Well kept secrets of the genome.
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Genome, Human↗
Biomedical subjects
H Schunkert
Publications and source records attributed to H Schunkert.
[64-year-old patient with dyspnea at risk and ankle edema in recurrent tachycardia. Heart failure].
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Diagnosis, Differential↗
Kinetics of heat shock protein 70 synthesis in the human heart after cold cardioplegic arrest.
OBJECTIVE: Protection of the myocardium against ischemia/reperfusion injury is a major challenge in cardiac surgery and cardiology. A cardioprotective role of heat shock proteins (Hsp), in particular Hsp 70, against ischemia has been demonstrated. A prerequisite for clinical exploitation of high Hsp 70 levels in the heart during ischemia is the determination of the efficacy and the kinetics of cardiac Hsp synthesis in vivo. METHODS: We examined Hsp 70 and other immediate early genes, that are induced by cardioplegia and reperfusion, in right atrial biopsies taken from 15 patients during coronary artery bypass grafting. Specimens were obtained before cardioplegia and after ending of reperfusion and subsequently studied by immunohistochemistry and Western blot analyses. RESULTS: Overall Hsp 70 increased 2.0+/-1.1-fold (P<0.01) in the nucleus as well as in the cytosol of myocytes and endothelial cells during open-heart surgery. As determined by comparison to a dilution series of recombinant protein, Hsp 70 levels amounted up to 6 per thousand of total cellular protein. The increase of Hsp 70 correlated well with the duration of cardioplegia and reperfusion (P<0.005) showing a markedly accelerated increase at periods longer than 2 h. Further, the immediate early gene c-Fos also increased 2.4+/-2.2-fold during open-heart surgery (P<0.05), whereas other members of the Hsp family, like Hsp 27 and Hsp 90, showed no significant changes in protein levels during cardioplegia and reperfusion. CONCLUSIONS: These findings demonstrate that protein levels of Hsp 70 in the myocardium increase to significant amounts within few hours after induction. The optimum time point for induction of Hsp 70 appears to be at least 2 h before open-heart surgery.
Blotting, Western↗
Obesity and target organ damage: the heart.
In most patients, coronary atherosclerosis or congestive heart failure develop as an integrated response to multiple cardiovascular risk factors. Obesity increases the prevalence of most cardiovascular risk factors and is the predominant cause of diabetes mellitus and arterial hypertension. Moreover, obesity shifts the manifestation of these risk factors to younger age groups, such that subsequent damage results prematurely in clinically overt cardiac diseases. In addition, due to clustering of obesity-related risk factors, obesity may amplify the risk by synergistic mechanisms acting in parallel. Finally, an elevated body mass index (BMI) results in an increase in heart rate and blood volume, as well as increased systolic and diastolic blood pressure. These changes affect cardiac geometry and mass in addition to the alterations of the coronary vasculature. At the population level, the role of obesity in promoting multiple risk factors and, subsequently, the development of heart diseases cannot be underestimated. In individual patients, however, the clinical presentation may be dominated by obesity-related hypertension, diabetes, metabolic and inflammatory derangements or clinical symptoms of heart failure or coronary artery disease. Weight reduction remains a crucial component of the therapeutic strategy to ameliorate insulin resistance, hypertension and left ventricular hypertrophy, among other risk factors, with profound implications for the individual's prognosis.
Body Mass Index↗
Old and simple tools may do better--sometimes.
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Electrocardiography↗
The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data.
Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in various tissues and organs, most notably on the endothelium but also within parenchyma and inflammatory cells. Tissue ACE is now recognized as a key factor in cardiovascular and renal diseases. Endothelial dysfunction, in response to a number of risk factors or injury such as hypertension, diabetes mellitus, hypercholesteremia, and cigarette smoking, disrupts the balance of vasodilation and vasoconstriction, vascular smooth muscle cell growth, the inflammatory and oxidative state of the vessel wall, and is associated with activation of tissue ACE. Pathologic activation of local ACE can have deleterious effects on the heart, vasculature, and the kidneys. The imbalance resulting from increased local formation of angiotensin II and increased bradykinin degradation favors cardiovascular disease. Indeed, ACE inhibitors effectively reduce high blood pressure and exert cardio- and renoprotective actions. Recent evidence suggests that a principal target of ACE inhibitor action is at the tissue sites. Pharmacokinetic properties of various ACE inhibitors indicate that there are differences in their binding characteristics for tissue ACE. Clinical studies comparing the effects of antihypertensives (especially ACE inhibitors) on endothelial function suggest differences. More comparative experimental and clinical studies should address the significance of these drug differences and their impact on clinical events.
Angiotensin-Converting Enzyme Inhibitors↗
Effectiveness of and adverse events after percutaneous coronary intervention in patients with mild versus severe renal failure.
Patients with renal failure undergoing percutaneous coronary intervention (PCI) experience reduced procedural success rates and increased in-hospital and long-term follow-up major adverse cardiac events. This study was designed to determine whether the severity of preprocedural renal failure influences the outcomes of patients with renal failure undergoing PCI. We compared the immediate and long-term outcomes of 192 patients with mild renal failure (creatinine 1.6 to 2.0 mg/dl, mean 1.76) with those of 131 patients with severe renal failure (creatinine >2.0 mg/dl, mean 2.90), selected from 3,334 consecutive patients undergoing PCI between 1994 and 1997. Although the overall population with renal failure represents a high-risk group, the severe renal failure cohort had a higher incidence of hypertension, multivessel disease, prior coronary bypass surgery, vascular disease, and congestive heart failure (all p values <0.05), yet had similar angiographic characteristics. Procedural success was higher in the group with severe renal failure (93.7% vs 87.7%, p = 0.04). There were no statistically significant differences in in-hospital mortality (11.5% vs 9.9%, p = 0.7), Q-wave myocardial infarction (0.5% vs 0%, p = 0.4), emergent bypass surgery (0% vs 0%, p = 1.0), and in-hospital major adverse cardiac events (11.5% vs 9.9%, p = 0.7) between the mild and severe renal groups, respectively. Kaplan-Meier analyses showed no statistically significant difference in long-term survival (log rank test, p = 0.1) or event-free survival (log rank test, p = 0.3) between the 2 groups. Finally, creatinine was not identified as an independent predictor of in-hospital or long-term follow-up major adverse cardiac events. In our high-risk population, patients with mild renal insufficiency undergoing PCI experience major adverse outcomes in the hospital and at long-term follow-up similar to those of patients with severe renal failure.
Aged↗
[Cardiovascular changes in obesity].
BACKGROUND: Obesity is associated with a number of adaptations in the cardiovascular system like arterial hypertension, a hypervolemic circulation or left ventricular hypertrophy. PATHOBIOCHEMICAL MECHANISMS: The specific mechanisms underlying these sequelae of obesity are not fully understood. Metabolic factors like insulin-resistance or the elevated activation of the sympathetic and the renin-angiotensin-aldosteron system have effects on a number of vascular and cardiac parameters. In addition, elevated serum levels of proinflammatoric parameters like C-reactive protein, interleukin-6 and TNF-alpha are found in patients with obesity. The consequence is a drastic increase of cardiovascular mortality. CONCLUSION: Depending on the fat distribution and the relation between the increase of body fat mass and fat-free mass different effects on heart and vessels are reported. The most important obesity-associated implications on the cardiovascular system are discussed below.
Body Composition↗
[Inpatient rehabilitation improves implementation of therapeutic guidelines for secondary prevention in patients with coronary heart disease].
In Germany, measures for secondary prevention in patients with coronary artery disease are poorly utilized. We therefore investigated whether a cardiac in-hospital rehabilitation and education program may enhance the implementation of respective guidelines in patients with severe coronary artery disease (CAD). Specifically, we developed a case-control design in siblings with severe CAD in order to achieve optimal matching for patients with or without participation in the rehabilitation program. By the screening of more than 200,000 patient charts in 15 cardiac rehabilitation clinics, we identified 1500 families in which at least two siblings suffered from severe coronary artery disease. In 268 such sibling pairs, siblings were discordant with respect to participation in a 3-4 week cardiac in-hospital rehabilitation program. The coronary risk profile was studied, first, retrospectively at the time of hospitalization for acute MI or revascularization procedures and, secondly, prospectively at the time of follow-up (on average 5.2 years later). At the time of the acute cardiac event, both groups showed an equal risk factor distribution suggesting appropriate matching. However, at follow-up the number of individuals taking antihypertensive medication and displaying effective antihypertensive treatment (< or = 140/90 mmHg) was significantly higher in the rehabilitation group (92.2 vs. 82.1%, p < 0.01; 59.7 vs. 37.2%). Accordingly, rehabilitation siblings presented with significantly lower systolic (137 +/- 1 vs. 145 +/- 1 mmHg; p < 0.01) and diastolic blood pressure (82 +/- 1 vs. 85 +/- 1 mmHg; p < 0.01). The utilization of CSE inhibitors was also significantly higher in siblings participating in the rehabilitation program (57.5 vs. 43.1%; p < 0.01), leading to significantly lower blood lipid levels in these siblings (total cholesterol 225 +/- 3 vs. 236 +/- 3 mg/dL, p < 0.01; LDL cholesterol 148 +/- 3 vs. 158 +/- 3 mg/dL, p < 0.01). Moreover, participation in the cardiac rehabilitation stimulated markedly more smokers to quit (80.8 vs. 57.6%, p < 0.01). Additionally, there was a strong temporal trend from 1997 until 2000 towards improved control of arterial hypertension in rehabilitation siblings. In parallel, the utilization of CSE inhibitors increased over time and LDL cholesterol decreased. These favorable temporal trends were also observed in siblings not participating in the rehabilitation program, however, to a lesser extent. Taken together, in the last four years, the implementation of secondary preventive strategies in patients with cardiac disease improved. Siblings who participated in a rehabilitation program displayed a better control of cardiovascular risk factors as compared to those not participating in such a program. Thus, an in-hospital cardiac rehabilitation program may successfully encourage the implementation of measures for secondary prevention and enhance the treatment of coronary risk factors.
Aged↗
[ACE inhibition in patients with myocardial infarct and ventricular dysfunction: inappropriate application of therapy standards in patient samples].
Several reports indicate the benefit of ACE inhibitors for patients with left ventricular systolic dysfunction after acute myocardial infarction (MI). We sought to determine the implementation of the treatment guidelines in patient samples from the general population. Furthermore we aimed to identify patient characteristics associated with the use of ACE inhibitors. Screening of two MI-registries allowed the identification of 226 MI patients with left ventricular dysfunction. Patients were considered to be eligible for ACE inhibitor therapy when a EF < or = 40% was documented in the patient records of cardiac rehabilitation clinics (REG-MI, n = 147) or detected by standardised echocardiography (KORA, n = 78). On average 5.5 years following MI, a standardised questionnaire and a detailed medical history was obtained. Specifically, information was collected regarding current medication and potential contraindications for ACE inhibitors. MI patients with LV dysfunction received ACE inhibitors in 62% (REG-MI) and 45% (KORA). The doses prescribed were substantially smaller than target doses used in the large-scale studies (REG-MI: 40 +/- 4%, KORA: 23 +/- 3%, % of target doses). Only 13% (REG-MI) and 3% (KORA) received more than 50% of the target dosage. Additionally, actual doses of the most frequently used ACE inhibitors were significantly different (captopril: 23 +/- 2%, enalapril: 42 +/- 5% of target doses). The likelihood of receiving ACE inhibitors was significantly higher in patients with written recommendation for such medication (odds ratio 6.02, confidence interval 1.93-20.16) and in patients visiting cardiologists (odds ratio 3.69, confidence interval 1.26-11.07) as revealed by multivariate analysis of the REG-MI database. Despite national and international guidance, a large proportion of MI patients with left ventricular dysfunction is not receiving ACE inhibitors, and when used, the doses prescribed are markedly smaller than target doses used in clinical trials that established the utility of these drugs. Medical care by cardiologists and written recommendation of ACE inhibition in patient records were independent predictors of a more appropriate prescription of ACE inhibitors.
Aged↗
Association between a polymorphism in the G protein beta3 subunit gene (GNB3) with arterial hypertension but not with myocardial infarction.
OBJECTIVE: A polymorphism at position 825(C-->T) of the G protein beta3 (GNB3) gene was found to be associated with enhanced transmembrane signalling as well as with an increased prevalence of arterial hypertension. The aim of the present study was to further investigate the association of the GNB3 C825T allele status with arterial hypertension in a large population-based sample and its association with specific end organ damage, i.e. myocardial infarction (MI). METHODS: Individuals from a population-based sample (n=2052) and patients suffering from premature MI (age at first MI < or = 60 years, n = 606) were studied by questionnaire as well as by physical examination and biochemical analyses. RESULTS: In the population-based sample, the prevalence of arterial hypertension (blood pressure > or = 160/95 mmHg and/or antihypertensive medication) was higher in individuals with the TT genotype (41.8%) as compared to heterozygote individuals (36.6%) or those with the CC genotype (32.75%) (P = 0.02). This association was predominantly found in men. Moreover, men without antihypertensive medication carrying the TT genotype showed higher diastolic blood pressure than those carrying the CC genotype (86.5 vs. 83.7 mmHg, P = 0.04). However, the genotype distribution and the allele frequencies were similar in both, the population-based and the MI patient sample. Furthermore, neither the age at the time of MI nor the location of the MI were related to the genotype distribution. Similarly, gender and age stratified analyses did not show any association of the GNB3 genotype and MI. CONCLUSIONS: In male individuals from a large population-based sample, the T allele of the GNB3 polymorphism was associated with arterial hypertension. However, the effects of the GNB3 825T allele on blood pressure were small and did not translate to a clinically relevant increase of risk for MI.
Antihypertensive Agents↗
Marked suppression of renin levels by beta-receptor blocker in patients treated with standard heart failure therapy: a potential mechanism of benefit from beta-blockade.
OBJECTIVES: Recent trials demonstrated beneficial effects of beta-blockers in combination with standard heart failure medication. The mechanisms underlying this benefit are incompletely understood. We hypothesized that beta-blockers may augment the inhibition of the renin-angiotensin system in patients with left ventricular (LV) dysfunction treated with angiotensin-converting enzyme (ACE) inhibitors and/or diuretics by prevention of renin upregulation that occurs in such patients. DESIGN: We examined plasma renin levels (direct radioimmunometric assay) in 312 men with previous myocardial infarction (MI) and echocardiographic LV dysfunction. Patients took medication according to their physicians' prescriptions: antiplatelet agents alone (n=62) or in combination with ACE inhibitors, diuretics or beta-blockers (n=250). RESULTS: Plasma renin levels were elevated in patients taking ACE inhibitors or diuretics and ACE inhibitors plus diuretics (adjusted means from multiple regression analysis were 28.5 mU L-1 [95% CI=20.6-39.5] and 73.7 mU L-1 [95% CI = 49.9- 109.9], respectively) compared with patients on antiplatelets alone (16.1 mU L-1, 95% CI = 13.5-19.3, P < 0.05 each). The combinations of beta-blockers with ACE inhibitors or diuretics and beta-blockers with ACE inhibitors plus diuretics were related to markedly suppressed plasma renin levels (adjusted means 16.4 [13.1-20.6] and 32.1 [23.3-44.3]) as compared with respective patient groups without beta-blockers (P < 0.01 each). CONCLUSIONS: Concomitant beta-blocker treatment can prevent the reactive renin stimulation and potentially the escape from effective inhibition of the renin-angiotensin system in patients with LV dysfunction after MI treated with ACE-inhibitors and/or diuretics.
Adrenergic beta-Antagonists↗
The D-allele of the ACE polymorphism is related to increased QT dispersion in 609 patients after myocardial infarction.
AIMS: Prolongation of QT dispersion can be observed in some patients with myocardial infarction and serves as a possible independent risk factor for sudden cardiac death. Angiotensin-converting enzyme (ACE) inhibition has been shown to reduce QT dispersion in myocardial infarction patients. We hypothesized that ACE gene I/D polymorphism, which is known to modulate ACE activity, may also affect QT dispersion after myocardial infarction. METHODS AND RESULTS: We studied 609 myocardial infarction patients (532 men, aged 56.1+/-0.3; mean 5.5 years after myocardial infarction) from a population-based myocardial infarction register by standardized questionnaire, anthropometry, ECG, echocardiography, and genotyping of ACE I/D polymorphism. In addition, 540 unaffected siblings (251 men, age 54.6+/-0.4 years) of these patients were studied by the same protocol. As compared with their healthy siblings, mean QT dispersion was prolonged in myocardial infarction patients (65.9+/-1.4 ms vs 91.2+/-2.3 ms, respectively, P<0.001). QT dispersion was negatively correlated to left ventricular ejection fraction (P<0.005). The ACE DD-genotype was associated with longer QT dispersion in myocardial infarction patients (103.0+/-4.6 ms vs 81.9+/-4.5 ms in the II group, P<0.001). This association was noted to be strong in multivariate analyses that included age, gender, ejection fraction, left ventricular end-diastolic diameter, medication, and heart rate. In contrast, no association between the ACE DD-genotype and QT dispersion was detected in healthy siblings of myocardial infarction patients. CONCLUSION: Thus, the ACE D-allele may be associated with increased QT dispersion in patients after myocardial infarction but not in healthy subjects. An interaction of myocardial damage and genetic predisposition that both enhance the activity of the renin angiotensin system may decrease the repolarization homogeneity of the heart.
Alleles↗
Siblings of myocardial infarction patients are overlooked in primary prevention of cardiovascular disease.
AIMS: Patients with arterial hypertension or hypercholesterolaemia may benefit from medical therapy for primary prevention of myocardial infarction. Preventive therapy may be particularly effective in individuals with a positive family history for myocardial infarction since such subjects are at high risk for coronary events. The objective of this population-based study was to analyse the risk profile as well as the current utilization of preventive strategies in asymptomatic siblings of patients with myocardial infarction. METHODS AND RESULTS: We studied siblings of 325 patients with premature myocardial infarction from the Augsburg MONICA myocardial infarction registry by standardized questionnaire, blood pressure recordings, and biochemical measurements. Out of 580 siblings, 510 were free of coronary heart disease symptoms. With multiple risk factors being present in most asymptomatic siblings, 29.4% of asymptomatic individuals had an estimated individual 10-year risk for a major cardiovascular event of > or = 20%, or when projected to the age of 60. According to the guidelines of the European Societies of Cardiology, Atherosclerosis, and Hypertension (ESC/EAS/ESH) from 1994 (1998 guidelines in parenthesis) dietary and lifestyle interventions were indicated for arterial hypertension in 48.1% (43.0%) and/or for hypercholesterolaemia in 17.3% (78.8%). Drug treatment was indicated for arterial hypertension in 27.9% (30.6%) and for hypercholesterolaemia in 13.6% (19.1%) of asymptomatic siblings. Of those individuals with the respective indication, actual drug treatment was given for arterial hypertension in 91.5% (83.3%) and for hypercholesterolaemia in 46.4% (33.0%). However, treatment targets were reached in only 31.0% (28.2%) with arterial hypertension and in 7.2% (5.2%) with hypercholesterolaemia, respectively. CONCLUSIONS: Most asymptomatic individuals with positive fraternal family history have more than one modifiable risk factor. Interestingly, a large number of these individuals appears to be under medical surveillance as many receive some sort of drug treatment. However, this therapy did not meet the treatment goals in the majority of those with arterial hypertension and/or hypercholesterolaemia. Thus, although individuals with a positive fraternal history for myocardial infarction can be easily identified, implementation of sufficient preventive strategies continues to be poor in a Western European country.
Adult↗
Long-term effects of in-hospital cardiac rehabilitation on the cardiac risk profile. A case-control study in pairs of siblings with myocardial infarction.
AIMS: In the general population, measures for secondary prevention of myocardial infarction are poorly utilized. Our aim was therefore to analyse whether post-myocardial infarction in-hospital rehabilitation and education programmes improve the subsequent utilization of preventive strategies. METHODS AND RESULTS: We screened 93 500 patient charts in cardiac rehabilitation clinics to identify a myocardial infarction patient with a sibling, who likewise had a myocardial infarction prior to the age of 60 years but was discordant with respect to the participation in cardiac in-hospital rehabilitation. In 92 such sibling pairs the coronary risk profile was studied by standardized questionnaire, biochemical measurements and physical examination. At the time of the acute myocardial infarction, both groups showed an equal risk factor distribution. However, at follow-up (on average 5.5 years after myocardial infarction), rehabilitation-siblings presented with significantly lower systolic (137+/-2 vs 150+/-3 mmHg, P<0.01) and diastolic blood pressure (82+/-1 vs 89+/-1 mmHg, P<0.01). Antihypertensive drug therapy resulted more often in effective (<or=140/90 mmHg) control of blood pressure (58% vs 29%, P<0.01). Blood lipid levels and smoking prevalence tended to be lower in rehabilitation-siblings. Significantly fewer rehabilitation-siblings presented with two or more modifiable risk factors (OR 0.36 (CI 0.17-0.76); P<0.01). There was a strong tendency towards fewer recurrent cardiac events (re-myocardial infarction, coronary angioplasty, coronary artery bypass grafting) during follow-up in rehabilitation-siblings (OR 0.57 (CI 0.31-1.04); P=0.07). CONCLUSION: An in-hospital programme for cardiac rehabilitation may successfully encourage therapy to modify risk factors and thus enhance the long-term implementation of secondary prevention.
Case-Control Studies↗
A heart price to pay for anaemia.
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Anemia↗
Indexation of left ventricular mass in adults with a novel approximation for fat-free mass.
BACKGROUND: Indexation to fat-free mass (FFM) seems to be the best option for adjusting left ventricular (LV) mass. However, measurements of FFM are frequently not available. OBJECTIVES: To define the relation of FFM with commonly available anthropometric measures in order to derive an approximation formula of FFM that can be used for valid indexation of LV mass. SUBJECTS AND METHODS: A total of 1,371 subjects from a community survey were examined by echocardiography to measure LV mass and by bioelectrical impedance analyses (BIA) for the determination of FFM. An approximation of FFM was generated in a healthy subgroup of 213 men and 291 women by non-linear regression techniques. RESULTS: Compared with body height, height2.0, height2.7, (the superscripts following weight and height are raised powers used as a more appropriate method for indexing LV mass) or body surface area, FFM measured by BIA in the healthy subgroups was best predicted by gender-specific equations of the form: FFM = 5.1 x height1.14 x weight0.41 for men and FFM = 5.34 x height1.47 x weight0.33 for women. In the healthy reference group, indexation of LV mass for BIA-determined FFM and approximated FFM (FFMa), respectively, equally eliminated gender differences in LV mass and markedly reduced the influence of body mass index without affecting the associations between blood pressure and LV mass. Validation of FFMa in two independent population-based samples, aged 52 to 67 years, of the same source population confirmed that LV mass indexed by FFMa produced results that were highly consistent with those obtained with indexation by BIA-determined FFM. CONCLUSIONS: We propose a novel approximation of FFM based on exponentials of body height and weight. It performed well in the indexation of LV mass in middle-aged men and women of this study. Evaluation of the equation in other populations should be awaited before its use is recommended in situations where direct determination of FFM is not possible.
Adult↗
Renin-angiotensin system gene polymorphisms: potential mechanisms for their association with cardiovascular diseases.
Since the first description of the angiotensin-converting enzyme insertion/deletion polymorphism more than a decade ago, many hundreds of investigations have reported associations between this polymorphism and cardiovascular diseases. Subsequently, similar studies were performed in relationship with several other renin-angiotensin system gene polymorphisms, most notably the angiotensinogen M235T polymorphism and the angiotensin AT(1) receptor A1166C polymorphism. Surprisingly however, especially in view of the many contradictory results that have been obtained, very little attention has been paid to the mechanism(s) that may link these genetic variants and respective diseases. Here, we review the limited evidence that is currently available on the functional consequences (including compensatory mechanisms) of the above three renin-angiotensin system gene polymorphisms, in order to provide an explanation for the reported associations (or lack thereof) between these polymorphisms and cardiovascular diseases.
Animals↗