Shared Genetic Causes of Cardiac Hypertrophy in Children and Adults

Further information: Hypertrophic Cardiomyopathy from Cardiovascular Medicine, 3rd Edn*

Although genetically similar to cardiomyopathies of adulthood, the role of childhood-onset idiopathic hypertrophic cardiomyopathy (HC) occurring with no family history is not known. Diagnosis is made because of abnormal physical findings that occur in the absence of either symptoms or sudden death. Rate of death and transplantation among these children is 40%, even when the affected child is well-managed medically. In adults, the onset of HC is a genetic condition caused either by inherited or by new mutations in genes that encode sarcomere proteins. To determine whether childhood onset of left ventricular hypertrophy has a shared genetic cause with HC, the authors of this paper [1] sequenced genes encoding eight sarcomeres in 84 children who were diagnosed with isolated idiopathic left ventricular hypertrophy before 15 years of age. Sixty-three of the children were boys and 21 were girls.

Mutations were identified in 21 of 33 children who had familial cardiomyopathy (CM). In 11 of the 25 children with presumed sporadic disease, four were carriers of new mutations and seven had inherited mutations. In over 75% of the children, mutations occurred in MYH7 and MYBPC3. A larger number of MYBPC3 missense mutations were detected than occur in adult-onset CM (P<0.005). In considering the differences in severity of left ventricular hypertrophy or contractile function in children with and in those without a mutation, there were no significant differences found. There was a significant difference between children with presumed sporadic disease and those with a family history of CM in the number who received implanted cardio-defibrillators (ICD). Significantly more who had a family history received an ICD (P=0.007). The authors determined that approximately one half of all childhood-onset cardiomyopathies were caused by mutated genes.

[1] Morita H, Rehm HL, Menesses A, et al. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med 2008;358:1899-908.

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Cardiac Troponin and Outcome in Acute Heart Failure

Further information: The Medical Management of Heart Failure from Cardiovascular Medicine, 3rd Edn*

The authors of this study [1] used data from the Acute Decompensated Heart Failure National Registry (ADHERE) to conduct a study for the evaluation of short-term outcomes associated with elevated troponin levels in patients with acute decompensated heart failure upon their admission to the hospital. Although cardiac troponin levels are measured to evaluate patients admitted to the hospital with acute coronary syndromes, the measurement is not routinely used in the risk-stratification process for evaluation of patients admitted with acute decompensated heart failure.

Data recorded by ADHERE of patients hospitalized between October 2001 and January 2004 with entry criteria that included a troponin level obtained at the time of hospitalization and a serum creatinine level of less than 2.0 mg/dl (177 µmol/l) were evaluated. A positive troponin test was defined as a cardiac troponin I level of 1.0 µg/l or higher or a cardiac troponin T level of 0.1 µg per liter or higher. Among 105,388 patients admitted for decompensated heart failure, troponin was measured in 84,872 patients (80%). Of these, 67,924 had a creatinine level of less than 2.0 mg/dl. Cardiac troponin I was measured in 61,924 patients, cardiac troponin T was measured in 7880 patients, and both proteins were measured in 1335 patients.

A total of 4240 (6%) patients measured positive for troponin, and those patients had lower systolic blood pressures on admission, lower LV ejection fractions, and higher in-hospitalization mortalities (8 % vs. 3%, P<0.001) than those who measured negative for troponin. Investigators determined that patients presenting with acute decompensated heart failure were similar to patients presenting with acute coronary syndromes in that a positive troponin status indicated high-risk patients.

The results suggest that measurement of troponin adds important diagnostic and prognostic information to the initial evaluation of patients with acute decompensated heart failure and should be used in the early assessment of risk.

[1] Peacock WF, De Marco T, Fonarow GC, et al. Cardiac troponin and outcome in acute heart failure. N Engl J Med 2008;358:2117-26

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Findings from the International LQTS Registry on congenital LQTS in children and adults

Further information: Sudden Cardiac Death from Cardiovascular Medicine, 3rd Edn*

The authors of the first paper [1] studied congenital long-QT syndrome (LQTS), a genetic disorder caused by mutations that encode regulatory channels for sodium, potassium, and calcium currents, as well as by a mutation in the cytoskeletal gene (ankyrin B) that affects sodium and calcium kinetics and leads to prolonged ventricular tachyarrhythmias that result in sudden cardiac death (SCD) in children. There is usually no structural heart disease associated with LQTS. Using the International Long QT Syndrome Registry, the authors evaluated data from the contributing centers on >3000 children (1–12 years old) and focused on aborted cardiac arrest (ACA) or SCD.

Significant predictors of both conditions were identified as clinical risk factors during childhood and included corrected QT interval (QTc) duration > 500ms (hazard ratio [HR], 2.72; 95% confidence interval [CI], 1.50–4.92; P=0.001) and prior syncope (recent syncope, <2 years: HR, 6.16; 95% CI 3.41–11.15; P<0.001; remote syncope, ≥2 years: HR, 2.67; 95% CI, 1.22–5.85; P=0.01, in boys. In girls, prior syncope was the only significant risk factor (recent syncope: HR, 27.82; 95% CI, 9.72–79.60; P<0.001; remote syncope: HR, 12.04; 95% CI, 3.79–38.26; P<0.001).

Although LQTSs were identified 50 years ago, and in recent years, advances have been made to identify the genotype-phenotype relationships and risk factors for cardiac events, these studies addressed the data using syncope as the primary part of the composite event end points. The authors of this study evaluated the genetic and clinical factors in the LQTS children that contributed toward the development of fatal (SCD) or near-fatal (ACA) events, and they identified clinical risk factors of marked QTc prolongation that were >500 ms in boys and syncope in both boys and girls to be significant predictors of ACA or SCD during childhood, but in girls, prior syncope was the only significant risk factor. The use of β-blocker therapy to prevent ACA or SCD was also assessed, and authors found that it is associated with a significant reduction in the risk of life-threatening events.

Using the same International LQTS Registry, the authors of the second paper (several of whom were also collaborators to the first paper) studied adults more than 40 years old with congenital LQTS [2]. Other studies by these authors assessed the syndrome in the decades of life leading up to 40 years, but until the present, the syndrome had not been studied in the aforementioned population. The belief had been prevalent that subjects affected with the congenital genetic disorder who had lived to the age of 40 or more years had a lower risk of ACA or SCD events. The authors evaluated 2759 subjects from the registry who were ages 41–75 years and categorized them into three subgroups. The groups included electrocardiographically affected (corrected QT interval [QTc] ≥470 ms), borderline (QTc 440–469 ms), and unaffected (QTc <440 ms). The patient population used in this study was made up of LQTS patients enrolled in the registry and their unaffected family members. Genetic testing was performed on 871 unaffected patients who had not been tested previously. A total of 539 genotyped subjects were identified as LQTS carriers and were categorized as genotype positive, and 332 subjects in the registry were not carriers and were categorized as genotype negative.

Affected versus unaffected individuals adjusted HR for ACA or SCD was 2.65 (P<0.001) in ages 41–60 years and 1.23 (P=0.31) in ages 61–75 years. Risk factors for ACA or SCD after age 40 in affected LQTS patients include female gender and time-dependent syncope, but in the unaffected subjects, men in this age group are shown to have a higher risk of life-threatening cardiac events. Additionally, presence of the LQT3 genotype was associated with a five-fold increase in the risk of ACA or SCD.

The authors concluded that for LQTS genotypes in the 40 years or older age group, affected subjects are influenced by age-specific factors related to gender and clinical history, and congenital LQTS continues as a risk factor for life-threatening cardiac events.

[1] Goldberg I, Moss AJ, Peterson R, et al. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital Long-QT syndrome. Circulation 2008;117:2184-2191

[2] Goldenberg I, Moss AJ, Bradley J, et al. Long-QT syndrome after age 40. Circulation 2008;117:2192-2201

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Treatment of Hypertension in Patients 80 Years of Age or Older

Further information: Aging and the Cardiovascular System from Cardiovascular Medicine, 3rd Edn*

The age group consisting of persons 80 years of age or older is the fastest growing segment of the general population, and although reduction of blood pressure is considered effective in stroke prevention and other vascular events, guidelines for the treatment of patients 80 years of age or older have been inconclusive as to the benefit achieved, perhaps even suggesting that risks are involved in blood pressure reduction therapy in the older population. A recent meta-analysis of a cohort of patients 80 years or older reported shorter survivals for patients with systolic blood pressures below 140 mmHg after adjustment for known predictors of death. In the Hypertension in the Very Elderly Trial (HYVET), investigators aimed to resolve the areas of uncertainty regarding the relative benefits and risks of antihypertensive treatment in patients 80 years of age or older [1].

To enroll in the trial, patients had to be 80 years old or older with persistent hypertension defined as sustained systolic blood pressure of 160 mm Hg. HYVET was a double-blind, randomized, placebo-controlled clinical trial that enrolled 3845 patients, and the investigators evaluated the effect of stepped-care therapy that began with a patient’s receiving the diuretic indapamide (sustained release, 1.5 mg) or placebo, and may have included the addition of perindopril, angiotensin-converting-enzyme (ACE) inhibitor), or placebo if necessary to attain and maintain the target blood pressure of 150/80 mmHg. Primary end point was fatal or nonfatal stroke. Both the active-treatment group of 1933 patients and the placebo-controlled group of 1912 patients were well-matched.

Active treatment was associated with a 30% reduction in the rate of fatal or nonfatal strokes (95% confidence interval [CI], -1 to 51; P=0.06), a 39% reduction in the rate of death from stroke (95% CI, 1–62; P=0.05); a 21% reduction in the rate of death from any cause (95% CI, 4–35; P=0.02), a 23% reduction in the rate of death from cardiovascular causes (95% CI, -1 to 40; P=0.06), and a 64% reduction in the rate of heart failure (95% CI, 42–78; P<0.001). There were 358 serious adverse events in the active-treatment group (358) vs. 448 adverse events in the placebo group (P=0.001); therefore, the results of HYVET provided evidence of the usefulness of treating hypertension in persons 80 years old or older, as well as providing important guidelines in the treatment of such patients.

[1] Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358:1887-98.

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Reversibility of Cardiac Abnormalities in Morbidly Obese Adolescents

Further information: The Medical Management of Heart Failure from Cardiovascular Medicine, 3rd Edn*

Over one million adolescents and young adults are affected by morbid obesity, defined as body mass index (BMI) ≥ 40 kg/m^2. It is common for obesity to be continued from adolescence to adulthood. The investigators of this study designed it to determine if cardiac abnormalities of structure and function, such as abnormal left ventricular (LV) mass (concentric LV hypertrophy), high-risk forms of LV geometry, cardiac workload, and abnormal diastolic function, could be reversed as a result of significant weight loss in adolescents [1].

Included in the study were all adolescents (≤19 years old) undergoing bariatric surgery at Cincinnati Children’s Hospital Medical Center who were considered morbidly obese by having a BMI in the ≥99th percentile. Bariatric surgery was used as the model since the surgery results in rapid and profound weight loss over a short period of time. Patients with congenital heart disease were excluded. There were 38 adolescents in the study ranging from 13 to 19 years old, and 29 were female, 9 were male, 33 were Caucasian, and five were African-American.

Mean weight loss was 59±15 kg. Preoperative BMI was 60±9 kg/m^2, and postoperative BMI was 40±8 kg/m^2 (P>0.0001). Change in LVM index was 54±13 g/m^2.7 to 42±10 g/m^2.7 (P<0.0001) which correlated with weight loss (r=0.41, P=0.01). Presence of concentric LV hypertrophy improved from 28% preoperatively to only 3% postoperatively (P=0.007), and normal LV geometry improved from 36% to 79% postoperatively (P=0.009). Diastolic function also improved (mitral E/Ea lateral 7.7±2.3 vs. 6.3±1.6, P=0.003). Cardiac workload decreased as shown in rate-pressure product (P<0.001).

The authors of this study demonstrated for the first time that abnormalities of cardiac structure and function in morbidly obese adolescents could be reversed with weight loss, and this fact should be an indicator of the importance of early intervention in obese youth. Long-term follow-up studies are needed to determine if the improvements in LVM and cardiac structure and function mean a long-term reduction in their CV morbidity in adulthood.

[1] Ippisch HM, Inge TH, Daniels SR et al. Reversibility of cardiac abnormalities in morbidly obese adolescents. JAMA 2008;51:1342-8

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Triple-Site vs. Dual-Site Ventricular Stimulation in Patients with Congestive Heart Failure

Further information: The Medical Management of Heart Failure from Cardiovascular Medicine, 3rd Edn*

“The Triple Resynchronization in Paced Heart Failure Patients (TRIP-HF)” was a multicenter, single-blind randomized crossover study designed to compare the safety and efficacy of triple-site (3-V) versus dual-site (2-V) biventricular stimulation in patients who after receiving optimal medical therapy and presenting with permanent atrial fibrillation (AF) had remained in New York Heart Association (NYHA) functional class III to IV [1]. Primarily, the aim of the study was to compare the quality of ventricular resynchronization (VR) by 2-V versus 3-V stimulation by calculating the Z ratio, an echocardiographic marker of abnormal ventricular activation. The main secondary endpoint was change in left ventricular end-systolic volume (LVESV) to assess the degree of LV reverse remodeling with 2-V versus 3-V stimulation. Additional secondary objectives were assessment of change in quality of life (QOL) as determined by the Minnesota Living With Heart Failure questionnaire and level of exercise capacity as measured by the 6-minute hall walk (6-MHW) test.

Enrolled in the study were 40 patients who had received optimal drug treatment, but still had severe to moderate heart failure. Patients had a mean age of 70±9 years, a mean LV ejection fraction (LVEF) of 26±11%, and permanent AF that required pacing for slow ventricular rates. A cardiac resynchronization therapy (CRT) device was implanted in 34 patients, and after 3 months of biventricular stimulation, the patients were randomly assigned to stimulation for 3 months with either 1 RV and 2 LV leads (3-V), or to conventional stimulation with one RV and one LV lead (2-V), and then crossed over for 3 months to the other configuration. Data from the 6 and 9 month visits were combined to compare end points associated with 2-V versus 3-V. Data from 26 patients were eligible for analysis.

There was no significant difference found between 2-V and 3-V in Z ratio, QOL, or 6-MHW. However, patients had significantly higher LVEFs (27±11% vs. 35±11%, P=0.001) and smaller LV end-systolic volumes (157±69 cm3 vs. 134±75 cm3; P=0.02) and diameters (57±12 mm vs. 54±10 mm, P=0.02) were observed with 3-V rather than with 2-V.

The investigators concluded that triple-site biventricular stimulation, including simultaneous stimulation of 2 distant L sites, resulted in greater benefits in LVEFs and LVESVs than standard biventricular stimulation. This study was conducted in a small group of patients, and the results need to be confirmed in a larger population of patients over a longer time period.

[1] Leclercq C, Gadler F, Kranig W et al. A randomized comparison of triple-site versus dual-site ventricular stimulation in patients with congestive heart failure. J Am Coll Cardiol 2008;51:1455-62

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Local Delivery of Paclitaxel to Inhibit Restenosis During Angioplasty of the Leg

Further information: Endovascular Procedures for the Treatment of Peripheral Vascular Disease from Cardiovascular Medicine, 3rd Edn*

Investigators at the universities of Tubingen and Berlin and at the Herz-Zentrum Bad Krozingen in Germany conducted a prospective, randomized, multicenter trial (Local Taxane with Short Exposure for Reduction of Restenosis in Distal Arteries [THUNDER]) to evaluate percutaneous transluminal angioplasty for revascularization of the superficial femoral artery [1].

Whereas drug-eluting stents reduce restenosis in coronary arteries and other vascular beds, their efficacy has not been proven in peripheral arteries. The purpose of the current study was to investigate the effect of paclitaxel on restenosis after angioplasty of superficial femoral or popliteal arteries when restenosis had occurred. A total of 154 patients between 18 and 95 years of age who had symptomatic peripheral artery disease and one or more obstructive lesions, either new or restenotic, were randomized into three groups: standard balloon catheters coated with paclitaxel, uncoated balloons with paclitaxel in contrast medium, or uncoated balloons (no paclitaxel) as control. The mean age was 68±8 years. Of the 154 patients, 24% smoked, 49% were diabetic, 27% of the lesions were totally occluded, and 36% of them were restenotic lesions.

The mean lesion length was 7.4±6.5 cm, and there were no significant differences in baseline characteristics between the three groups. No adverse events were attributable to the paclitaxel-coated balloons. At six months, the mean late lumen loss was 1.7±1.8 mm in the control group, as compared to 0.4±1.2 mm (P<0.001) in the group treated with paclitaxel-coated balloons and 2.2±1.6 mm (P=0.11) in the group treated with paclitaxel in the contrast medium. The revascularization rate of target lesions at 6 months was 20 of 54 (37%) in the control group, 2 of 48 in (4%) in the group treated with paclitaxel-coated balloons (P<0.001 vs. control), and 15 of 52 (29%) in the group treated with paclitaxel in the contrast medium (P=0.41 vs. control). At 24 months, the rates increased to 28 of 54 (52%), 7 of 48 (15%), and 21 of 52 (40%), respectively.

These results show significant reductions in late lumen loss and femoralpopliteal disease associated with the use of paclitaxel-coated angioplasty balloons during percutaneous treatment.

[1] Tepe G, Zeller T, Albrecht T et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2008;358:689-99

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