important to consider the biology and clinical correlates of a specific measured atherosclerosis phenotype in order to select the most appropriate modality.

Hegele RA. · Robarts Research Institute, 406-100 Perth Drive, London, Ontario N6A 5K8, Canada. · Trends Cardiovasc Med. · Pubmed #15177263 No free full text.

Abstract: The metabolic syndrome (MetS) is a common multiplex cluster of phenotypes strongly related to cardiovascular disease that includes central obesity with hypertension, dyslipidemia, and type 2 diabetes. The core molecular defect of the MetS is insulin resistance; indeed, the terms "MetS" and "insulin resistance syndrome" often are used interchangeably. The successful translation to clinical medicine of molecular genetic research on other rare monogenic metabolic disorders has stimulated the evaluation of such rare monogenic forms of insulin resistance as partial lipodystrophy resulting from mutations in either LMNA or PPARG genes. Careful phenotypic evaluation of carriers of monogenic insulin resistance using a range of diagnostic methods--an approach sometimes called "phenomics"--may help to find early presymptomatic biomarkers of cardiovascular disease, which, in turn, may uncover new pathways and targets for interventions for the common MetS, diabetes, and atherosclerosis.

Hegele RA, Al-Shali KZ, House AA, Hanley AJ, Harris SB, Mamakeesick M, Fenster A, Zinman B, Cao H, Spence JD. · Robarts Research Institute, London, Ontario, Canada. · Stroke. · Pubmed #16282543 links to  free full text

Abstract: BACKGROUND AND PURPOSE: Cytosolic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32), encoded by PCK1, catalyzes the first committed step in gluconeogenesis. We previously showed that a -232C>G promoter polymorphism within a cis-acting element required for basal and cAMP-mediated PCK1 gene transcription results in loss of negative regulation by insulin, contributing to worsened metabolic control in the context of insulin resistance. We hypothesized that this polymorphism would be associated with carotid atherosclerosis in a sample of 150 aboriginal Canadians. METHODS: Dependent variables were 2 distinct carotid traits, namely intima-media thickness (IMT) assessed using B-mode ultrasound and total carotid plaque volume (TPV) assessed using 3D ultrasound. RESULTS: Multivariate analysis showed significant but opposite associations of PCK1 genotype with these traits. Specifically, subjects with the PCK1-232G/G genotype had more carotid IMT (0.80+/-0.02 versus 0.73+/-0.03 mm; P=0.007) but less TPV (0.10+/-0.09 versus 0.38+/-0.13; P=0.03) than subjects with other genotypes. CONCLUSIONS: The findings connect the key enzyme in gluconeogenesis with atherosclerosis. The meaning of the opposing associations of PCK1 genotype with IMT and TPV is unclear; more work is required to confirm whether these might be distinct quantitative traits with different biological determinants.

Ley SH, Harris SB, Mamakeesick M, Noon T, Fiddler E, Gittelsohn J, Wolever TM, Connelly PW, Hegele RA, Zinman B, Hanley AJ. · Department of Nutritional Sciences, University of Toronto, Toronto, Ont. · CMAJ. · Pubmed #19289805 links to  free full text

Abstract: BACKGROUND: Risk factors for type 2 diabetes remain poorly characterized among Aboriginal Canadians. We aimed to determine the incidence of type 2 diabetes in an Aboriginal community and to evaluate prospective associations with metabolic syndrome and its components. METHODS: Of 606 participants in the Sandy Lake Health and Diabetes Project from 1993 to 1995 who were free of diabetes at baseline, 540 (89.1%) participated in 10-year follow-up assessments. Baseline anthropometry, blood pressure, fasting insulin and serum lipid levels were measured. Fasting and 2-hour postload glucose levels were obtained at follow-up to determine incident cases of type 2 diabetes. RESULTS: The 10-year cumulative incidence of diabetes was 17.5%. High adiposity, dyslipidemia, hyperglycemia, hyperinsulinemia and hypertension at baseline were associated with an increased risk of diabetes after adjustment for age and sex (all p < or = 0.03). Metabolic syndrome had high specificity (75%-88%) and high negative predictive value (85%-87%) to correctly detect diabetes-free individuals at follow-up. It had low sensitivity (26%-48%) and low positive predictive value (29%-32%) to detect future diabetes. Metabolic syndrome at baseline was associated with incident diabetes after adjustment for age and sex, regardless of whether the syndrome was defined using the National Cholesterol Education Program criteria (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.10-3.75) or the International Diabetes Federation criteria (OR 2.14, 95% CI 1.29-3.55). The association was to the same degree as that for impaired glucose tolerance assessed using the oral glucose tolerance test (OR 2.87, 95% CI 1.52-5.40; p > 0.05 for comparison of C statistics). INTERPRETATION: Metabolic syndrome and its components can be identified with readily available clinical measures. As such, the syndrome may be useful for identifying individuals at risk of type 2 diabetes in remote Aboriginal communities.

Ley SH, Harris SB, Connelly PW, Mamakeesick M, Gittelsohn J, Hegele RA, Retnakaran R, Zinman B, Hanley AJ. · Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada. · Diabetes Care. · Pubmed #18339973 links to  free full text

Abstract: OBJECTIVE: The aim of this study was to investigate associations of adiponectin, leptin, C-reactive protein (CRP), interleukin (IL)-6, and serum amyloid A (SAA), individually or in combinations, with risk of incident type 2 diabetes in a Aboriginal Canadian [corrected] population. RESEARCH DESIGN AND METHODS: Of the 606 Sandy Lake Health and Diabetes Project cohort subjects who were free of diabetes at baseline, 540 (89.1%) participated in 10-year follow-up assessments. Concentrations of fasting adiponectin, leptin, CRP, IL-6, SAA, and covariates were measured at baseline. Fasting glucose and a 75-g oral glucose tolerance test were obtained at baseline and follow-up to determine incident type 2 diabetes, defined as clinically diagnosed type 2 diabetes or as fasting plasma glucose > or =7.0 mmol/l or 2-h postload plasma glucose > or =11.1 mmol/l at follow-up. RESULTS: Low adiponectin, high leptin, and low adiponectin-to-leptin ratio at baseline were associated with increased risk of incident type 2 diabetes after adjustment for age, sex, triglycerides, HDL cholesterol, hypertension, and impaired glucose tolerance (odds ratio 0.63 [95% CI 0.48-0.83], 1.50 [1.02-2.21], and 0.54 [0.37-0.77], respectively). When the models were additionally adjusted for waist circumference or BMI, however, only low adiponectin remained significantly associated with increased incident diabetes (0.68 [0.51-0.90]). Combinations of leptin, CRP, IL-6, and/or SAA with adiponectin, assessed using either the ratio or joint effects, did not improve diabetes prediction. CONCLUSIONS: Low baseline adiponectin is associated with increased risk of incident type 2 diabetes independent of leptin, CRP, IL-6, SAA, and metabolic syndrome variables including obesity.

Weber CL, Frohlich J, Wang J, Hegele RA, Chan-Yan C. · Department of Medicine, Section of Nephrology, Laboratory Medicine, University of British Columbia/St Paul's Hospital, 1081 Burrard Street, Providence Building, Room 6010A, Vancouver, British Columbia, Canada V6Z 1Y6. · Nephrol Dial Transplant. · Pubmed #17452402 links to  free full text

This publication has no abstract.

Morel CF, Thomas MA, Cao H, O'Neil CH, Pickering JG, Foulkes WD, Hegele RA. · Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, London, Ontario, Canada. · J Clin Endocrinol Metab. · Pubmed #16636128 links to  free full text

Abstract: CONTEXT: To date, all cases of familial partial lipodystrophy type 2 (FPLD2; Mendelian Inheritance in Man 151660) result from missense mutations in LMNA, which encodes nuclear lamin A/C (Mendelian Inheritance in Man 150330). OBJECTIVE: The objective of the study was to carry out mutational analysis of LMNA in two sisters with a particularly severe FPLD2 phenotype. DESIGN: This was a descriptive case report with molecular studies. SETTING: The study was conducted at a referral center. PATIENTS: We report two sisters of South Asian origin. The first presented with acanthosis nigricans at age 5 yr, diabetes with insulin resistance, hypertension and hypertriglyceridemia at age 13 yr, and partial lipodystrophy starting at puberty. Her sister and their mother had a similar metabolic profile and physical features, and their mother died of vascular disease at age 32 yr. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES AND RESULTS: LMNA sequencing showed that the sisters were each heterozygous for a novel G>C mutation at the intron 8 consensus splice donor site, which was absent from the genomes of 300 healthy individuals. The retention of intron 8 in mRNA predicted a prematurely truncated lamin A isoform (516 instead of 664 amino acids) with 20 nonsense 3'-terminal residues. The mutant lamin A isoform failed to interact normally with emerin and failed to localize to the nuclear envelope. CONCLUSIONS: This is the first LMNA splicing mutation to be associated with FPLD2, and it causes a severe clinical and metabolic phenotype.

Pollex RL, Mamakeesick M, Zinman B, Harris SB, Hanley AJ, Hegele RA. · Robarts Research Institute, London, Ontario, Canada. · Cardiovasc Diabetol. · Pubmed #16274479 links to  free full text

Abstract: BACKGROUND: Individuals with diabetes are twice as likely to develop peripheral arterial disease (PAD), the manifestation of extensive atherosclerosis throughout the lower extremities. One putative determinant of PAD is the 677C>T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR), which has previously been found to associate with various diabetic complications including retinopathy, nephropathy, atherosclerosis and coronary heart disease. The objective of this study was to investigate a possible role for the MTHFR 677C>T gene polymorphism with PAD in subjects with type 2 diabetes from an isolated aboriginal Canadian population. METHODS: The 677C>T MTHFR gene polymorphism was genotyped in 138 subjects of Oji-Cree descent. Participants were selected from a community-wide survey that included PAD assessment by ankle-brachial index (ABI) measurement, and also intermittent claudication assessment by the Rose questionnaire. RESULTS: MTHFR 677T allele carriers had an increased risk of PAD with an odds ratio of 3.54 (95% CI 1.01, 12.4), P = 0.049, after adjustment for age, sex, duration of diabetes, hypertension, current smoking habits, and use of insulin or oral treatment for diabetes. None of these additional co-variables was significantly associated with PAD. No association was found between MTHFR genotype and intermittent claudication. CONCLUSION: The genetic influence of the MTHFR 677C>T genotype on diabetic PAD is modest, yet for the Oji-Cree it is a major risk factor in comparison to other traditional risk factors.

Gros R, Ding Q, Chorazyczewski J, Andrews J, Pickering JG, Hegele RA, Feldman RD. · Cell Signaling Research Group, Robarts Research Institute, 100 Perth Dr., London, ON, Canada N6A 5K8. · Mol Pharmacol. · Pubmed #16223959 links to  free full text

Abstract: The effects of vasodilator hormones acting through receptors linked to adenylyl cyclase are impaired in the hypertensive state. This has been ascribed to impaired receptor-G protein coupling. However, these receptors also act via effectors not linked to adenylyl cyclase activation. These "alternate" mechanisms may be especially important in growth regulation and might be unaffected (or enhanced) with G protein-coupled receptor-G protein uncoupling. Therefore, we assessed the effects of beta-adrenergic activation on 1) regulation of phosphatidylinositol 3-kinase (PI3 kinase) and extracellular signal-regulated kinase (ERK) activation-two tyrosine kinase-dependent enzymes linked to cell growth-and 2) microarray analysis in vascular smooth muscle cells from spontaneously hypertensive rats (SHR). Isoproterenol-stimulated phosphorylation of ERK1/2 was impaired in SHR. The effect of forskolin was unaltered. In contrast, both vasopressin and angiotensin 2-mediated stimulation of ERK activation was enhanced in SHR. In addition, beta-adrenergic-mediated inhibition of PI3 kinase activity was attenuated in SHR (whereas the effect of forskolin remained intact). In microarray studies, the effect of isoproterenol to regulate transcription was significantly impaired in SHR (as was the effect of forskolin). Together, these data support the hypothesis that the blunted vasodilator effects of hormones linked to adenylyl cyclase activation are an index of a more generalized impairment in modulating growth regulatory pathways. Furthermore, this study supports the hypothesis that the blunting of beta-adrenergic responses relating to increased G protein-coupled receptor kinase 2 expression reflects a "generalized uncoupling" of beta-adrenergic-mediated responses and do not support the concept of "enhanced coupling" of "alternate" pathways of beta-adrenergic growth regulatory pathways in the hypertensive state.

Pollex RL, Spence JD, House AA, Fenster A, Hanley AJ, Zinman B, Harris SB, Hegele RA. · Robarts Research Institute, London, Ontario, Canada. · Cardiovasc Ultrasound. · Pubmed #15958169 links to  free full text

Abstract: BACKGROUND: Subjects with type 2 diabetes are at an increased risk of vascular complications. The use of carotid ultrasound remains an attractive, non-invasive method to monitor atherosclerotic disease progression and/or response to treatment in patients with type 2 diabetes, with intima-media thickness routinely used as the gold standard to detect pathology. However, alternative measurements, such as plaque area or volume, may represent a potentially more powerful approach. Thus, the objective of this study was to compare the traditional intima-media thickness measurement against the novel total plaque volume measurement in analyzing carotid atherosclerosis development in individuals with type 2 diabetes. METHODS: The case-control study included 49 Oji-Cree adults with diabetes or impaired glucose tolerance, aged 21-69, and 49 sex- and age-matched normoglycemic subjects. At baseline, metabolic variables were measured, including body mass index, waist circumference, total cholesterol: high density lipoprotein ratio, plasma triglycerides, plasma glucose, and serum insulin. Carotid ultrasound measurements, 7 years later, assessed carotid arterial intima-media thickness and total plaque volume. RESULTS: At baseline, the two groups were well matched for smoking habits, hypertension, body mass index, and waist circumference. Differences were noted in baseline measurements of total cholesterol:high density lipoprotein (P = 0.0006), plasma triglycerides (P < 0.0001) and fasting glucose (P < 0.0001). After seven years, carotid ultrasound scans revealed that total plaque volume measurements (P = 0.037), but not intima-media thickness measurements, were higher in subjects with diabetes/impaired glucose tolerance compared to the normoglycemic controls. Correlation between intima-media thickness and total plaque volume was moderate. Based on our study findings, to achieve power levels > 0.70 when comparing intima-media thickness measurements for diabetics versus non-diabetics, thousands of study subjects are required. For comparing total plaque volume measurements, only hundreds of study subjects are required. CONCLUSION: The development of atherosclerotic plaque is greater in subjects with diabetes/impaired glucose tolerance. Total plaque volume appears to capture the atherosclerotic disease burden more effectively in subjects with type 2 diabetes, and would be an appropriate outcome measure for studies aimed at changing the diabetic milieu.

Al-Shali K, House AA, Hanley AJ, Khan HM, Harris SB, Mamakeesick M, Zinman B, Fenster A, Spence JD, Hegele RA. · Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406-100 Perth Drive, London, Ont., Canada N6A 5K8. · Atherosclerosis. · Pubmed #15694940 No free full text.

Abstract: Ultrasound measurements are both surrogate markers and risk factors for atherosclerosis end points. Carotid intima-media thickness (IMT) is most commonly used, but ultrasound can also define structures in higher spatial dimensions, such as total plaque area (TPA) and total plaque volume (TPV). Because there are minimal data regarding the relationship between IMT, TPA and TPV, we measured these variables in 272 Oji-Cree subjects. We found pairwise correlations for IMT:TPA, IMT:TPV and TPA:TPV of 0.507, 0.588 and 0.846, respectively (transformed variables, all P <0.0001). In a subset of 168 subjects with complete cardiovascular risk factor data, we performed multivariate regression analysis to identify sources of variation for IMT, TPA and TPV. We found that the ultrasound traits showed different correlations with individual cardiovascular risk factors. In particular, IMT was significantly associated with hypertension, TPA with smoking and plasma cholesterol, and TPV with diabetes. Therefore, these ultrasound measures of carotid artery morphology, while somewhat correlated, likely represent distinctive quantitative traits with different biological determinants, as underscored by different risk factor associations in the multivariate regression analysis. Because the measurements have different implications and determinants, investigators might need to be selective about the particular measurements they choose for specific applications.

Kelemen LE, Anand SS, Hegele RA, Stampfer MJ, Rosner B, Willett WC, Montague PA, Lonn E, Vuksan V, Teo KK, Devanesen S, Yusuf S. · Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, USA. · Atherosclerosis. · Pubmed #15380460 No free full text.

Abstract: BACKGROUND: Few studies have evaluated the associations of plasma homocysteine concentration, the methylenetetrahydrofolate reductase (MTHFR) C677T genotype and B vitamin concentration with intima media thickness (IMT) in multiethnic populations. METHODS: In the Study of Health Assessment and Risk in Ethnic groups (SHARE), we measured carotid IMT, fasting serum folate, serum B12, plasma pyridoxal-5'-phosphate (PLP) and plasma homocysteine and determined the MTHFR C677T genotype in a cross-sectional study of 818 South Asian, Chinese and European Canadians without previous history of CVD, cancer or diabetes during 1996-1998. RESULTS: Plasma homocysteine was inversely related to serum folate, serum B12, plasma PLP, B vitamin supplement use and Chinese ethnicity, and was positively associated with hypertension, smoking, IMT, MTHFR 677T/T genotype and South Asian ethnicity. Although ethnicity was not a statistically significant modifier, among carriers of the MTHFR 677T/T genotype with serum folate < or =14 nmol/L compared to >14 nmol/L, plasma homocysteine was significantly higher among South Asians (50.9% increase, P < 0.001) and Europeans (52.4% increase, P < 0.001) but not Chinese (11.0% increase, P > 0.05). Plasma homocysteine > 11.7 micromol/L was associated with a 5.9% (95% CI: 1.9%, 10.0%) increase in IMT (approximately 0.04 mm) in the pooled-data analyses with similar increases noted in the ethnic-specific analyses. The 677T/T genotype was not associated with a significant change in IMT in the pooled-data analyses (2.7%; 95% CI: -1.7%, 7.2%) nor in ethnic-specific analyses compared to other genotypes, although there were only 63 677T/T homozygotes. CONCLUSION: The combination of lower serum folate and the MTHFR 677T/T genotype is associated with increased plasma homocysteine among South Asians and Europeans, but the association is not evident among Chinese possibly because their serum folate may not have been low enough to compromise MTHFR activity. Plasma homocysteine > 11.7 micromol/L appears to be associated with a clinically important increase in IMT.

Hegele RA, Leff T. · Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406-100 Perth Drive, London, Ontario N6A 5K8, Canada. · J Clin Invest. · Pubmed #15254581 links to  free full text

Abstract: Lipodystrophy and insulin resistance are the core features of human PPARgamma deficiency states. Metabolic complications in PPARgamma deficiency, such as hypertension, have been considered to be secondary to insulin resistance. However, a new mouse model that expresses the analog of a human PPARG mutation displays minimal lipodystrophy and insulin resistance but rather severe hypertension. Furthermore, the mutant protein appears to directly modulate the renin-angiotensin system in adipose tissue, providing evidence of the pleiotropic effects of PPARgamma.

Bjerregaard P, Dewailly E, Young TK, Blanchet C, Hegele RA, Ebbesson SE, Risica PM, Mulvad G. · National Institute of Public Health, Svanemollevej 25, DK-2100 Copenhagen, Denmark. · Scand J Public Health. · Pubmed #12745758 No free full text.

Abstract: AIMS: Studies of blood pressure among various Inuit (Eskimo) populations in the Arctic have given inconsistent results. Most studies reported lower blood pressure among the Inuit as compared with the predominantly white national populations. This has been attributed to traditional subsistence practices and lifestyle. This study compared the blood pressure among the major Inuit population groups with other populations and examined the associations with factors like age, gender, obesity and smoking. METHODS: The study comprised four Inuit populations from Alaska, Canada, and Greenland with participation rates ranging from 51% to 73%. In a cross-sectional design, 2,509 randomly selected adults from 31 villages were examined. Blood pressure, anthropometric measurements, smoking, and medication were recorded. RESULTS: Mean systolic blood pressures ranged from 116 to 124 mm Hg among men and 110 to 118 among women in the four populations. Mean diastolic blood pressures ranged from 75 to 78 mm Hg among men and from 71 to 73 among women. Systolic blood pressure increased with age. Male gender, obesity, being a non-smoker, and being on anti-hypertensive treatment were associated with high systolic and diastolic blood pressure. Adjusted for age, body mass index, smoking, and anti-hypertensive treatment, blood pressure differed among the populations (p </= 0.001). Mean systolic blood pressure was low among the Inuit compared with most European populations of the INTERSALT study, but higher than in several Asian populations and the Amazonian Indians. CONCLUSIONS: Inuit blood pressures rank intermediate on a global scale but low in comparison with most European populations. The Inuit population is not homogeneous, and this is reflected in blood pressure differences among the four regional subgroups. The role of the traditional diet, a rural lifestyle with a low level of psychosocial stress, and genetics must be further explored.