Garvan C. Kane

2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

Jeffrey L. Anderson, MD, FACC, FAHA, Chair Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect Nancy M. Albert, PhD, RN, FAHA Biykem Bozkurt, MD, PhD, FACC, FAHA Ralph G. Brindis, MD, MPH, MACC Lesley H. Curtis, PhD, FAHA David DeMets, PhD[¶¶][1] Lee A. Fleisher, MD, FACC, FAHA Samuel

Stem cell differentiation requires a paracrine pathway in the heart

Members of the transforming growth factor pβ (TGF‐β) superfamily‐namely, TGF‐β and BMP2—applied to undifferentiated murine embryonic stem cells up‐regulated mRNA of mesodermal (Brachyury) and cardiac specific transcription factors (Nkx2.5, MEF2C). Embryoid bodies generated from stem cells primed with these growth factors demonstrated an increased potential for cardiac differentiation with a significant increase in beating areas and enhanced myofibrillogenesis. In an environment of postmitotic cardiomyocytes, stem cells engineered to express a fluorescent protein under the control of a cardiac promoter differentiated into fluorescent ventricular myocytes beating in synchrony with host cells, a process significantly enhanced by TGF‐β or BMP2. In vitro, disruption of the TGF‐β/BMP signaling pathways by latency‐associated peptide and/or noggin prevented differentiation of stem cells. In fact, only host cells that secrete a TGF‐β family member induced a cardiac phenotype in stem cells. In vivo, transplantation of stem cells into heart also resulted in cardiac differentiation provided that TGF‐β/BMP2 signaling was intact. In infarcted myocardium, grafted stem cells differentiated into functional cardiomyocytes integrated with surrounding tissue, improving contractile performance. Thus, embryonic stem cells are directed to differentiate into cardiomyocytes by signaling mediated through TGF‐β/BMP2, a cardiac paracrine pathway required for therapeutic benefit of stem cell transplantation in diseased heart.—Behfar, A., Zingman, L. V., Hodgson, D. M., Rauzier, J.‐M., Kane, G. C., Terzic, A., Pucéat, M. Stem cell differentiation requires a paracrine pathway in the heart. FASEB J. 16, 1558–1566 (2002)

Progression of Left Ventricular Diastolic Dysfunction and Risk of Heart Failure

CONTEXT Heart failure incidence increases with advancing age, and approximately half of patients with heart failure have preserved left ventricular ejection fraction. Although diastolic dysfunction plays a role in heart failure with preserved ejection fraction, little is known about age-dependent longitudinal changes in diastolic function in community populations. OBJECTIVE To measure changes in diastolic function over time and to determine the relationship between diastolic dysfunction and the risk of subsequent heart failure. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort of participants enrolled in the Olmsted County Heart Function Study. Randomly selected participants 45 years or older (N = 2042) underwent clinical evaluation, medical record abstraction, and echocardiography (examination 1 [1997-2000]). Diastolic left ventricular function was graded as normal, mild, moderate, or severe by validated Doppler techniques. After 4 years, participants were invited to return for examination 2 (2001-2004). The cohort of participants returning for examination 2 (n = 1402 of 1960 surviving [72%]) then underwent follow-up for ascertainment of new-onset heart failure (2004-2010). MAIN OUTCOME MEASURES Change in diastolic function grade and incident heart failure. RESULTS During the 4 (SD, 0.3) years between examinations 1 and 2, diastolic dysfunction prevalence increased from 23.8% (95% confidence interval [CI], 21.2%-26.4%) to 39.2% (95% CI, 36.3%-42.2%) (P < .001). Diastolic function grade worsened in 23.4% (95% CI, 20.9%-26.0%) of participants, was unchanged in 67.8% (95% CI, 64.8%-70.6%), and improved in 8.8% (95% CI, 7.1%-10.5%). Worsened diastolic dysfunction was associated with age 65 years or older (odds ratio, 2.85 [95% CI, 1.77-4.72]). During 6.3 (SD, 2.3) years of additional follow-up, heart failure occurred in 2.6% (95% CI, 1.4%-3.8%), 7.8% (95% CI, 5.8%-13.0%), and 12.2% (95% CI, 8.5%-18.4%) of persons whose diastolic function normalized or remained normal, remained or progressed to mild dysfunction, or remained or progressed to moderate or severe dysfunction, respectively (P < .001). Diastolic dysfunction was associated with incident heart failure after adjustment for age, hypertension, diabetes, and coronary artery disease (hazard ratio, 1.81 [95% CI, 1.01-3.48]). CONCLUSIONS In a population-based cohort undergoing 4 years of follow-up, prevalence of diastolic dysfunction increased. Diastolic dysfunction was associated with development of heart failure during 6 years of subsequent follow-up.

Kir6.2 is required for adaptation to stress

Reaction to stress requires feedback adaptation of cellular functions to secure a response without distress, but the molecular order of this process is only partially understood. Here, we report a previously unrecognized regulatory element in the general adaptation syndrome. Kir6.2, the ion-conducting subunit of the metabolically responsive ATP-sensitive potassium (KATP) channel, was mandatory for optimal adaptation capacity under stress. Genetic deletion of Kir6.2 disrupted KATP channel-dependent adjustment of membrane excitability and calcium handling, compromising the enhancement of cardiac performance driven by sympathetic stimulation, a key mediator of the adaptation response. In the absence of Kir6.2, vigorous sympathetic challenge caused arrhythmia and sudden death, preventable by calcium-channel blockade. Thus, this vital function identifies a physiological role for KATP channels in the heart.

Age-Associated Increases in Pulmonary Artery Systolic Pressure in the General Population

Background— In contrast to the wealth of data on isolated systolic hypertension involving the systemic circulation in the elderly, much less is known about age-related change in pulmonary artery systolic pressure (PASP) and its prognostic impact in the general population. We sought to define the relationship between PASP and age, to evaluate which factors influence PASP, and to determine whether PASP is independently predictive of mortality in the community. Methods and Results— A random sample of the Olmsted County, Minn, general population (n=2042) underwent echocardiography and spirometry and was followed up for a median of 9 years. PASP was measured from the tricuspid regurgitation velocity. Left ventricular diastolic pressure was estimated with Doppler echocardiography (E/e′ ratio), and arterial stiffening was assessed from the brachial artery pulse pressure. Among 1413 subjects (69%) with measurable PASP (age, 63±11 years; 43% male), median PASP was 26 mm Hg (25th to 75th percentile, 24 to 30 mm Hg) and increased with age (r=0.31, P<0.001). Independent predictors of PASP were age, pulse pressure, and mitral E/e′ (all P≤0.003). Increasing PASP was associated with higher mortality (hazard ratio, 2.73 per 10 mm Hg; P<0.001). In subjects without cardiopulmonary disease (any heart failure, coronary artery disease, hypertension, diabetes mellitus, or chronic obstructive lung disease), the age-adjusted hazard ratio was 2.74 per 10 mm Hg (P=0.016). Conclusions— We provide the first population-based evidence of age-related increase in pulmonary artery pressure, its association with increasing left heart diastolic pressures and systemic vascular stiffening, and its negative impact on survival. Pulmonary artery pressure may serve as a novel cardiovascular risk factor and potential therapeutic target.

Drug–Grapefruit Juice Interactions

Grapefruit juice, a beverage consumed in large quantities by the general population, is an inhibitor of the intestinal cytochrome P-450 3A4 system, which is responsible for the first-pass metabolism of many medications. Through the inhibition of this enzyme system, grapefruit juice interacts with a variety of medications, leading to elevation of their serum concentrations. Most notable are its effects on cyclosporine, some 1,4-dihydropyridine calcium antagonists, and some 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. In the case of some drugs, these increased drug concentrations have been associated with an increased frequency of dose-dependent adverse effects. The P-glycoprotein pump, located in the brush border of the intestinal wall, also transports many cytochrome P-450 3A4 substrates, and this transporter also may be affected by grapefruit juice. This review discusses the proposed mechanisms of action and the medications involved in drug-grapefruit juice interactions and addresses the clinical implications of these interactions.

Right Ventricular Strain for Prediction of Survival in Patients With Pulmonary Arterial Hypertension

BACKGROUND Pulmonary arterial hypertension (PAH) is a devastating illness of pulmonary vascular remodeling, right-sided heart failure, and limited survival. Whether strain-based measures of right ventricular (RV) systolic function predict future right-sided heart failure and/or death is untested. METHODS RV longitudinal systolic strain and strain rate were evaluated by echocardiography in 80 patients with World Health Organization group 1 pulmonary hypertension (PH) (72% were functional class [FC] III or IV). Survival status was assessed over 4 years. RESULTS All patients had a depressed RV systolic strain (-15% ± 5%) and strain rate (-0.80 ± 0.29 s(-1)). Of the parameters assessed, average RV free wall systolic strain worse than -12.5% identified a cohort with greater severity of disease (82% were FC III/IV), greater RV systolic dysfunction (RV stroke volume index 26 ± 9 mL/m(2)), and higher right atrial pressure (12 ± 5 mm Hg). Patients with an RV free wall strain worse than -12.5% were associated with a greater degree of disease progression within 6 months, a greater requirement for loop diuretics, and/or a greater degree of lower extremity edema, and it also predicted 1-, 2-, 3-, and 4-year mortality (unadjusted 1-year hazard ratio, 6.2; 2.1-22.3). After adjusting for age, sex, PH cause, and FC, patients had a 2.9-fold higher rate of death per 5% absolute decline in RV free wall strain at 1 year. CONCLUSIONS Noninvasive assessment of RV longitudinal systolic strain and strain rate independently predicts future right-sided heart failure, clinical deterioration, and mortality in patients with PAH.

Outcome Prediction by Quantitative Right Ventricular Function Assessment in 575 Subjects Evaluated for Pulmonary Hypertension

Background— Although right ventricular (RV) dysfunction is a major determinant of outcome in patients with pulmonary hypertension (PH), the optimal measure of RV function is poorly defined. We hypothesized that RV strain measured by speckle-tracking echocardiography predicts outcome in PH over a broad range of pulmonary pressures. Methods and Results— Prospective peak RV longitudinal systolic strain measurement was performed on 575 patients (mean age, 56±18 years; 63% women) referred for echocardiography for known or suspected PH. Survival status was assessed over a median of 16.5 (interquartile range, 7.6–20.0) months. There were 406 patients with PH (71%) (74% group 1, 14% group 3, and 12% group 4) and 169 patients without evidence of PH (29%). Among patients with PH, 46% were World Health Organization functional class III–IV. The mean RV strain was −21.2±6.7% for all patients. RV strain declined with worse functional class, shorter 6-minute walk distances, higher N-terminal pro-B-type natriuretic peptide levels, and the presence of right heart failure. RV strain predicted outcome across pulmonary pressures and groups of PH. Eighteen-month survival was 92%, 88%, 85%, and 71% according to RV strain quartile (P<0.001), with a 1.46 higher risk of death (95% confidence interval, 1.05–2.12) per 6.7% decline in RV strain. RV strain predicted survival when adjusted for pulmonary pressure, pulmonary vascular resistance, and right atrial pressure and provided incremental prognostic value over conventional clinical and echocardiographic variables. Conclusions— Quantitative assessment of RV free-wall systolic strain is feasible and is a powerful predictor of the clinical outcome of patients with known or suspected PH.

2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery: Executive Summary

Preamble 2216 1. Introduction 2217 2. Clinical Risk Factors: Recommendations 2220 3. Approach to Perioperative Cardiac Testing 2221 4. Supplemental Preoperative Evaluation: Recommendations 2221 5. Perioperative Therapy: Recommendations 2224 6. Anesthetic Consideration and Intraoperative Management: Recommendations 2228 7. Surveillance and Management for Perioperative MI: Recommendations 2229 8. Future Research Directions 2230 Appendix 1. Author Relationships With Industry and Other Entities (Relevant) 2237 Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant) 2239 Appendix 3. Related Recommendations From Other CPGs 2244 References 2230 The American College of Cardiology (ACC) and the American Heart Association (AHA) are committed to the prevention and management of cardiovascular diseases through professional education and research for clinicians, providers, and patients. Since 1980, the ACC and AHA have shared a responsibility to translate scientific evidence into clinical practice guidelines (CPGs) with recommendations to standardize and improve cardiovascular health. These CPGs, based on systematic methods to evaluate and classify evidence, provide a cornerstone of quality …

Cellular remodeling in heart failure disrupts KATP channel‐dependent stress tolerance

ATP‐sensitive potassium (KATP) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on KATP channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor α induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, KATP channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, KATP channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by KATP channel openers. Thus, disease‐induced KATP channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy.