Michael A. Fifer

2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

Writing committee me tions to which their s ply; see Appendix ACCF/AHATask Fo Surgeons Representa tative. Heart Rhythm ography and Int Echocardiography Re ciety of America Rep resentative. kkACCF/ Task Force member d This document was app Board of Trustees and ordinating Committee gery, American Soc Cardiology, Heart Fa for Cardiovascular A geons approved the d The American Associat as follows: Gersh BJ Naidu SS, Nishimura Bernard J. Gersh, MB, ChB, DPhil, FACC, FAHA, Co-Chair* Barry J. Maron, MD, FACC, CoChair* Robert O. Bonow, MD, MACC, FAHA, Joseph A. Dearani, MD, FACC,§,k Michael A. Fifer, MD, FACC, FAHA,* Mark S. Link, MD, FACC, FHRS,* Srihari S. Naidu, MD, FACC, FSCAI,* Rick A. Nishimura, MD, FACC, FAHA, Steve R. Ommen, MD, FACC, FAHA, Harry Rakowski, MD, FACC, FASE,** Christine E. Seidman, MD, FAHA, Jeffrey A. Towbin, MD, FACC, FAHA, James E. Udelson, MD, FACC, FASNC, and Clyde W. Yancy, MD, FACC, FAHAkk

2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons

Alice K. Jacobs, MD, FACC, FAHA, Chair, 2009–2011; Sidney C. Smith, Jr, MD, FACC, FAHA, Immediate Past Chair, 2006–2008[¶¶][1]; Jeffrey L. Anderson, MD, FACC, FAHA, Chair-Elect; Nancy M. Albert, PhD, CCNS, CCRN, FAHA; Christopher E. Buller, MD, FACC[¶¶][1]; Mark A. Creager, MD, FACC, FAHA;

Preload dependence of doppler-derived indexes of left ventricular diastolic function in humans

To determine the effect of filling pressure on the pattern of left ventricular filling in humans, the mitral flow velocity profile was measured by pulsed wave Doppler echocardiography during right and left heart catheterization in 11 patients before and during nitroglycerin infusion. Nitroglycerin reduced mean arterial pressure from 90 +/- 9 to 80 +/- 11 mm Hg (p less than 0.001) and mean pulmonary capillary wedge pressure from 9 +/- 4 to 4 +/- 2 mm Hg (p less than 0.001). Cardiac output fell from 6.6 +/- 1.5 to 5.5 +/- 1.4 liters/min (p less than 0.001) and heart rate increased from 60 +/- 13 to 65 +/- 14 beats/min (p less than 0.002). The time constant of isovolumic relaxation (TI.) decreased from 51 +/- 9 to 46 +/- 8 ms (p less than 0.01), indicating faster left ventricular relaxation. Nitroglycerin altered the Doppler characteristics of the early filling (E) wave but not those of the atrial contraction (A) wave. Peak velocity of the E wave decreased from 56 +/- 14 to 44 +/- 9 cm/s (p less than 0.001), peak velocity of the A wave did not change and the ratio of peak velocities of the E and A waves decreased from 0.97 +/- 0.33 to 0.77 +/- 0.20 (p less than 0.02). The deceleration of the E wave decreased from 289 +/- 138 to 186 +/- 71 cm/s2 (p less than 0.02). The ratio of velocity-time integral of the A wave to total velocity-time integral (that is, contribution of atrial contraction to total filling) increased from 0.31 +/- 0.09 to 0.36 +/- 0.08 (p less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Executive Summary

2011;58;2703-2738; originally published online Nov 8, 2011; J. Am. Coll. Cardiol. W. Yancy Rakowski, Christine E. Seidman, Jeffrey A. Towbin, James E. Udelson, and Clyde Fifer, Mark S. Link, Srihari S. Naidu, Rick A. Nishimura, Steve R. Ommen, Harry Bernard J. Gersh, Barry J. Maron, Robert O. Bonow, Joseph A. Dearani, Michael A. Thoracic Surgeons Society for Cardiovascular Angiography and Interventions, and Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, of Thoracic Surgery, American Society of Echocardiography, American Society Developed in Collaboration With the American Association for Guidelines Cardiology Foundation/American Heart Association Task Force on Practice Cardiomyopathy: Executive Summary: A Report of the American College of 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic This information is current as of May 14, 2012 http://content.onlinejacc.org/cgi/content/full/58/25/2703 located on the World Wide Web at: The online version of this article, along with updated information and services, is

The Creatine Kinase System in Normal and Diseased Human Myocardium

We measured creatine kinase activity, isozyme composition, and total creatine content in biopsy samples of left ventricular myocardium from 34 adults in four groups: subjects with normal left ventricles, patients with left ventricular hypertrophy due to aortic stenosis, patients with coronary artery disease without left ventricular hypertrophy, and patients with coronary artery disease and left ventricular hypertrophy due to aortic stenosis. As compared with specimens of normal left ventricles, those from all patients with left ventricular hypertrophy had lower creatine kinase activity, higher MB creatine kinase isozyme content and activity, and lower creatine content. Specimens from the patients without left ventricular hypertrophy had normal creatine kinase activity, increased MB creatine kinase isozyme content and activity, and decreased total creatine content. The normal ventricles showed almost no MB isozyme content or activity. These data suggest that changes in the creatine kinase system occur in both pressure-overload hypertrophy and coronary artery disease. Patients with myocardial infarction who have mild or no preexisting fixed coronary artery disease or pressure-overload hypertrophy would not be expected to have elevation of serum MB creatine kinase.

Hemodynamic effects of inhaled nitric oxide in heart failure.

OBJECTIVES This study was performed to assess the utility of inhaled nitric oxide as a selective pulmonary vasodilator in patients with severe chronic heart failure and to compare its hemodynamic effects with those of nitroprusside, a nonselective vasodilator. BACKGROUND Preoperative pulmonary vascular resistance is a predictor of right heart failure after heart transplantation. Non-selective vasodilators administered preoperatively to assess the reversibility of pulmonary vasoconstriction cause systemic hypotension, limiting their utility. METHODS Systemic and pulmonary hemodynamic measurement were made at baseline, during oxygen inhalation and with the addition of graded doses of inhaled nitric oxide or intravenous nitroprusside in 16 patients with New York Heart Association class III or IV heart failure referred for heart transplantation. RESULTS Pulmonary vascular resistance decreased to a greater extent with 80 ppm nitric oxide (mean +/- SEM 256 +/- 41 to 139 +/- 14 dynes.s.cm-5) than with the maximally tolerated dose of nitroprusside (264 +/- 49 to 169 +/- 30 dynes.s.cm-5, p < 0.05, nitric oxide vs. nitroprusside). Pulmonary capillary wedge pressure increased with 80 ppm nitric oxide (26 +/- 2 to 32 +/- 2 mm Hg, p < 0.05). Mean arterial pressure did not change with nitric oxide but decreased with nitroprusside. Seven of the 16 patients, including 1 patient who did not have an adequate decrease in pulmonary vascular resistance with nitroprusside but did with nitric oxide, have undergone successful heart transplantation. CONCLUSIONS Inhaled nitric oxide is a selective pulmonary vasodilator in patients with pulmonary hypertension due to left heart failure and may identify patients with reversible pulmonary vasoconstriction in whom agents such as nitroprusside cause systemic hypotension. Inhaled nitric oxide causes an increase in left ventricular filling pressure by an unknown mechanism.

Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside.

Milrinone is a potent positive inotropic and vascular smooth muscle-relaxing agent in vitro, and therefore, it is not known to what extent each of these actions contributes to the drugs hemodynamic effects in patients with heart failure. In 11 patients with New York Heart Association class III or IV congestive heart failure, incremental intravenous doses of milrinone were administered to determine the dose-response relationships for heart rate, systemic vascular resistance, and inotropic state, the latter measured by peak positive left ventricular derivative of pressure with respect to time (dP/dt). To clarify further the role of a positive inotropic action, the relative effects of milrinone and nitroprusside on left ventricular stroke work and dP/dt were compared in each patient at doses matched to cause equivalent reductions in mean arterial pressure or systemic vascular resistance, indices of left ventricular afterload. Milrinone caused heart rate, stroke volume, and dP/dt to increase, and systemic vascular resistance to decrease in a concentration-related manner. At the two lowest milrinone doses resulting in serum concentrations of 63 +/- 4 and 156 +/- 5 ng/ml, respectively, milrinone caused significant increases in stroke volume and dP/dt, but no changes in systemic vascular resistance or heart rate. At the maximum milrinone dose administered (mean serum concentration, 427 +/- 11 ng/ml), heart rate increased from 92 +/- 4 to 99 +/- 4 bpm (P less than 0.01), mean aortic pressure fell from 82 +/- 3 to 71 +/- 3 mmHg (P less than 0.01), right atrial pressure fell from 15 +/- 2 to 7 +/- 1 mmHg (P less than 0.005), left ventricular end-diastolic pressure fell from 26 +/- 3 to 18 +/- 3 (P less than 0.005), stroke volume index increased from 20 +/- 2 to 30 +/- 2 ml/m2 (P less than 0.005), stroke work index increased from 14 +/- 2 to 21 +/- 2 g X m/m2 (P less than 0.01), and dP/dt increased from 858 +/- 54 to 1,130 +/- 108 mmHg/s (P less than 0.005). When compared with nitroprusside for a matched reduction in mean aortic pressure or systemic vascular resistance, milrinone caused a significantly greater increase in stroke work index at the same or lower left ventricular end-diastolic pressure. Milrinone caused a concentration-related increase in dP/dt (32% increase at maximum milrinone dose), whereas nitroprusside had no effect. These data in patients with severe heart failure indicate that in addition to a vasodilating effect, milrinone exerts a concentration-related positive inotropic action that contributes significantly to the drugs overall hemodynamic effects. The positive inotropic action occurs at drug levels that do not exert significant chronotropic or vasodilator effects.

Metabolite profiling of blood from individuals undergoing planned myocardial infarction reveals early markers of myocardial injury

Emerging metabolomic tools have created the opportunity to establish metabolic signatures of myocardial injury. We applied a mass spectrometry-based metabolite profiling platform to 36 patients undergoing alcohol septal ablation treatment for hypertrophic obstructive cardiomyopathy, a human model of planned myocardial infarction (PMI). Serial blood samples were obtained before and at various intervals after PMI, with patients undergoing elective diagnostic coronary angiography and patients with spontaneous myocardial infarction (SMI) serving as negative and positive controls, respectively. We identified changes in circulating levels of metabolites participating in pyrimidine metabolism, the tricarboxylic acid cycle and its upstream contributors, and the pentose phosphate pathway. Alterations in levels of multiple metabolites were detected as early as 10 minutes after PMI in an initial derivation group and were validated in a second, independent group of PMI patients. A PMI-derived metabolic signature consisting of aconitic acid, hypoxanthine, trimethylamine N-oxide, and threonine differentiated patients with SMI from those undergoing diagnostic coronary angiography with high accuracy, and coronary sinus sampling distinguished cardiac-derived from peripheral metabolic changes. Our results identify a role for metabolic profiling in the early detection of myocardial injury and suggest that similar approaches may be used for detection or prediction of other disease states.

A pipeline that integrates the discovery and verification of plasma protein biomarkers reveals candidate markers for cardiovascular disease

We developed a pipeline to integrate the proteomic technologies used from the discovery to the verification stages of plasma biomarker identification and applied it to identify early biomarkers of cardiac injury from the blood of patients undergoing a therapeutic, planned myocardial infarction (PMI) for treatment of hypertrophic cardiomyopathy. Sampling of blood directly from patient hearts before, during and after controlled myocardial injury ensured enrichment for candidate biomarkers and allowed patients to serve as their own biological controls. LC-MS/MS analyses detected 121 highly differentially expressed proteins, including previously credentialed markers of cardiovascular disease and >100 novel candidate biomarkers for myocardial infarction (MI). Accurate inclusion mass screening (AIMS) qualified a subset of the candidates based on highly specific, targeted detection in peripheral plasma, including some markers unlikely to have been identified without this step. Analyses of peripheral plasma from controls and patients with PMI or spontaneous MI by quantitative multiple reaction monitoring mass spectrometry or immunoassays suggest that the candidate biomarkers may be specific to MI. This study demonstrates that modern proteomic technologies, when coherently integrated, can yield novel cardiovascular biomarkers meriting further evaluation in large, heterogeneous cohorts.

Improvement in indexes of diastolic performance in patients with congestive heart failure treated with milrinone.

To elucidate the mechanisms by which the new bipyridine inotropic agent milrinone improves cardiac function, we examined multiple indexes of left ventricular diastolic function before and after administration of milrinone to patients with advanced (NYHA class III or IV) congestive heart failure. In 13 patients left ventricular pressure measurements were made with a micromanometer to permit assessment of peak negative dP/dt and the time constant of left ventricular isovolumic relaxation, T, before and after milrinone. In nine patients radionuclide ventriculographic studies were performed during left heart catheterization, allowing calculation of left ventricular peak filling rate, volumes, and the diastolic pressure-volume relationship before and after milrinone. After intravenous administration of milrinone, peak negative dP/dt increased (+ 18%; p less than .01) and T decreased (-30%; p less than .01), while heart rate increased by only 8% (87 +/- 12 to 94 +/- 15 beats/min; p less than .01), left ventricular systolic pressure did not change, and mean aortic pressure fell by 11% (p less than .01). Left ventricular peak filling rate increased (1.2 +/- 0.6 to 1.7 +/- 0.7 end-diastolic volumes/sec; p less than or equal to .02) despite a decrease in left ventricular filling pressure (mean pulmonary wedge pressure 27 +/- 7 to 18 +/- 9 mm Hg; p less than .01). There was a fall in left ventricular end-diastolic pressure (28.6 +/- 6 to 19 +/- 7 mm Hg; p less than or equal to .01), with no significant change in left ventricular end-diastolic volume. This was associated with a downward shift in the left ventricular diastolic pressure-volume relationship in most cases.(ABSTRACT TRUNCATED AT 250 WORDS)