Multicenter, Prospective, Randomized Controlled Trial of High-Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial.

BACKGROUND: Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. METHODS: In a multicenter, prospective, randomized, open-label, blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk nonrandomized patients with cardiac troponin I concentrations in the lower 2 tertiles, we hypothesized the absence of a 6-month change in left ventricular ejection fraction and tested for equivalence of ±2%. RESULTS: Between October 2017 and June 2021, 175 patients (mean age, 53 years; 87% female; 71% with breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy, respectively. After adjustment for age, pretreatment left ventricular ejection fraction, and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was -0.37% (95% CI, -3.59% to 2.85%; P=0.82). In low-risk nonrandomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3%, respectively: estimated mean difference, 2.87% (95% CI, 1.63%-4.10%; P=0.92, not equivalent). CONCLUSIONS: Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk nonrandomized patients had similar declines in left ventricular ejection fraction, bringing into question the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy need to be better defined in patients receiving high-dose anthracycline. REGISTRATION: URL: https://doi.org; Unique identifier: 10.1186/ISRCTN24439460. URL: https://www.clinicaltrialsregister.eu/ctr-search/search; Unique identifier: 2017-000896-99.

Rationale and Design of the Cardiac CARE Trial: A Randomized Trial of Troponin-Guided Neurohormonal Blockade for the Prevention of Anthracycline Cardiotoxicity.

BACKGROUND: Anthracyclines are effective cytotoxic drugs used in the treatment of breast cancer and lymphoma but are associated with myocardial injury, left ventricular dysfunction, and heart failure. Anthracycline-induced cardiotoxicity is highly variable in severity and without a proven therapeutic intervention. ß-Adrenergic receptor blockers and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients. METHODS: The Cardiac CARE trial is a multicentre prospective randomized open-label blinded end point trial of combination ß-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapy in patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy that is associated with myocardial injury. Patients at higher risk of cardiotoxicity with plasma high-sensitivity cTnI (cardiac troponin I) concentrations in the upper tertile at the end of chemotherapy are randomized to standard of care plus combination candesartan and carvedilol therapy or standard of care alone. All patients undergo cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. The primary end point is the change in left ventricular ejection fraction at 6 months after chemotherapy. In low-risk nonrandomized patients, left ventricular ejection fraction before and 6 months after anthracycline will be compared with define the specificity of the high-sensitivity cTnI assay for identifying low-risk participants who do not develop left ventricular systolic dysfunction. DISCUSSION: Cardiac CARE will examine whether cardiac biomarker monitoring identifies patients at risk of left ventricular dysfunction following anthracycline chemotherapy and whether troponin-guided treatment with combination candesartan and carvedilol therapy prevents the development of left ventricular dysfunction in these high-risk patients.

Ferumoxytol-enhanced MRI in patients with prior cardiac transplantation.

Objectives: Ultra-small superparamagnetic particles of iron oxide (USPIO)-enhanced MRI can detect cellular inflammation within tissues and may help non-invasively identify cardiac transplant rejection. Here, we aimed to determine the normal reference values for USPIO-enhanced MRI in patients with a prior cardiac transplant and examine whether USPIO-enhanced MRI could detect myocardial inflammation in patients with transplant rejection. Methods: Ten volunteers and 11 patients with cardiac transplant underwent T2, T2* and late gadolinium enhancement 1.5T MRI, with further T2* imaging at 24 hours after USPIO (ferumoxytol, 4 mg/kg) infusion, at baseline and 3 months. Results: Ten patients with clinically stable cardiac transplantation were retained for analysis. Myocardial T2 values were higher in patients with cardiac transplant versus healthy volunteers (53.8±5.2 vs 48.6±1.9 ms, respectively; p=0.003). There were no differences in the magnitude of USPIO-induced change in R2* in patients with transplantation (change in R2*, 26.6±7.3 vs 22.0±10.4 s-1 in healthy volunteers; p=0.28). After 3 months, patients with transplantation (n=5) had unaltered T2 values (52.7±2.8 vs 52.12±3.4 ms; p=0.80) and changes in R2* following USPIO (29.42±8.14 vs 25.8±7.8 s-1; p=0.43). Conclusion: Stable patients with cardiac transplantation have increased myocardial T2 values, consistent with resting myocardial oedema or fibrosis. In contrast, USPIO-enhanced MRI is normal and stable over time suggesting the absence of chronic macrophage-driven cellular inflammation. It remains to be determined whether USPIO-enhanced MRI may be able to identify acute cardiac transplant rejection. Trial registration number: NCT02319278349 (https://clinicaltrials.gov/ct2/show/NCT02319278) Registered 03.12.2014 EUDraCT 2013-002336-24.

Ferumoxytol-enhanced magnetic resonance imaging in acute myocarditis.

OBJECTIVES: Ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI can detect tissue-resident macrophage activity and identify cellular inflammation within tissues. We hypothesised that USPIO-enhanced MRI would provide a non-invasive imaging technique that would improve the diagnosis and management of patients with acute myocarditis. METHODS: Ten volunteers and 14 patients with suspected acute myocarditis underwent T2, T2* and late gadolinium enhancement (LGE) 3T MRI, with further T2* imaging at 24 hours after USPIO (ferumoxytol, 4 mg/kg) infusion, at baseline and 3 months. Myocardial oedema and USPIO enhancement were determined within areas of LGE as well as throughout the myocardium. RESULTS: Myocarditis was confirmed in nine of the 14 suspected cases of myocarditis. There was greater myocardial oedema in regions of LGE in patients with myocarditis when compared with healthy volunteer myocardium (T2 value, 57.1±5.3 vs 46.7±1.6 ms, p<0.0001). There was no demonstrable difference in USPIO enhancement between patients and volunteers even within regions displaying LGE (change in R2*, 35.0±15.0 vs 37.2±9.6 s-1, p>0.05). Imaging after 3 months in patients with myocarditis revealed a reduction in volume of LGE, a reduction in oedema measures within regions displaying LGE and improvement in ejection fraction (mean -19.7 mL, 95% CI (-0.5 to -40.0)), -5.8 ms (-0.9 to -10.7) and +6% (0.5% to 11.5%), respectively, p<0.05 for all). CONCLUSION: In patients with acute myocarditis, USPIO-enhanced MRI does not provide additional clinically relevant information to LGE and T2 mapping MRI. This suggests that tissue-resident macrophages do not provide a substantial contribution to the myocardial inflammation in this condition.Clinical trial registration NCT02319278; Results.

Mitochondrial uncoupling proteins regulate angiotensin-converting enzyme expression: crosstalk between cellular and endocrine metabolic regulators suggested by RNA interference and genetic studies.

Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3-55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8-fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role.

Ferumoxytol-enhanced magnetic resonance imaging methodology and normal values at 1.5 and 3T.

BACKGROUND: Ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) can detect tissue-resident macrophage activity and identify cellular inflammation. Clinical studies using this technique are now emerging. We aimed to report a range of normal R2* values at 1.5 and 3 T in the myocardium and other tissues following ferumoxytol administration, outline the methodology used and suggest solutions to commonly encountered analysis problems. METHODS: Twenty volunteers were recruited: 10 imaged each at 1.5 T and 3 T. T2* and late gadolinium enhanced (LGE) MRI was conducted at baseline with further T2* imaging conducted approximately 24 h after USPIO infusion (ferumoxytol, 4 mg/kg). Regions of interest were selected in the myocardium and compared to other tissues. RESULTS: Following administration, USPIO was detected by changes in R2* from baseline (1/T2*) at 24 h in myocardium, skeletal muscle, kidney, liver, spleen and blood at 1.5 T, and myocardium, kidney, liver, spleen, blood and bone at 3 T (p < 0.05 for all). Myocardial changes in R2* due to USPIO were 26.5 ± 7.3 s-1 at 1.5 T, and 37.2 ± 9.6 s-1 at 3 T (p < 0.0001 for both). Tissues showing greatest ferumoxytol enhancement were the reticuloendothelial system: the liver, spleen and bone marrow (216.3 ± 32.6 s-1, 336.3 ± 60.3 s-1, 69.9 ± 79.9 s-1; p < 0.0001, p < 0.0001, p = ns respectively at 1.5 T, and 275.6 ± 69.9 s-1, 463.9 ± 136.7 s-1, 417.9 ± 370.3 s-1; p < 0.0001, p < 0.0001, p < 0.01 respectively at 3 T). CONCLUSION: Ferumoxytol-enhanced MRI is feasible at both 1.5 T and 3 T. Careful data selection and dose administration, along with refinements to echo-time acquisition, post-processing and analysis techniques are essential to ensure reliable and robust quantification of tissue enhancement. TRIAL REGISTRATION: ClinicalTrials.gov Identifier - NCT02319278 . Registered 03.12.2014.

Mitochondrial uncoupling proteins regulate angiotensin-converting enzyme expression: crosstalk between cellular and endocrine metabolic regulators suggested by RNA interference and genetic studies.

Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3-55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8-fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role.

Biomarkers of acute rejection following cardiac transplantation.

Cardiac transplantation can be a life-saving treatment for selected patients with heart failure. However, despite advances in immunosuppressive therapy, acute allograft rejection remains a significant cause of morbidity and mortality. The current 'gold standard' for rejection surveillance is endomyocardial biopsy, which aims to identify episodes of rejection prior to development of clinical manifestations. This is an invasive technique with a risk of false-positive and false-negative results. Consequently, a wide variety of noninvasive alternatives have been investigated for their potential role as biomarkers of rejection. This article reviews the evidence behind proposed alternatives such as imaging techniques, electrophysiological parameters and peripheral blood markers, and highlights the potential future role for biomarkers in cardiac transplantation as an adjunct to biopsy.

Left ventricular wall thickness and the presence of asymmetric hypertrophy in healthy young army recruits: data from the LARGE heart study.

BACKGROUND: To use cardiovascular magnetic resonance to investigate left ventricular wall thickness and the presence of asymmetrical hypertrophy in young army recruits before and after a period of intense exercise training. METHODS AND RESULTS: Using cardiovascular magnetic resonance, the left ventricular wall thickness was measured in all 17 segments and a normal range was calculated for each. The prevalence of asymmetrical wall thickening was assessed before and after training and defined by a ventricular wall thickness ≥13.0 mm that was >1.5× the thickness of the opposing myocardial segment. Five hundred forty-one men (mean age, 20±2 years) were recruited, 309 underwent repeat scanning. Considerable variation in wall thickness was observed across the ventricle with progressive thickening on moving from the apex to base (P<0.001) and in the basal and midcavity septum compared with the lateral wall (11.0±1.4 versus 10.1±1.3 mm; P<0.001). Twenty-three percent had a maximal wall thickness ≥13.0 mm, whereas the prevalence of asymmetrical wall thickening increased from 2.2% to 10% after the exercise-training program. In those who developed asymmetry, the wall thickness/diastolic volume ration remained normal (0.09±0.02 mm⋅m(2)⋅mL(-1)), indicative of a remodeling response to exercise. CONCLUSIONS: In a cohort of healthy young white men, we have demonstrated that wall thickness frequently measures ≥13.0 mm and that asymmetrical wall thickening is common and can develop as part of the physiological response to exercise. A diagnosis of hypertrophic cardiomyopathy in young athletic men should, therefore, not be made purely on the basis of regional wall thickening.

Bone structure and geometry in young men: the influence of smoking, alcohol intake and physical activity.

BACKGROUND: The development of osteoporosis is influenced by peak bone mass attained in youth - the influence of lifestyle factors upon which is poorly described, especially amongst males. We sought to address this issue in a large scale study. METHODS: Hip bone mineral density (dual X-ray absorptiometry, DXA), bone microarchitecture (calcaneal quantitative ultrasound, QUS) and femoral geometry (magnetic resonance imaging, MRI) were characterised in 723 healthy male military recruits (mean ± S.E. age 19.92 ± 0.09 years [range 16-18 years], height 177.67 ± 0.24 cm, weight 73.17 ± 0.37 kg) on entry to UK Army training. Association was sought with prior physical activity, smoking status and alcohol intake. RESULTS: DXA measures were made in 651, MRI measures in 650, and QUS measures in 572 recruits. Increasing levels of weight-bearing physical activity enhanced periostial bone apposition, increases in both total hip and femoral neck bone mineral density (BMD; p ≤ 0.0001 in both cases), and cortical [p<0.0001] and periostial bone volumes [p=0.016]. Smoking habit was associated with preserved bone geometry, but worse BMD [p=0.0001] and QUS characteristics [p ≤ 0.0005]. Moderate alcohol consumption was associated with greater BMD [p ≤ 0.015]. CONCLUSIONS: Whilst exercise (and perhaps moderate alcohol intake) is beneficial to bone morphometry, smoking is detrimental to bone mineral density in young males notable for the likely short duration of smoking to influence skeletal properties. However, differences in socio-economic status, lifestyle and related environmental factors may to some extent confound our results.

Use of implantable cardioverter defibrillators in patients with left ventricular assist devices.

Patients with left ventricular assist devices (LVADs) are at high risk of sustained ventricular arrhythmias, but these may be remarkably well tolerated and the association with sudden death is unclear. Many patients who receive an LVAD already have an implantable cardioverter defibrillator (ICD). While it is standard practice to reactivate a previously implanted ICD in an LVAD recipient, this should include discussion of the revised risks and benefits of ICD therapy following LVAD implantation. In particular, patients should be warned that they might receive a significant number of ICD shocks that may not be life saving. When ICDs are reactivated, device programming should minimize the risk of repeated shocks for non-sustained or well-tolerated ventricular arrhythmias. Implantation of a primary prevention ICD after implantation of an LVAD is not supported by current evidence, poses potential risks, and should be the subject of a clinical trial before it becomes standard practice.

Variation in the uncoupling protein 2 and 3 genes and human performance.

Uncoupling proteins 2 and 3 (UCP2 and UCP3) may negatively regulate mitochondrial ATP synthesis and, through this, influence human physical performance. However, human data relating to both these issues remain sparse. Examining the association of common variants in the UCP3/2 locus with performance phenotypes offers one means of investigation. The efficiency of skeletal muscle contraction, delta efficiency (DE), was assessed by cycle ergometry in 85 young, healthy, sedentary adults both before and after a period of endurance training. Of these, 58 were successfully genotyped for the UCP3-55C>T (rs1800849) and 61 for the UCP2-866G>A (rs659366) variant. At baseline, UCP genotype was unrelated to any physical characteristic, including DE. However, the UCP2-866G>A variant was independently and strongly associated with the DE response to physical training, with UCP2-866A allele carriers exhibiting a greater increase in DE with training (absolute change in DE of -0.2 ± 3.6% vs. 1.7 ± 2.8% vs. 2.3 ± 3.7% for GG vs. GA vs. AA, respectively; P = 0.02 for A allele carriers vs. GG homozygotes). In multivariate analysis, there was a significant interaction between UCP2-866G>A and UCP3-55C>T genotypes in determining changes in DE (adjusted R(2) = 0.137; P value for interaction = 0.003), which was independent of the effect of either single polymorphism or baseline characteristics. In conclusion, common genetic variation at the UCP3/2 gene locus is associated with training-related improvements in DE, an index of skeletal muscle performance. Such effects may be mediated through differences in the coupling of mitochondrial energy transduction in human skeletal muscle, but further mechanistic studies are required to delineate this potential role.

The Lichfield bone study: the skeletal response to exercise in healthy young men.

The skeletal response to short-term exercise training remains poorly described. We thus studied the lower limb skeletal response of 723 Caucasian male army recruits to a 12-wk training regime. Femoral bone volume was assessed using magnetic resonance imaging, bone ultrastructure by quantitative ultrasound (QUS), and bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA) of the hip. Left hip BMD increased with training (mean ± SD: 0.85 ± 3.24, 2.93 ± 4.85, and 1.89 ± 2.85% for femoral neck, Ward's area, and total hip, respectively; all P < 0.001). Left calcaneal broadband ultrasound attenuation rose 3.57 ± 0.5% (P < 0.001), and left and right femoral cortical volume by 1.09 ± 4.05 and 0.71 ± 4.05%, respectively (P = 0.0001 and 0.003), largely through the rise in periosteal volume (0.78 ± 3.14 and 0.59 ± 2.58% for right and left, respectively, P < 0.001) with endosteal volumes unchanged. Before training, DXA and QUS measures were independent of limb dominance. However, the dominant femur had higher periosteal (25,991.49 vs. 2,5572 mm(3), P < 0.001), endosteal (6,063.33 vs. 5,983.12 mm(3), P = 0.001), and cortical volumes (19,928 vs. 19,589.56 mm(3), P = 0.001). Changes in DXA, QUS, and magnetic resonance imaging measures were independent of limb dominance. We show, for the first time, that short-term exercise training in young men is associated not only with a rise in human femoral BMD, but also in femoral bone volume, the latter largely through a periosteal response.

CMR Features in Cardiac Sarcoidosis.

Sarcoidosis is a multisystemic disorder of unknown aetiology characterised by the formation of noncaseating epithelioid cell granuloma involving various organ systems. Cardiac involvement has an important prognostic factor as it can present with life-threatening arrythmias and sudden death. Here, we present a case of cardiac sarcoidosis in a 46-year-old gentleman who presented with nonspecific signs and symptoms. We also discuss diagnostic difficulties especially when cardiac involvement is the only clinical sign. In this case, cardiac magnetic resonance (CMR) played an important role in the diagnosis and followup of our patient.

C-reactive protein gene variant and the human left ventricular growth response to exercise: data from The LARGE Heart Study.

OBJECTIVE: Increased levels of C-reactive protein (CRP) are associated with left ventricular (LV) hypertrophy. This association may be causal (either directly or indirectly) or simply a confounder resulting from the recognized relationship between CRP and vascular disease. We attempted to clarify this issue, by assessing the association of a variant of the CRP gene with exercise-induced left ventricular hypertrophy in young healthy males: homozygosity for the T (rather than C) allele of the CRP +1444C>T gene variant is associated with serum CRP levels which are 0.68 mg/L higher than carriers of the C allele. METHODS AND RESULTS: LV mass was measured using cardiovascular magnetic resonance in 301 army recruits before and after an identical 12-week physical training program. Subjects were genotyped for the CRP +1444C>T gene variant. LV mass was 164.25 +/-24.52 g at entry and increased with training (+3.77 +/- 10.77 g). This increase was greatest among those homozygous for the rare T allele (+8.17 6 12.09 vs. +3.37 6 10.58 for TT genotype vs. C-allele carriers respectively, P = 0.033). CONCLUSIONS: CRP genotype is associated with a greater LV growth to exercise, supporting a causal association between CRP and LV growth. Whether such an association might be directly mediated or results from alterations in phenotypes which themselves drive LV growth (for instance, altered arterial compliance) is not clear.

The use of 3D transoesophageal echocardiography in clarifying the mechanism underlying a 'flexing' strut of a mitral valve replacement.

We report the case of a 76-year-old lady who had a mitral valve (MV) replacement for severe MV stenosis. Several days following the procedure, a routine transthoracic echocardiogram (TTE) was performed. Despite the prosthesis leaflets opening well anterograde maximum velocities were elevated; MV peak velocity of 2.4 m/s. A transoesophageal echocardiogram (TEE) demonstrated the superior strut of the prosthesis appearing to rotate inwards such that the ventricular (non-fixed) end of the struts approximate to one another during systole, reducing the effective orifice area for anterograde flow. A 3D TEE was performed. This showed that the valve struts were not parallel, with the planes of the struts converging from the base to the apex. However, this abnormal conformation appeared to be fixed rather than worsening in systole. The apparent movement of the posterior strut seen in the 2D TEE images appears to have resulted from systole movement of this strut partially out of the plane of the TEE (2D) cut. We believe the case demonstrates the value of 3D real-time TEE in the assessment of the MV prosthesis function.

Electrocardiographic (ECG) criteria for determining left ventricular mass in young healthy men; data from the LARGE Heart study.

BACKGROUND: Doubts remain over the use of the ECG in identifying those with increased left ventricular (LV) mass. This is especially so in young individuals, despite their high prevalence of ECG criteria for LV hypertrophy. We performed a study using cardiovascular magnetic resonance (CMR), which provides an in vivo non-invasive gold standard method of measuring LV mass, allowing accurate assessment of electrocardiography as a tool for defining LV hypertrophy in the young. METHODS AND RESULTS: Standard 12-lead ECGs were obtained from 101 Caucasian male army recruits aged (mean +/- SEM) 19.7 +/- 0.2 years. LV mass was measured using CMR. LV mass indexed to body surface area demonstrated no significant correlation with the Cornell Amplitude criteria or Cornell Product for LV hypertrophy. Moderate correlations were seen with the Sokolow-Lyon Amplitude (0.28) and Sokolow-Lyon Product (0.284). Defining LV hypertrophy as a body surface area indexed left ventricular mass of 93 g/m(2), calculated sensitivities [and specificities] were as follows; 38.7% [74.3%] for the Sokolow-Lyon criteria, 43.4% [61.4%] for the Sokolow-Lyon Product, 19.4% [91.4%] for Cornell Amplitude, and 22.6% [85.7%] for Cornell Product. These values are substantially less than those reported for older age groups. CONCLUSION: ECG criteria for LV hypertrophy may have little value in determining LV mass or the presence of LV hypertrophy in young fit males.

Different contributions of the angiotensin-converting enzyme C-domain and N-domain in subjects with the angiotensin-converting enzyme II and DD genotype.

BACKGROUND: Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism-related differences in ACE concentration do not result in differences in angiotensin levels. METHODS AND RESULTS: To investigate whether this relates to differences in the contribution of the ACE C-domain and N-domain, we quantified, using the C-domain-selective inhibitors quinaprilat and RXPA380, and the N-domain-selective inhibitor RXP407, the contribution of both domains to the metabolism of angiotensin I, bradykinin, the C-domain-selective substrate Mca-BK(1-8), and the N-domain-selective substrate Mca-Ala in serum of IIs, DDs, and 'hyperACE' subjects (i.e., subjects with increased ACE due to enhanced shedding). During incubation with angiotensin I, the highest angiotensin II levels were observed in sera with the highest ACE activity. This confirms that ACE is rate-limiting with regard to angiotensin II generation. C-domain-selective concentrations of quinaprilat fully blocked angiotensin I-II conversion in DDs, whereas additional N-domain blockade was required to fully block conversion in IIs. Both domains contributed to bradykinin hydrolysis in all subjects, and the inhibition profile of RXP407 when using Mca-Ala was identical in IIs and DDs. In contrast, the RXPA380 concentrations required to block C-domain activity when using Mca-BK (1-8) were three-fold higher in IIs than DDs. CONCLUSION: The contributions of the C-domain and N-domain differ between DDs and IIs, and RXPA380 is the first inhibitor capable of distinguishing D-allele ACE from I-allele ACE. The lack of angiotensin II accumulation in DDs in vivo is not because of the often quoted concept that ACE is a nonrate-limiting enzyme. It may relate to the fact that in IIs both the N-domain and C- domain generate angiotensin II, whereas in DDs only the C-domain converts angiotensin I.

Haplotype of growth hormone and angiotensin I-converting enzyme genes, serum angiotensin I-converting enzyme and ventricular growth: pathway inference in pharmacogenetics.

OBJECTIVES: An insertion/deletion (I/D) polymorphism in the angiotensin I-converting enzyme (ACE) gene is associated with variations in circulating and tissue angiotensin I-converting enzyme activity, and differences in exercise-induced left ventricular hypertrophic response. A genetic marker (CSH1.01) in the syntenic GH-CSH gene cluster correlates with metabolic syndrome in adult life in males. Approximately 24% linkage disequilibrium between CSH1.01T and D alleles of ACE I/D has also been reported. The objective was to examine the hypothesis that effects ascribed to ACE genotype may reflect causality in the GH-CSH cluster. METHODS: The ACE I/D polymorphism and GH-CSH BglII-B single nucleotide polymorphism (in strong linkage disequilibrium with CSH1.01) were determined in 847 British Army recruits. Serum angiotensin I-converting enzyme activity and left ventricular mass were measured before and after a 12-week physical training program. Genotype and haplotype analyses of both markers were performed in relation to these phenotypes. RESULTS: The ACE I/D polymorphism was in linkage disequilibrium with BglII-B (D'=0.3). Strong association was seen between ACE I/D genotypes and serum angiotensin I-converting enzyme activity (P<0.0001), but not left ventricular mass change. BglII-B genotypes also associated significantly with serum angiotensin I-converting enzyme level (P<0.0001). Haplotype analysis, however, showed that most of this association resulted from linkage disequilibrium between BglII-B and ACE I/D. BglII-B did not associate with left ventricular mass change. CONCLUSIONS: GH-CSH BglII-B genotype associates significantly with angiotensin I-converting enzyme levels, but only through linkage disequilibrium with ACE I/D. Every phenotype with which ACE I/D has been associated merits investigation of potential causal effects originating in the GH-CSH cluster (and vice versa), otherwise the chain of causality could be misinterpreted.