Further information: Medical Treatment of Unstable Angina, Acute Non–ST-Elevation Myocardial Infarction, and Coronary Artery Spasm (see p937), Pathophysiology and Clinical Impact of Diastolic Heart Failure (see p1201) and Dilated Cardiomyopathy (see p1233) from Cardiovascular Medicine, 3rd Edn*

This article [1] contains observations from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary-Thrombolysis in Myocardial Infarction 36) Trial (MERLIN-TIMI 36), a trial conducted at 440 sites between 2004 and 2007 to determine the efficacy and safety of ranolazine in long-term treatment of 6500 patients with non-ST segment elevation acute coronary syndromes (ACS). As part of the MERLIN-TIMI 36 trial, investigators designed a prospective evaluation of the interaction between B-type natriuretic peptide (BNP) and the effect of ranolazine in patients with ACS. Because elevated BNP and the N-terminal portion of BNP prohormone identify patients at high risk of death and heart failure (HF), intense effort is being made to find treatments that would mitigate the risk of elevated BNP. There were 4543 baseline samples in which BNP had been measured from patients who had been randomized to ranolazine or placebo, and the patients were followed for 343 days. BNP elevation was defined as >80 pg/ml. The primary end point was a composite of cardiovascular (CV) death, myocardial infarction (MI), and recurrent ischemia.

Results showed that in 1935 patients with elevated BNP (>80 pg/ml), the risk of the primary end-point was higher (26.4% vs. 20.4%, P=0.0001), higher for CV death (8.0% vs. 2.1%, P<0.001, and higher for MI (10.6% vs. 5.8%, P<0.001) at 1 year. The primary end-point was reduced by ranolazine (hazard ratio [HR]; 0.79; 95% confidence internal [CI]: 0.66–0.94, P=0.009). For recurrent ischemia in patients with elevated BNP, the effect of ranolazine was directionally similar (HR: 0.78; 95% CI: 0.62–0.98; P=0.04) and CV death or MI (HR: 0.83; 95% CI: 0.66–1.05, P=0.12). Ranolazine had no effect on patients without elevated BNP, did not reduce BNP concentration over time, and did not reduce the clinical end-point for patients with new or worsening HF. Nevertheless, it did identify patients at high risk of recurrent myocardial ischemia ameliorated by ranolazine. Therefore, the investigators concluded that the effects of ranolazine warrant additional study.

In an editorial [2] in this same issue of JACC, the authors stated that while this carefully done study does not provide conclusive evidence that ranolazine should be used in patients with ACS and elevated BNP levels, it does lay the groundwork for a prospective clinical trial.

[1] Morrow DA, Scirica BM, Sabatine MS, et al. B-Type Natriuretic Peptide and the Effect of Ranolazine in Patients with Non-ST Segment Elevation Acute Coronary Syndromes. J Am Coll Cardiol 2009;55:1189-96

[2] Califf RM, Shah SH, Newby LK. Biomarker Bonanza? J Am Coll Cardiol 2009;55:1197-99
 
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Further information: Pathophysiology and Clinical Recognition of Heart Failure (see p1379) from Cardiovascular Medicine, 3rd Edn*

In heart failure (HF), sudden cardiac death (SCD) causes 50% of all deaths, yet it is difficult to predict the heart failure patients who are at risk of SCD. Investigators conducted a post-hoc, nested case-control study of patients enrolled from April 2003 to December 2004 in the MUerte Súbita en Insuficiencia Cardíaca (MUSIC) registry [1]. The registry consisted of a three-year enrollment of ambulatory patients in the New York Heart Association functional class II to III. The patients had a left ventricular ejection fraction less than or equal to 45%, and data were consistently collected that included electrical, clinical, echocardiographic, and demographic information. The purpose of the study was to determine whether increased sST2 (an interleukin-1 receptor family member) concentrations, which have been predictive of the mortality rate for patients with acute coronary syndromes, could also be predictive for HF patients at risk of SCD. At the 3-year follow-up, 36 patients had died of SCD.

The concentrations of sST2 were greater in the deceased patients than in the 63 control patients (0.23 ng/ml [interquartile range 0.16–0.43 ng/ml] vs. 0.12 ng/ml [interquartile range 0.06–0.23 ng/ml], P=0.001) and were predictive of experiencing SCD (+0.1 ng/ml, odds ratio: 1.39, 95% confidence interval: 1.09–1.78, P=0.006). When N-terminal pro-B-type natriuretic peptide (NT-proBNP), an already established HF marker, and sST2 concentrations were both considered, only 4% of patients experienced SCD for neither sST2 nor NT-proBNP above characteristic cut-off points (0.15 ng/ml and 2,000 ng/l, respectively), 34% for either biomarker, and 71% for both biomarkers above (P<0.001 for trend). This study, the first to show that elevated sST2 concentrations may predict SCD, also provides complementary data to NT-proBNP, but future studies need to be conducted to determine if sST2 concentrations alone serve as a biomarker for SCD.

[1] Pascual-Figal DA, Ordonez-Llanos J, Tornel PL, et al. Soluble ST2 for predicting sudden cardiac death in patients with chronic heart failure and left ventricular systolic dysfunction (MUSIC). J Am Coll Cardiol 2009;54:2174-9

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Further information: Surgical Treatment of Advanced Heart Failure (see p1461) from Cardiovascular Medicine, 3rd Edn*

In this study for advanced heart failure patients who were ineligible for heart transplantation [1], patients were randomized to receive either a pulsatile-flow left ventricular assist device (LVAD) or a continuous-flow LVAD in an effort to determine which device showed more improvement in rate of survival, quality of life, and functional capacity of patients. Conducted at 38 cities in the US, a total of 200 patients were enrolled and randomly assigned to implantation of the continuous-flow LVAD (n=134) or the pulsatile-flow LVAD (n=66) between March 2005 and May 2007. The primary end point was a composite of survival at 2 years, absence of disabling stroke (Rankin score >3), or reoperation to replace the device. Secondary endpoints were actuarial survival, frequency of adverse events, functional status, and the quality of life. In both treatment groups, the baseline characteristics were similar and included a median age of 64 years, a mean LV ejection fraction (EF) of 17%, and approximately 80% of patients received intravenous inotropic agents.

In comparison of the two devices, more patients who received the continuous-flow LVAD achieved the primary composite end point than those with pulsatile-flow LVADs (62 of 134 [46%] vs. 7 of 66 [11%]; P<0.001 hazard ratio, 0.38; 95% confidence interval, 0.27–0.54; P<0.001). Patients who received continuous-flow LVADs had superior actuarial survival rates at 2 years (58% vs. 24%, P=0.008). Quality of life and functional capacity were improved significantly in both groups, while adverse events and device replacements were less frequent in patients with continuous-flow LVADs. Therefore, the investigators in this study believe that the continuous-flow LVAD provides greater long-term benefits to the heart failure patient.

[1] Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist device (HeartMate II). N Engl J Med 2009;361:2241-2251

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Further information: Hypertrophic Cardiomyopathy (see p1261) and Muscular Dystrophies Affecting the Heart (see p2567) from Cardiovascular Medicine, 3rd Edn*

Over the past 25 years, infertility has become an increasing problem in the US as couples have delayed marriage and childbearing years. Among other efforts to solve infertility issues, sperm banks have been created to provide a woman a means to achieve pregnancy when her partner is infertile. The Food and Drug Administration (FDA) has in place an inspection process for the purpose of preventing the spread of infectious diseases, but at this time, there is no screening process to identify genetic diseases.

The authors of this paper [1] have provided a brief report of a case report that involved sperm donation and inherited heart diseases, in this case, hypertrophic cardiomyopathy (HCM). Because the donor’s contract with a sperm bank was for a 2-year period, and there were no restrictions as to the number of pregnancies permitted for the donor, 22 children were produced (13 families, including his own) and nine were positive for the HCM mutation. The donor in this report was healthy and had no prior knowledge of his underlying heart disease. The currently used standard testing procedure prior to sperm donation revealed no negative results, and the donor’s disease was not identified until after the disease was identified in his offspring. An important conclusion reached from this study stressed the significant value of a genetic screening requirement for sperm donors.

[1] Maron BJ, Lesser JR, Schiller NB. Implications of hypertrophic cardiomyopathy transmitted by sperm donation. JAMA 2009;302:1681-4

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Further information: Restrictive Cardiomyopathy (see p1285) and Autonomic Dysfunction and Hypotension (see p1883) from Cardiovascular Medicine, 3rd Edn*

From a pool of 233 patients who presented with systemic amyloidosis between 1990 and May 2008 to centers in Bologna and Pavia, Italy, the investigators of this study [1] compared the diagnostic/clinical profiles of the three types of systemic cardiac amyloidoses, namely acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated, transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt). There were 157 AL patients, 61 ATTRm patients, and 15 ATTRwt patients in this longitudinal study.

Myocardial involvement is common in all three forms, but while there are profound pathogenic differences in each form, most clinical studies to this point have addressed the disease as a single form. Generally considered a restrictive cardiomyopathy, the primary noninvasive marker of that form of cardiomyopathy (restrictive filling pattern) is not present in a majority of patients in each of the three groups. Although ventricular wall thickness, as well as systolic and diastolic function, commonly describe the severity of cardiac amyloidosis, these cardiac indicators are expressed differently in each of the three types. In addition, each group showed relevant hemodynamic differences and considerable allelic genetic heterogeneity. Average age at diagnosis was higher in AL than in ATTRm patients; all ATTRwt patients except one were elderly men. At diagnosis, mean left ventricular wall thickness was higher in ATTRwt than in ATTRm and AL. Left ventricular ejection fraction was moderately depressed in ATTRwt but not in AL or ATTRm. ATTRm patients displayed low QRS voltage less frequently (25% vs. 60% in AL; P<0.0001) or low voltage-to-mass ratio (1.1±0.5 vs.0.9±0.5; P=0.0001). AL patients appeared to have greater hemodynamic impairment. On multivariate analysis, ATTRm was a strongly favorable predictor of survival, and ATTRwt predicted freedom from major cardiac events.

The investigators concluded that AL, ATTRm, and ATTRwt should be evaluated as three different cardiac diseases from disease classification, diagnosis, and clinical management of the disease.

[1] Rapezzi C, Merlini G, Quarta CC, et al. Systemic Cardiac Amyloidoses. Circulation 2009;120:1203-1212

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Further information: The Medical Management of Heart Failure (see p1397) from Cardiovascular Medicine, 3rd Edn*

The authors of this meta-analysis [1] examined 23 heart failure trials to evaluate which factor accounted for the effectiveness of treatment in heart failure β-blocker trials, i.e. β-blocker dose or degree of heart rate reduction. Of the 548 trials examined by the authors, 23 randomized, placebo-controlled heart failure trials that also reported all-cause mortality were selected.

Analyses of trials resulted in data showing that β-blockers reduce the risk for death in heart failure patients by 25%. For every heart rate reduction of 5 beats per minute with β-blocker treatment, there was an 18% reduction in the risk of death (confidence interval [CI], 6%–29%). There was no indication of significant relationship between all-cause mortality and β-blocker dosing (risk ratio [RR] for death, 0.74 [CI, 0.64–0.86]) in high-dose β-blocker trials vs. 0.78 [CI, 0.63–0.96] in low-dose β-blocker trials; P for meta-regression=0.69). The authors of this study concluded that while there is a statistically significant survival benefit associated with β-blocker use, the dose is not statistically significant.

[1] McAlister FA, Wiebe N, Ezekowitz JA, et al. Meta-analysis: β-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med 2009;150:784-794

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Further information: The Medical Management of Heart Failure (see p1397) from Cardiovascular Medicine, 3rd Edn*

Heart Failure: A Controlled Trial Investigating Outcomes of exercise training (HF-ACTION) was a multicenter, randomized controlled trial of 2331 patients who were enrolled from April 2003 to February 2007. It represents the largest multicenter, randomized controlled trial of exercise training in heart failure (HF) to date and involved 82 centers within the United States, Canada, and France. Patients were randomized to either an exercise training (ET) group plus usual care or a usual care group, and all patients had left ventricular ejection fractions (LVEF) of 35% or less and New York Heart Association (NYHA) class II to IV symptoms, despite optimal HF therapy for at least 6 weeks.

The first paper [1] evaluated trial data to report the efficacy and safety of ET among patients with HF. Median follow-up was 30 months. The patients who were randomized to usual care plus an ET group received 36 sessions of supervised aerobic exercise, while the usual care group were not given a formal exercise program. Composite primary end-point was all-cause mortality or hospitalization and prespecified secondary end-points were all-cause mortality, cardiovascular mortality, or HF hospitalization.

A total of 759 patients (65%) in the ET group died or were hospitalized compared with 796 patients (68%) in the usual care group (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.84–1.02]; P=0.13). There were nonsignificant reductions in the ET group for mortality (189 patients [16%] in the ET group vs. 198 patients [17%] in the usual care group; HR, 0.96; 95% CI, 0.79–1.71; P=0.70, cardiovascular mortality or HF hospitalization (632 [55%] in the ET group vs. 677 [58%] in the usual care group; HR, 0.92; 95% CI, 0.83–1.03; P=0.14), and cardiovascular mortality or HF hospitalization (344 [30%] in the exercise training group vs. 393 [34%] in the usual care group; HR, 0.87; 95% CI, 0.75–1.00; P=0.06. In prespecified supplementary analyses adjusting for highly prognostic baseline characteristics, the HRs were 0.89 (95% CI, 0.81–0.99; P=0.03) for all-cause mortality or hospitalization, 0.91 (95% CI, 0.82–1.01; P=0.09) for cardiovascular mortality or cardiovascular hospitalization, and 0.85 (95% CI, 0.74–0.99; P=0.03) for cardiovascular mortality or HF hospitalization. Other adverse events were similar between the groups.

The results showed that regular ET was safe, but it produced nonsignificant reductions in the primary and secondary end points. However, in protocol-specified supplementary analyses adjusted for prognostic factors, the treatment effect was statistically significant, and the HF-ACTION results support a prescribed ET program for patients with reduced LVF and HF.

The second paper [2] evaluated trial data to report the effects of ET on health status among patients with HF. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was used to measure health status every 3 months for 12 months, and annually thereafter for 4 years The KCCQ scored patients from 0 to 100, and higher scores corresponded to better health status.

At 3 months, usual care plus ET led to greater improvement in the KCCQ overall summary score (mean, 5.21; 95% confidence interval [CI], 4.42–6.00) compared with usual care alone (3.28; 95% CI, 2.48–4.09). The additional 1.93-point increase (95% CI, 0.84–3.01) in the ET group was statistically significant (P<0.001). After 3 months, there were no further significant chances in KCCQ score for either group (P=0.85 for the difference between slopes), resulting in a sustained, greater improvement overall for the entire ET group (P<0.001) Results were similar on the KCCQ subscales, and no subgroup interactions were detected. Results of the trial indicated that participation in an exercise program provided a modest, but significant improvement on patient-reported health status.

[1] O’Connor C M, Whellan D J, Lee K L et al. Efficacy and safety of exercise training in patients with chronic heart failure HF-ACTION randomized controlled trial. JAMA 2009;301(14):1439-1450

[2] Flynn K E, Pina I L, Whellan D J et al. Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA 2009;301(14):1451-1459

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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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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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