Yasushige Shingu

Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload

AIMS Left ventricular hypertrophy is a risk factor for heart failure. However, it also is a compensatory response to pressure overload, accommodating for increased workload. We tested whether the changes in energy substrate metabolism may be predictive for the development of contractile dysfunction. METHODS AND RESULTS Chronic pressure overload was induced in Sprague-Dawley rats by aortic arch constriction for 2, 6, 10, or 20 weeks. Contractile function in vivo was assessed by echocardiography and by invasive pressure measurement. Glucose and fatty acid oxidation as well as contractile function ex vivo were assessed in the isolated working heart, and respiratory capacity was measured in isolated cardiac mitochondria. Pressure overload caused progressive hypertrophy with normal ejection fraction (EF) at 2, 6, and 10 weeks, and hypertrophy with dilation and impaired EF at 20 weeks. The lung-to-body weight ratio, as marker for pulmonary congestion, was normal at 2 weeks (indicative of compensated hypertrophy) but significantly increased already after 6 and up to 20 weeks, suggesting the presence of heart failure with normal EF at 6 and 10 weeks and impaired EF at 20 weeks. Invasive pressure measurements showed evidence for contractile dysfunction already after 6 weeks and ex vivo cardiac power was reduced even at 2 weeks. Importantly, there was impairment in fatty acid oxidation beginning at 2 weeks, which was associated with a progressive decrease in glucose oxidation. In contrast, respiratory capacity of isolated mitochondria was normal until 10 weeks and decreased only in hearts with impaired EF. CONCLUSION Pressure overload-induced impairment in fatty acid oxidation precedes the onset of congestive heart failure but mitochondrial respiratory capacity is maintained until the EF decreases in vivo. These temporal relations suggest a tight link between impaired substrate oxidation capacity in the development of heart failure and contractile dysfunction and may imply therapeutic and prognostic value.

Glucagon-like peptide-1 reduces contractile function and fails to boost glucose utilization in normal hearts in the presence of fatty acids

UNLABELLED GLP-1 and exendin-4, which are used as insulin sensitizers or weight reducing drugs, were shown to improve glucose uptake in the heart. However, the direct effects of GLP-1 or exendin-4 on normal hearts in the presence of fatty acids, the main cardiac substrates, have never been investigated. We therefore assessed the effects of GLP-1 or exendin-4 on myocardial glucose uptake (GU), glucose oxidation (GO) and cardiac performance (CP) under conditions of fatty acid utilization. METHODS AND RESULTS Rat hearts were perfused with only glucose (5 mM) or glucose (5 mM) plus oleate (0.4 mM) as substrates for 60 min. After 30 min, GLP-1 or exendin-4 (0.5 nM or 5 nM) was added. In the absence of oleate, GLP-1 increased both GU and GO. Exendin-4 increased GO but showed no effect on GU. Neither GLP-1 nor exendin-4 affected CP. However, when oleate was present, GLP-1 failed to stimulate glucose utilization and exendin-4 even decreased GU. Furthermore, now GLP-1 reduced CP. In contrast to prior reports, this negative inotropic effect could not be blocked by the protein kinase A inhibitor H-89. We then measured myocardial GO and CP in rats receiving a 4-week GLP-1 infusion. Interestingly, this chronic treatment resulted in a significant reduction in both GO and CP. CONCLUSIONS Under the influence of oleate, GLP-1 reduces contractile function and fails to stimulate glucose utilization in normal hearts. Exendin-4 may acutely reduce cardiac glucose uptake but not contractility. We suggest advanced investigation of heart function and metabolism in patients treating with these peptides.

Surgical Strategy for Ischemic Mitral Regurgitation Adopting Subvalvular and Ventricular Procedures

PURPOSE The progression of left ventricular (LV) remodeling and subsequent mitral valve tethering impair the results of reduction annuloplasty for ischemic mitral regurgitation (MR). METHODS We studied 90 patients who underwent surgical repair of ischemic MR between 1999 and 2013 according to our surgical strategy adding submitral and ventricular procedures to annuloplasty as follows: annuloplasty alone (stage 1, n = 30), additional papillary muscle approximation (PMA) for progression of tethering (stage 2, n = 26), and additional left ventriculoplasty with PMA for progression of LV remodeling and tethering (stage 3, n = 34). RESULTS The preoperative New York Heart Association (NYHA) functional classes (2.5 ± 0.7, 3.1 ± 0.7 and 3.3 ± 0.7 for stages 1, 2 and 3, respectively, P <0.001), LV end-diastolic diameters (56 ± 7 mm, 66 ± 5 mm and 70 ± 7 mm, P <0.001), and LV ejection fractions (45 ± 12%, 32 ± 9% and 27 ± 9%, P <0.001) significantly differed among the stages. In contrast, the MR grades did not significantly differ (2.9 ± 0.8, 3.0 ± 1.0, and 2.9 ± 1.1, respectively; P = 0.93). Both the rates of cardiac-related survival and freedom from reoperation were comparable among the 3 groups (log-rank P = 0.92 and 0.58, respectively). CONCLUSION Additional submitral and ventricular procedures can compensate for the possible impairment of the outcomes after annuloplasty alone for ischemic MR in patients with severe LV remodeling and tethering.

Slope in preload recruitable stroke work relationship predicts survival after left ventriculoplasty and mitral repair in patients with idiopathic cardiomyopathy

BACKGROUND Left ventriculoplasty (LVP) and mitral valve plasty (MVP) are sometimes effective for patients with idiopathic dilated cardiomyopathy (DCM) who are not eligible for heart transplantation. Strict patient selection is warranted for these controversial procedures. METHODS AND RESULTS The subjects were 18 patients with idiopathic DCM and mitral regurgitation who had not been indicated for heart transplantation due to either older age or patient refusal, and who underwent LVP and MVP. Their mean age was 57±14 years and 50% were dependent on catecholamine infusion. The preload recruitable stroke work (PRSW) relationship and its slope (Mw) were estimated by a single-beat technique using transthoracic echocardiography. There were one 30-day mortality and six (33%) hospital deaths due to heart failure. The one-year survival rate was 50%. Left ventricular end-diastolic dimension (LVDd) decreased from 77±11 to 68±11mm (p=0.001) whereas the ejection fraction did not change. Preoperative Mw was significantly higher in one-year survivors than that in non-survivors (54±17ergcm(-3)10(3) vs. 31±10ergcm(-3)10(3), p=0.005). Preoperative LVDd was not different between the groups. The cut-off value of 42ergcm(-3)10(3) for Mw predicted one-year survival with high sensitivity (100%) and specificity (77%). CONCLUSIONS Mw, the slope in the PRSW relationship, may predict survival after LVP and MVP in patients with idiopathic DCM.

Augmentation Index Is Elevated in Aortic Aneurysm and Dissection

BACKGROUND The augmentation index, the ratio of the ejection pressure from the heart to the reflection pressure from the arterial system, has recently been recognized as one of the indexes of left ventricular afterload. We studied it in patients with aortic aneurysm and dissection, using carotid artery diameter waveform obtained from an echo-tracking system. METHODS Forty-six patients were divided into the following three groups based on pathology: group A, 21 patients with thoracic aortic aneurysm; group B, 15 patients with chronic aortic dissection; and group C, 10 patients without any aortic diseases. Using an echo-tracking system on the carotid artery, we measured stiffness parameter beta, arterial compliance, and the augmentation index. RESULTS There was no significant difference in stiffness parameter beta and arterial compliance among the three groups. The augmentation index was significantly higher in groups A and B than group C (22 +/- 10%, 22 +/- 13% vs 8 +/- 17%; p = 0.012). Female (p = 0.028) and heart rate (p = 0.005) were significantly associated with the augmentation index and the significance of aortic diseases was marginal (p = 0.056). CONCLUSIONS The carotid augmentation index is elevated in patients with aortic aneurysm and dissection.

Echocardiography Alone Allows the Determination of Heart Failure Stages in Rats with Pressure Overload

BACKGROUND There is currently no standard for the assessment of contractile function in animals. We aimed to determine whether transthoracic echocardiography in rats with chronic pressure overload allows determining the stage of hypertrophy and heart failure (HF). METHODS Pressure overload was created by placement of a metal clip around the thoracic aorta at a weight of 40 to 50 g. After 1, 2, 6, 10, and 20 weeks, we performed echocardiography according to the American Heart Association guidelines (n = 26, four to six rats for each time point). We also obtained heart, lung, and body weights and regularly evaluated clinical signs of HF. RESULTS : Pressure overload caused significant hypertrophy within 1 week. Contractile function was normal until 6 weeks when diastolic dysfunction appeared. After 10 weeks of pressure overload, systolic function decreased. At 20 weeks, hearts were dilated and cardiac index was decreased. These findings correlated with increased lung-to-body weight ratio after 6 weeks and clinical signs of HF after 20 weeks. CONCLUSION Echocardiography alone allows the reproducible determination of HF stages after aortic constriction in rats.

Triheptanoin Alleviates Ventricular Hypertrophy and Improves Myocardial Glucose Oxidation in Rats With Pressure Overload

OBJECTIVE Cardiac hypertrophy is characterized by changes in substrate utilization and activity of the Krebs cycle. We assessed the effects of triheptanoin, an odd-chain fat that might support the Krebs cycle, on cardiac metabolism and function in a model of cardiac hypertrophy. METHODS AND RESULTS Rats were subjected to aortic banding (AoB) to induce pressure overload (PO). Starting at 1 week after AoB, rats were blindly fed a control diet or a special diet containing triheptanoin at 7% (T7 group) or 30% (T30 group) of total energy value. Six weeks after AoB, echocardiography revealed attenuated hypertrophy and improved diastolic function of the left ventricle. Isolated working heart perfusion showed similar cardiac power, fatty acid oxidation, substrate preference, and insulin response among groups. However, cardiac glucose oxidation (GO) was increased in the T30 group compared with the T7 and control groups. Blood levels of the odd-chain ketone body beta-hydroxypentanoate confirmed adequate bioavailability of triheptanoin. Importantly, they were directly proportional to cardiac GO. CONCLUSIONS Treatment with triheptanoin-enriched diet reduces ventricular hypertrophy and improves diastolic function in rats with PO, which is associated with enhanced cardiac GO. The results suggest targeting supplementation of the Krebs cycle to approach ventricular and metabolic remodeling in cardiac hypertrophy.

Left-ventricular electromechanical delay is prolonged in patients with postoperative atrial fibrillation

OBJECTIVE Although several risk factors for postoperative atrial fibrillation (AF) have been proposed, it remains the most common complication after cardiac surgery, even in low-risk patients. There is still no single reliable and reproducible parameter for predicting AF, and no standardized recommendation exists for this issue. Electromechanical delay (excitation-contraction coupling delay) is the time delay from the electrical activation to the actual systolic motion, and it reflects abnormality in calcium-handling proteins, which is considered one mechanism of postoperative AF. We hypothesized that left-ventricular electromechanical delay (LVEMD) is correlated to postoperative AF and serially examined it by echocardiography. METHODS We prospectively included 16 patients with relatively low risk for AF, who underwent cardiac surgery. The inclusion criteria were younger than 80 years, an ejection fraction greater than 45%, a left-atrial dimension less than 50mm, and a brain natriuretic peptide (BNP) value less than 250 pg ml⁻¹. Postoperative AF for 10 postoperative days was monitored by 24-h electrocardiogram. The LVEMD was assessed by pulse-wave tissue Doppler echocardiography before and 1, 3, and 7 days after the operation. Serum BNP, adrenalin, and noradrenalin levels were also examined at the same time. RESULTS Postoperative AF was detected in six (37.5%) patients. There was no significant difference in heart rate, QRS duration, and serum hormones between the non-AF (n = 10) and AF (n = 6) groups. Although the preoperative LVEMD was comparable, that on postoperative day 1 of the AF group was significantly longer than that of the non-AF group (in the septal wall, 174 ± 50 vs 101 ± 36 ms, p = 0.020; in the lateral wall, 195 ± 71 and 111 ± 37 ms, p = 0.029). A LVEMD on postoperative day 1 greater than 150 ms well predicted postoperative AF (sensitivity, 75% and 75%; specificity, 100% and 86%, in septal and lateral LVEMDs, respectively). CONCLUSIONS LVEMD is prolonged in patients with postoperative AF. This could be a new predicting parameter for AF in low-risk patients.

Immunohistochemical identification of Propionibacterium acnes in granuloma and inflammatory cells of myocardial tissues obtained from cardiac sarcoidosis patients

Background Although rare, cardiac sarcoidosis (CS) is potentially fatal. Early diagnosis and intervention are essential, but histopathologic diagnosis is limited. We aimed to detect Propionibacterium acnes, a commonly implicated etiologic agent of sarcoidosis, in myocardial tissues obtained from CS patients. Methods and results We examined formalin-fixed paraffin-embedded myocardial tissues obtained by surgery or autopsy and endomyocardial biopsy from patients with CS (n = 26; CS-group), myocarditis (n = 15; M-group), or other cardiomyopathies (n = 39; CM-group) using immunohistochemistry (IHC) with a P. acnes-specific monoclonal antibody. We found granulomas in 16 (62%) CS-group samples. Massive (≥14 inflammatory cells) and minimal (<14 inflammatory cells) inflammatory foci, respectively, were detected in 16 (62%) and 11 (42%) of the CS-group samples, 10 (67%) and 10 (67%) of the M-group samples, and 1 (3%) and 18 (46%) of the CM-group samples. P. acnes-positive reactivity in granulomas, massive inflammatory foci, and minimal inflammatory foci were detected in 10 (63%), 10 (63%), and 8 (73%) of the CS-group samples, respectively, and in none of the M-group and CM-group samples. Conclusions Frequent identification of P. acnes in sarcoid granulomas of originally aseptic myocardial tissues suggests that this indigenous bacterium causes granuloma in many CS patients. IHC detection of P. acnes in massive or minimal inflammatory foci of myocardial biopsy samples without granulomas may be useful for differentiating sarcoidosis from myocarditis or other cardiomyopathies.

Surgery for Left Ventricular Outflow Tract Obstruction with a Relatively Thin Interventricular Septum

Abstract Background To examine the results of myectomy and mitral valve surgery for systolic anterior motion (SAM) of the mitral valve and left ventricular outflow tract obstruction (LVOTO) with a relatively thin interventricular septum. Methods The subjects were 12 patients with SAM and LVOTO. Eight had hypertrophic obstructive cardiomyopathy (HOCM) with a mean interventricular septal thickness of 16 mm. Three had sigmoid septum and one had an unknown etiology. For HOCM, isolated extended myectomy was performed when mitral regurgitation was mild (n = 1) and extended myectomy plus mitral valve surgery was performed when mitral regurgitation was more than mild (n = 4) or primary valve etiologies existed (n = 3). Myectomy was performed for the three cases with sigmoid septum. Myectomy plus height reduction of the posterior mitral leaflet was performed for the one case with the unknown etiology of SAM. Results In the patients with HOCM, the maximum LVOT pressure gradient significantly decreased from 140 ± 18 to 16 ± 6 and 3 ± 3 mm Hg, while mitral regurgitation significantly decreased from 2.3 ± 0.5 to 0.5 ± 0.3 and 0.4 ± 0.2 at pre‐op, early post‐op, and last follow‐up (3 ± 1 years), respectively. In the other etiologies, the maximum LVOT pressure gradient changed from 56 ± 15 to 25 ± 15 and 5 ± 4 mm Hg; mitral regurgitation changed from 2.0 ± 0.6 to 1.3 ± 0.3 and 1.3 ± 0.8, at pre‐op, early post‐op, and the last follow‐up (3 ± 2 years), respectively. Conclusion Myectomy with mitral valve surgery is an option for SAM and LVOTO in patients with a relatively thin interventricular septum.