Kenji Ueshima

Transient left ventricular apical ballooning without coronary artery stenosis : a novel heart syndrome mimicking acute myocardial infarction

Abstract OBJECTIVES To determine the clinical features of a novel heart syndrome with transient left ventricular (LV) apical ballooning, but without coronary artery stenosis, that mimics acute myocardial infarction, we performed a multicenter retrospective enrollment study. BACKGROUND Only several case presentations have been reported with regard to this syndrome. METHODS We analyzed 88 patients (12 men and 76 women), aged 67 ± 13 years, who fulfilled the following criteria: 1) transient LV apical ballooning, 2) no significant angiographic stenosis, and 3) no known cardiomyopathies. RESULTS Thirty-eight (43%) patients had preceding aggravation of underlying disorders (cerebrovascular accident [n = 3], epilepsy [n = 3], exacerbated bronchial asthma [n = 3], acute abdomen [n = 7]) and noncardiac surgery or medical procedure (n = 11) at the onset. Twenty-four (27%) patients had emotional and physical problems (sudden accident [n = 2], death/funeral of a family member [n = 7], inexperience with exercise [n = 6], quarreling or excessive alcohol consumption [n = 5] and vigorous excitation [n = 4]). Chest symptoms (67%), electrocardiographic changes (ST elevation [90%], Q-wave formation [27%] and T-wave inversion [97%]) and elevated creatine kinase (56%) were found. After treatment of pulmonary edema (22%), cardiogenic shock (15%) and ventricular tachycardia/fibrillation (9%), 85 patients had class I New York Heart Association function on discharge. The LV ejection fraction improved from 41 ± 11% to 64 ± 10%. Transient intraventricular pressure gradient and provocative vasospasm were documented in 13/72 (18%) and 10/48 (21%) of the patients, respectively. During follow-up for 13 ± 14 months, two patients showed recurrence, and one died suddenly. CONCLUSIONS A novel cardiomyopathy with transient apical ballooning was reported. Emotional or physical stress might play a key role in this cardiomyopathy, but the precise etiologic basis still remains unclear.

Effects of Candesartan Compared With Amlodipine in Hypertensive Patients With High Cardiovascular Risks: Candesartan Antihypertensive Survival Evaluation in Japan Trial

The Candesartan Antihypertensive Survival Evaluation in Japan Trial was designed to compare the long-term effects of the angiotensin II receptor blocker candesartan and the calcium channel blocker amlodipine on the incidence of cardiovascular events, represented as a composite of sudden death and cerebrovascular, cardiac, renal, and vascular events in high-risk Japanese hypertensive patients. We conducted a prospective, randomized, open-label study with blinded assessment of the end point in 4728 Japanese hypertensive patients (mean age: 63.8 years; mean body mass index: 24.6 kg/m2). Patients were followed for an average of 3.2 years. Blood pressure was well controlled with both treatment-based regimens (systolic blood pressure/diastolic blood pressure: 136.1/77.3 mm Hg for candesartan-based regimens and 134.4/76.7 mm Hg for amlodipine-based regimens after 3 years). Primary cardiovascular events occurred in 134 patients with both the candesartan- and amlodipine-based regimens. The 2 treatment-based regimens produced no significant differences in cardiovascular morbidity or mortality in the high-risk Japanese hypertensive patients (hazard ratio: 1.01; 95% CI: 0.79 to 1.28; P=0.969). In each primary end point category, there was no significant difference between the 2 treatment-based regimens. New-onset diabetes occurred in fewer patients taking candesartan (8.7/1000 person-years) than in those taking amlodipine (13.6/1000 person-years), which resulted in a 36% relative risk reduction (hazard ratio: 0.64; 95% CI: 0.43 to 0.97; P=0.033). We disclosed that candesartan-based and amlodipine-based regimens produced no statistical differences in terms of the primary cardiovascular end point, whereas candesartan prevented new-onset diabetes more effectively than amlodipine.

Prediction of Cardiovascular Death in Men Undergoing Noninvasive Evaluation for Coronary Artery Disease

Clinical evaluation, exercise testing, and coronary angiography are used routinely by physicians to decide whether interventions are needed in patients with coronary artery disease [1, 2]. Various conflicting clinical prediction rules have been proposed [3]. In a first report, we described our method of outcome assessment in patients who had undergone exercise testing and coronary angiography within a 3-month period and compared our prediction rules with those from other samples [4]. Our two main findings were that the results of coronary angiography and exercise-induced ST depression were not independently associated with cardiovascular death or infarct-free survival. The purpose of this investigation was to predict cardiovascular death using variables available from a standard noninvasive work-up of patients with known or suspected coronary artery disease. The use of this larger cohort, uninfluenced by selection for cardiac catheterization, allowed assessment of work-up bias. Methods Patients Patients were selected from a consecutive series of 3609 persons who underwent routine clinical exercise testing between 1984 and 1990; 30% of this group had coronary angiography within 3 months of testing and were excluded from the analysis. Also excluded were women (who constituted less than 2% of the sample), patients with significant valvular disease, and those who had previous coronary artery bypass surgery. Most of the remaining 2456 (84%) patients had been referred for testing because of chest pain or for the evaluation of exercise capacity. Clinical Definitions Myocardial infarction was defined by the presence of two or more of the following factors: 1) serial electrocardiographic changes; 2) typical chest pain; and 3) myocardial enzyme increase. Congestive heart failure was defined by typical symptoms and signs, plus echocardiographic or radiographic confirmation of cardiomegaly and pulmonary edema. Before treadmill testing, angina pectoris was classified as typical if the patient described substernal pressure, tightness, or pain that was brought on by exertion or emotions, lasted several minutes, and was relieved by nitroglycerin or rest. Angina was considered atypical in the absence of one or more of these features if the pain was thought to be cardiac in origin. Exercise Testing The exercise test was done using a standard progressive treadmill protocol [5]. Except for patients undergoing testing before discharge after myocardial infarction, each test was sign or symptom limited using standard recommended criteria for termination [2]; fatigue or chest pain was the reason for termination in most patients. In addition to the maximal systolic blood pressure achieved, the blood pressure response during exercise was coded as a score reflecting exercise-associated changes in systolic blood pressure (0 points = increase > 40 mm Hg; 1 point = 31 to 40 mm Hg; 2 points = 21 to 30 mm Hg; 3 points = 11 to 20 mm Hg; 4 points = 0 to 11 mm Hg; and 5 points = decrease below standing systolic blood pressure taken before testing) [6]. The treadmill was stopped abruptly at the completion of exercise, and the patient was placed in the supine position within 1 minute [7]. Exercise capacity was estimated in multiples of resting oxygen consumption (METs) and was also analyzed as a percentage of normal for age according to an equation derived from a normal subset of our referral group [8]. Electrocardiographic Measurements Left ventricular hypertrophy was coded according to Romhilt and Estes criteria [9]. Patients lacking left ventricular hypertrophy with more than 0.5 mm ST depression in any lead were coded as having resting ST depression. The exercise electrocardiogram was interpreted as previously described [7]. Measurement of Outcome Variable Since 1984, the Department of Veterans Affairs Health Care System has developed a series of programs to support Veterans Affairs Medical Center clinical functions as part of the Decentralized Hospital Computer Project (DHCP). Death certificates are routinely completed by Veterans Affairs Medical Center physicians for inpatient and outpatient deaths. Information on care received elsewhere is routinely requested for clinical purposes, and all patients were scheduled for routine appointments at 6-month intervals after testing. Data on hospitalizations and deaths are entered, and retrieval programs are available to obtain dates and information regarding the most recent clinical visit and prescription received as well as those regarding hospitalization or death. To avoid bias, the coding of death certificates and other outcome variables was blinded to the predictor (exposure) variables. Although not designed for research purposes, this administrative and clinical database helped us obtain complete follow-up information. Data Analysis All data were entered into R:Base (Microrim, Redmond, Washington) and were analyzed using R:Base, Statgraphics (Statistical Graphics Corporation, Rockville, Maryland), True Epistat (Epistat Services, Richardson, Texas), Confidence Interval Analysis (American College of Physicians, Philadelphia, Pennsylvania), and EGRET (SERC, Seattle, Washington) on a standard 80386-SX-based personal computer (Vectra RS/20C, Hewlett Packard, Palo Alto, California). Survival time in person-days was measured from the time of the exercise test and was censored at the time of noncardiac death, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty. Survival Analysis Analysis was done to predict cardiovascular deaths and infarct-free survival (that is, cardiovascular death and nonfatal myocardial infarction). Kaplan-Meier survival curves were evaluated stratifying one or more variables to explore the data for interactions. The Cox proportional-hazard model was then applied to clinical and resting electrocardiographic variables, hemodynamic variables from treadmill testing, and electrocardiographic changes and angina during the treadmill test. Each variable grouping was also analyzed independently and by combining the strongest or most logical variables. Analysis was also done on the total group, including those who underwent catheterization (588 patients) because they were seen before the decision to catheterize. Results Follow-up Computed clinical information was available for all 2546 patients, and follow-up was initiated in February 1991. Of these, 85% were confirmed to be alive by a clinic visit or prescription filled at a minimum of 1 year after their treadmill date, and 187 (7.5%) had died after a mean follow-up period of 45 17 months. Contact either by telephone or letter led to follow-up and verification of vital status in 99%. After review of autopsy, death certificate, or hospital charts, 119 of the deaths (63%) were classified as cardiovascular. Forty-four patients had nonfatal myocardial infarctions, 34 developed congestive heart failure, 46 underwent coronary bypass surgery, and 18 received one or more angioplasties. The average annual cardiac mortality rate was 1.5%. Clinical Characteristics Table 1 shows the clinical characteristics of the study cohort grouped by end point. The mean age (SD) was 59 10 years. One fifth of the patients had typical angina pectoris, and one fifth had a history of previous myocardial infarction or electrocardiograms with diagnostic Q waves. Medications were not changed or withheld before exercise testing; 22% were taking -blockers, and 8% were taking digoxin. Statistically significant differences between the no cardiovascular event and cardiovascular death groups were observed for age, congestive heart failure, myocardial infarction, digoxin use, and most resting electrocardiographic abnormalities (P < 0.01). Table 1. Clinical Features of the Total Study Population and Number and Percentage with a Given End Point Hemodynamic and Electrocardiographic Responses Group averages for pre-exercise standing heart rate, systolic blood pressure, and double product were 76 beats per minute, 130 mm Hg, and 9800 (heart rate times systolic blood pressure), respectively. Table 2 shows the hemodynamic and electrocardiographic responses during the exercise test. No significant differences were found among end point groups for perceived exertion and occurrence of premature ventricular contractions. Table 2. Hemodynamic and Exercise Electrocardiographic Features of the Total Study Population* Cox Proportional Hazards Model The univariate scores and P values for the variables are listed in Appendix Table. No significant interactions were discovered, and thus none are included. Similar results were obtained both when infarct-free survival was considered as an end point (variable order, coefficients, and level of significance) and when the entire cohort was analyzed. The score test statistic listed is the relative weight or importance assigned the variables in the Cox model. Using stepwise selection, the Cox model was allowed to build on each variable group (clinical variables alone entered first with subsequent addition of other variables) to arrive at the final model that chose history of congestive heart failure or digoxin use, the change in systolic blood pressure score, exercise capacity (METs), and exercise-induced ST depression. A score was then formed using the coefficients from the Cox model with only these four variables entered as follows: 5 x (congestive heart failure or digoxin use [yes = 1; no = 0]) + exercise-induced ST depression in millimeters + change in systolic blood pressure score METs. Three groups were formed using a scoring system in which 2 indicated low risk, 2 to 2 indicated moderate risk, and greater than 2 indicated high risk. The hazard ratios, confidence intervals (CIs), and P values for these groups are shown in Table 3, and the Kaplan-Meier survival curves are shown in Figure 1. This score enabled identification of a low-risk group (77% of the cohort) with an annual cardiovascular mortality rate of less th

Inhibition of TRPC6 Channel Activity Contributes to the Antihypertrophic Effects of Natriuretic Peptides-Guanylyl Cyclase-A Signaling in the Heart

Rationale: Atrial and brain natriuretic peptides (ANP and BNP, respectively) exert antihypertrophic effects in the heart via their common receptor, guanylyl cyclase (GC)-A, which catalyzes the synthesis of cGMP, leading to activation of protein kinase (PK)G. Still, much of the network of molecular mediators via which ANP/BNP-GC-A signaling inhibit cardiac hypertrophy remains to be characterized. Objective: We investigated the effect of ANP-GC-A signaling on transient receptor potential subfamily C (TRPC)6, a receptor-operated Ca2+ channel known to positively regulate prohypertrophic calcineurin–nuclear factor of activated T cells (NFAT) signaling. Methods and Results: In cardiac myocytes, ANP induced phosphorylation of TRPC6 at threonine 69, the PKG phosphorylation site, and significantly inhibited agonist-evoked NFAT activation and Ca2+ influx, whereas in HEK293 cells, it dramatically inhibited agonist-evoked TRPC6 channel activity. These inhibitory effects of ANP were abolished in the presence of specific PKG inhibitors or by substituting an alanine for threonine 69 in TRPC6. In model mice lacking GC-A, the calcineurin-NFAT pathway is constitutively activated, and BTP2, a selective TRPC channel blocker, significantly attenuated the cardiac hypertrophy otherwise seen. Conversely, overexpression of TRPC6 in mice lacking GC-A exacerbated cardiac hypertrophy. BTP2 also significantly inhibited angiotensin II–induced cardiac hypertrophy in mice. Conclusions: Collectively, these findings suggest that TRPC6 is a critical target of antihypertrophic effects elicited via the cardiac ANP/BNP-GC-A pathway and suggest TRPC6 blockade could be an effective therapeutic strategy for preventing pathological cardiac remodeling.

T-type Ca2+ channel blockade prevents sudden death in mice with heart failure.

Background— Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca2+ channels contributes to the progression of heart failure. The ability of T-type Ca2+ channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however. Methods and Results— We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca2+ channel blockers, with those of nitrendipine, a selective L-type Ca2+ channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R(−)-isomer of efonidipine, a recently identified, highly selective T-type Ca2+ channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction. Conclusions— T-type Ca2+ channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca2+ channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca2+ channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

Prediction of cardiovascular death by means of clinical and exercise test variables in patients selected for cardiac catheterization

The objective of this report is the development of a population-specific prediction rule based on clinical and exercise test data that would estimate the risk of cardiovascular death in patients selected for cardiac catheterization. Prospective data and follow-up information were obtained from patients who underwent cardiac catheterization soon after clinical assessment and exercise testing. Males (n = 588) referred for evaluation of coronary heart disease from 1984 to 1990 were selected after exclusion of patients with significant valvular heart disease and patients with prior cardiac surgery. Half had a prior myocardial infarction and half complained of typical angina pectoris. All patients performed a treadmill test and were selected for clinical reasons to undergo coronary angiography within 3 months. Over a mean follow-up period of 2.5 years (+/- 1.4 years), there were 39 cardiovascular deaths and 45 nonfatal myocardial infarctions. The Cox proportional hazards model demonstrated the following characteristics to be statistically significant independent predictors of time until cardiovascular death: history of congestive heart failure (hazards ratio of 4), ST depression on the resting ECG (hazards ratio of 3), and a drop in systolic blood pressure below the resting value during exercise (hazards ratio of 5). Exercise-induced ST depression was not associated with either death or nonfatal myocardial infarction. A simple score based on one item of clinical information (history of congestive heart failure), a resting ECG finding (ST depression), and an exercise test response (exertional hypotension) stratified our patients for 4 years after testing from 75% with a low risk (annual cardiac mortality rate of 1%), 17% with a moderate risk (annual mortality rate of 7%), and 1% with a high risk (annual cardiac mortality rate of 12%, with a hazards ratio of 20 and 95% confidence interval from 6 to 70X). It was concluded that the variables available from the usual noninvasive workup of patients with known or suspected coronary artery disease enable prediction of risk of cardiovascular death. Three quarters of those usually undergoing cardiac catheterization can be identified by simple noninvasive variables as being at such low risk that invasive intervention is unlikely to improve prognosis.

Reciprocal expression of MRTF-A and myocardin is crucial for pathological vascular remodelling in mice

Myocardin‐related transcription factor (MRTF)‐A is a Rho signalling‐responsive co‐activator of serum response factor (SRF). Here, we show that induction of MRTF‐A expression is key to pathological vascular remodelling. MRTF‐A expression was significantly higher in the wire‐injured femoral arteries of wild‐type mice and in the atherosclerotic aortic tissues of ApoE−/− mice than in healthy control tissues, whereas myocardin expression was significantly lower. Both neointima formation in wire‐injured femoral arteries in MRTF‐A knockout (Mkl1−/−) mice and atherosclerotic lesions in Mkl1−/−; ApoE−/− mice were significantly attenuated. Expression of vinculin, matrix metallopeptidase 9 (MMP‐9) and integrin β1, three SRF targets and key regulators of cell migration, in injured arteries was significantly weaker in Mkl1−/− mice than in wild‐type mice. In cultured vascular smooth muscle cells (VSMCs), knocking down MRTF‐A reduced expression of these genes and significantly impaired cell migration. Underlying the increased MRTF‐A expression in dedifferentiated VSMCs was the downregulation of microRNA‐1. Moreover, the MRTF‐A inhibitor CCG1423 significantly reduced neointima formation following wire injury in mice. MRTF‐A could thus be a novel therapeutic target for the treatment of vascular diseases.

Oxygen affinity of hemoglobin regulates O2 consumption, metabolism, and physical activity.

The oxygen affinity of hemoglobin is critical for gas exchange in the lung and O2 delivery in peripheral tissues. In the present study, we generated model mice that carry low affinity hemoglobin with the Titusville mutation in the α-globin gene or Presbyterian mutation in the β-globin gene. The mutant mice showed increased O2 consumption and CO2 production in tissue metabolism, suggesting enhanced O2 delivery by mutant Hbs. The histology of muscle showed a phenotypical conversion from a fast glycolytic to fast oxidative type. Surprisingly, mutant mice spontaneously ran twice as far as controls despite mild anemia. The oxygen affinity of hemoglobin may control the basal level of erythropoiesis, tissue O2 consumption, physical activity, and behavior in mice.

Hemodynamic determinants of exercise capacity in chronic atrial fibrillation

To evaluate the response of patients with chronic atrial fibrillation (AF) to exercise, 79 male patients (mean age 64 +/- 1 years) with AF underwent resting two-dimensional and M-mode echocardiography and symptom-limited treadmill testing with ventilatory gas exchange analysis. Patients were classified by underlying disease into five subgroups: no underlying disease (LONE: n = 17), hypertension (HT: n = 11), ischemic heart disease (n = 13), cardiomyopathy or history of congestive heart failure (CHF: n = 26), and valvular disease (n = 12). A higher maximal heart rate than expected for age was observed (175 vs 157 beats/min), which was most notable in the LONE and HT subgroups. Maximal oxygen uptake (VO2 max) was lower than expected for age in all groups. Patients with CHF had a lower resting ejection fraction than all other patients (p < 0.001), a lower VO2 max, and a lower maximal heart rate than LONE and HT patients (p < 0.001). Stepwise regression analysis demonstrated that echocardiographic measurements at rest were poor predictors of VO2 max and VO2 at the ventilatory threshold. Among clinical, morphologic, and exercise variables, maximal systolic blood pressure accounted for the greatest variance in exercise capacity, but it explained only 35%. In patients with AF the higher than predicted maximal heart rates may be a compensatory mechanism for maintaining exercise capacity after the loss of normal atrial function. However, even in the absence of underlying disease, it does not appear to compensate fully for a compromised exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of the Maze Procedure for Atrial Fibrillation on Atrial and Brain Natriuretic Peptide

We studied plasma levels of atrial and brain natriuretic peptides at rest and after exercise before and after intracardiac surgery with and without the maze procedure in patients with chronic heart failure secondary to valvular heart disease. The present study found that an increased response of both cardiac natriuretic peptides is attenuated with resulting water retention after the maze procedure.