Benefits of long-term β-blockade in experimental chronic aortic regurgitation

The objective of this study was to assess the long-term effects of β-blockade on survival and left ventricular (LV) remodeling in rats with aortic valve regurgitation (AR). The pharmacological management of chronic AR remains controversial. No drug has been definitively proven to delay the need for valve replacement or to affect morbidity and/or mortality. Our group has reported that the adrenergic system is activated in an animal model of AR and that adrenergic blockade may help maintain normal LV function. The effects of prolonged treatment with a β-blocker are unknown. Forty Wistar rats with severe AR were divided into 2 groups of 20 animals each and treated with metoprolol (Met, 25 mg·kg−1·day−1) or left untreated for 1 yr. LV remodeling was evaluated by echocardiography. Survival was assessed by Kaplan-Meir curves. Hearts were harvested for tissue analysis. All Met-treated animals were alive after 6 mo vs. 70% of untreated animals. After 1 yr, 60% of Met-treated animals were alive vs. 35% of untreated animals ( P = 0.028). All deaths, except one, were sudden. There were no differences in LV ejection fraction (all >50%) or LV dimensions. LV mass tended to be lower in the Met-treated group. There was less subendocardial fibrosis in this group, as well as lower LV filling pressures (LV end-diastolic pressure). β-Adrenergic receptor ratio (β1/β2) was improved. One year of treatment with Met was well tolerated. Met improved 1-yr survival, minimized LV hypertrophy, improved LV filling pressures, decreased LV subendocardial fibrosis, and helped restore the β-adrenergic receptor ratio.

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Initial Effects of the Left Ventricular Repair by Plication May Not Last Long in a Rat Ischemic Cardiomyopathy Model

Circulation ◽

10.1161/circ.104.suppl_1.i-241 ◽

2001 ◽

Vol 104 (suppl_1) ◽

Author(s):

Takeshi Nishina ◽

Kazunobu Nishimura ◽

Sadatoshi Yuasa ◽

Senri Miwa ◽

Takuya Nomoto ◽

...

Keyword(s):

Ischemic Cardiomyopathy ◽

Sham Group ◽

Diastolic Pressure ◽

Systolic Pressure ◽

Left Ventricular ◽

Long Term Results ◽

Lv Function ◽

Long Term Effects ◽

Second Surgery

Background Long term effects of left ventricle (LV) repair surgery (LVR) for ischemic cardiomyopathy are not well understood. Methods and Results Sixty-nine rats developed ischemic cardiomyopathy with large akinetic LV area 4 weeks after the left anterior descending artery was ligated. In a second surgery 4 weeks later, 33 rats underwent LVR by plication of the akinetic LV area (LVR group), and 36 underwent rethoracotomy alone (sham group). No medication was used in either group. All rats survived the second surgery. LV end-diastolic dimension as measured by echocardiography, LV fractional shortening, and the maximal end-systolic pressure-volume relationship (E max ) as calculated from the data by catheter-tipped manometer and echocardiography improved in the LVR group after the second surgery, but LV end-diastolic dimension and E max gradually deteriorated as time passed. LV end-diastolic pressure improved 1 week after LVR but rose significantly 4 weeks after LVR. Brain natriuretic peptide mRNA was lower in the LVR group than in the sham group 1 week after LVR but not 4 weeks postoperatively. Conclusions Initial improvement in LV function and neurohormonal status after LVR did not last for 4 weeks in this rat model when untreated medically. The mechanism of deterioration should be elucidated to improve long-term results of LVR.

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Acute and Long-Term Effects of Aortic Compliance Decrease on Central Hemodynamics: A Modeling Analysis

Frontiers in Physiology ◽

10.3389/fphys.2021.701154 ◽

2021 ◽

Vol 12 ◽

Author(s):

Stamatia Pagoulatou ◽

Dionysios Adamopoulos ◽

Georgios Rovas ◽

Vasiliki Bikia ◽

Nikolaos Stergiopulos

Keyword(s):

Augmentation Index ◽

Left Ventricular ◽

Central Hemodynamics ◽

Aortic Compliance ◽

Long Term Effects ◽

Wave Separation ◽

Modeling Analysis ◽

Lv Remodeling ◽

Type C

Aortic compliance is an important determinant of cardiac afterload and a contributor to cardiovascular morbidity. In the present study, we sought to provide in silico insights into the acute as well as long-term effects of aortic compliance decrease on central hemodynamics. To that aim, we used a mathematical model of the cardiovascular system to simulate the hemodynamics (a) of a healthy young adult (baseline), (b) acutely after banding of the proximal aorta, (c) after the heart remodeled itself to match the increased afterload. The simulated pressure and flow waves were used for subsequent wave separation analysis. Aortic banding induced hypertension (SBP 106 mmHg at baseline versus 152 mmHg after banding), which was sustained after left ventricular (LV) remodeling. The main mechanism that drove hypertension was the enhancement of the forward wave, which became even more significant after LV remodeling (forward amplitude 30 mmHg at baseline versus 60 mmHg acutely after banding versus 64 mmHg after remodeling). Accordingly, the forward wave’s contribution to the total pulse pressure increased throughout this process, while the reflection coefficient acutely decreased and then remained roughly constant. Finally, LV remodeling was accompanied by a decrease in augmentation index (AIx 13% acutely after banding versus −3% after remodeling) and a change of the central pressure wave phenotype from the characteristic Type A (“old”) to Type C (“young”) phenotype. These findings provide valuable insights into the mechanisms of hypertension and provoke us to reconsider our understanding of AIx as a solely arterial parameter.

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Abstract 14915: Incidence, Predictors and Clinical Impact of Left Ventricular Functional Recovery Following Coronary Artery Bypass Grafting in Patients With Ischemic Cardiomyopathy

Circulation ◽

10.1161/circ.142.suppl_3.14915 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Masaro Nakae ◽

Satoshi Kainuma ◽

Koichi Toda ◽

Shigeru Miyagawa ◽

Daisuke Yoshioka ◽

...

Keyword(s):

Ischemic Cardiomyopathy ◽

Artery Bypass ◽

Left Ventricular ◽

Lv Function ◽

Term Survival ◽

Function Recovery ◽

Lv Remodeling ◽

Relationship Of

Introduction: CABG is considered the standard treatment for patients with ischemic cardiomyopathy (ICM). However, it remains unknown who would achieve postoperative LV function recovery after CABG. Furthermore, the relationship of postoperative LV function recovery with long-term outcomes remains unclear. Hypothesis: In patients with ICM who undergo CABG, postoperative LV function recovery, which would be influenced by degree of LV remodeling at baseline, is associated with improved outcomes. Methods: This multicenter retrospective study comprised 490 cases with LVEF of ≤40% who underwent CABG between 1993 and 2015. Clinical follow-up was completed in 467 cases (95%), with a mean follow-up of 65±46 months (range, 0-266). A total of postoperative echocardiographic assessments were carried with an average number of 3.7±2.4. LV function recovery was defined as LVEF ≥35% at more than one exam. Association of LV function recovery with mortality after adjustments for clinically relevant covariates was estimated using Cox proportional hazard model. Pre- and intraoperative associates of LV function recovery were identified using logistic regression model. Results: During follow-up, there were 203 mortalities (41%) and overall 10-year survival was 45%. LV function recovery was found in 368 cases (75%), while not in 122 (25%). Overall 10-year survival was significantly higher in patients who achieved LV function recovery as compared with those who did not achieve it (52% vs. 23%). Multivariate analysis identified LV function recovery was independently associated with decreased overall mortality (adjusted HR 0.40, p<0.0001). Preoperative LVDs (adjusted OR 0.92, p<0.0001), eGFR (adjusted OR 1.12, p=0.016) and revascularization using bilateral internal thoracic arteries (BITA) (adjusted OR 2.81, p=0.018) are the independent predictors of LV function recovery. Conclusions: Among patients with ICM who underwent CABG, 75% achieved substantial postoperative LV function recovery, in association with better long-term survival, as compared with the remaining 25% of patients who did not achieve it. Preoperative less LV remodeling and preserved renal function as well as revascularization with use of BITA might be associated with LV function recovery.

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Physiology and Practicality of Left Ventricular Septal Pacing

Arrhythmia & Electrophysiology Review ◽

10.15420/aer.2021.21 ◽

2021 ◽

Vol 10 (3) ◽

pp. 165-171

Author(s):

Luuk Heckman ◽

Justin Luermans ◽

Floor Salden ◽

Antonius Martinus Wilhelmus van Stipdonk ◽

Masih Mafi-Rad ◽

...

Keyword(s):

Animal Studies ◽

Left Ventricular ◽

Lv Function ◽

Free Wall ◽

Long Term Effects ◽

Intraventricular Dyssynchrony ◽

Septal Pacing ◽

Ventricular Activation ◽

Patient Studies

Left ventricular septal pacing (LVSP) and left bundle branch pacing (LBBP) have been introduced to maintain or correct interventricular and intraventricular (dys)synchrony. LVSP is hypothesised to produce a fairly physiological sequence of activation, since in the left ventricle (LV) the working myocardium is activated first at the LV endocardium in the low septal and anterior free-wall regions. Animal studies as well as patient studies have demonstrated that LV function is maintained during LVSP at levels comparable to sinus rhythm with normal conduction. Left ventricular activation is more synchronous during LBBP than LVSP, but LBBP produces a higher level of intraventricular dyssynchrony compared to LVSP. While LVSP is fairly straightforward to perform, targeting the left bundle branch area may be more challenging. Long-term effects of LVSP and LBBP are yet to be determined. This review focuses on the physiology and practicality of LVSP and provides a guide for permanent LVSP implantation.

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Sympathetic augmentation of cardiac function in developing hypertension in conscious dogs

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1988.255.6.h1525 ◽

1988 ◽

Vol 255 (6) ◽

pp. H1525-H1534 ◽

Cited By ~ 2

Author(s):

R. J. Gelpi ◽

L. Hittinger ◽

A. M. Fujii ◽

V. M. Crocker ◽

I. Mirsky ◽

...

Keyword(s):

Diastolic Pressure ◽

Systolic Pressure ◽

Wall Stress ◽

Left Ventricular ◽

Rate Of Change ◽

Conscious Dogs ◽

Lv Function ◽

Adrenergic Blockade ◽

Mean Velocity ◽

Major Mechanism

To determine the alterations in left ventricular (LV) function and the mechanisms involved that occur during the development of perinephritic hypertension, dogs were instrumented with a miniature LV pressure transducer, aortic and left atrial catheters, and ultrasonic crystals to measure LV diameter in the short and long axes and wall thickness. At 2 wk after initiation of perinephritic hypertension, increases (P less than 0.05) were observed in LV systolic pressure, LV end-diastolic pressure, both short- and long-axis end-diastolic diameters, calculated LV end-diastolic volume, stroke volume, global average LV systolic wall stress, first derivative of LV pressure (LV dP/dt), and ejection fraction, whereas mean velocity of circumferential fiber shortening (Vcf) and rate of change of LV short-axis diameter (LV dD/dt) rose but not significantly. At three levels of matched preload and afterload induced by the administration of graded doses of phenylephrine, Vcf, LV dD/dt, and LV dP/dt increased in hypertension compared with the same levels of preload and afterload before hypertension. When the loading conditions in the normotensive and hypertensive dogs were matched, either after ganglionic blockade or beta-adrenergic blockade, both isovolumic and ejection-phase indexes of LV function remained similar before and after hypertension. Thus we conclude that 1) LV function in intact, conscious dogs with early hypertension is enhanced, and 2) the major mechanism for the increase in LV function involves the sympathetic nervous system.

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Premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice

BMC Pharmacology and Toxicology ◽

10.1186/s40360-021-00495-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Takaaki Furihata ◽

Satoshi Maekawa ◽

Shingo Takada ◽

Naoya Kakutani ◽

Hideo Nambu ◽

...

Keyword(s):

Drug Repositioning ◽

Chronic Phase ◽

Left Ventricular ◽

Lv Function ◽

Standard Diet ◽

Long Term Effects ◽

Treatment Groups ◽

Lv Dysfunction ◽

High Cumulative Dose

Abstract Background Doxorubicin (DOX) is widely used as an effective chemotherapeutic agent for cancers; however, DOX induces cardiac toxicity, called DOX-induced cardiomyopathy. Although DOX-induced cardiomyopathy is known to be associated with a high cumulative dose of DOX, the mechanisms of its long-term effects have not been completely elucidated. Pioglitazone (Pio) is presently contraindicated in patients with symptomatic heart failure owing to the side effects. The concept of drug repositioning led us to hypothesize the potential effects of Pio as a premedication before DOX treatment, and to analyze this hypothesis in mice. Methods First, for the hyperacute (day 1) and acute (day 7) DOX-induced dysfunction models, mice were fed a standard diet with or without 0.02% (wt/wt) Pio for 5 days before DOX treatment (15 mg/kg body weight [BW] via intraperitoneal [i.p.] administration). The following 3 treatment groups were analyzed: standard diet + vehicle (Vehicle), standard diet + DOX (DOX), and Pio + DOX. Next, for the chronic model (day 35), the mice were administrated DOX once a week for 5 weeks (5 mg/kg BW/week, i.p.). Results In the acute phase after DOX treatment, the percent fractional shortening of the left ventricle (LV) was significantly decreased in DOX mice. This cardiac malfunction was improved in Pio + DOX mice. In the chronic phase, we observed that LV function was preserved in Pio + DOX mice. Conclusions Our findings may provide a new pathophysiological explanation by which Pio plays a role in the treatment of DOX-induced cardiomyopathy, but the molecular links between Pio and DOX-induced LV dysfunction remain largely elusive.

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Left Ventricle Architecture and Valvular Integrity Following Microaxial Mechanical Support: A Two-Year Follow-Up Study

Journal of Clinical Medicine ◽

10.3390/jcm10061273 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1273

Author(s):

Georgios Chatzis ◽

Styliani Syntila ◽

Harald Schuett ◽

Christian Waechter ◽

Holger Ahrens ◽

...

Keyword(s):

Mitral Valve ◽

Structural Integrity ◽

Mitral Valve Regurgitation ◽

Left Ventricular ◽

Circulatory Support ◽

Lv Function ◽

Long Term Effects ◽

And Function

Although the use of microaxilar mechanical circulatory support systems may improve the outcome of patients with cardiogenic shock (CS), little is known about its effect on the long-term structural integrity of left ventricular (LV) valves as well as on the development of LV-architecture. Therefore, we aimed to study the integrity of the LV valves and architecture and function after Impella support. Thus, 84 consecutive patients were monitored over two years having received ImpellaTM CP (n = 24) or 2.5 (n = 60) for refractory CS (n = 62) or for high-risk percutaneous coronary interventions (n = 22) followed by optimal medical treatment. Beside a significant increase in LV ejection fraction after two years (p ≤ 0.03 vs. pre-implantation), we observed a statistically significant decrease in LV dilation (p < 0.001) and severity of mitral valve regurgitation (p = 0.007) in the two-year follow-up period, suggesting an improved LV architecture. Neither the duration of support, nor the size of the Impella device or the indication for its use revealed any devastating impact on aortic or mitral valve integrity. These findings indicate that Impella device is a safe means of support of LV-function without detrimental long-term effects on the structural integrity of LV valves regardless of the size of the device or the indication of support.

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Changes in left ventricular function and remodeling after myocardial infarction in hypothyroid rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00755.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. H259-H262 ◽

Cited By ~ 9

Author(s):

Yue-Feng Chen ◽

Rebecca A. Redetzke ◽

Suleman Said ◽

April J. Beyer ◽

A. Martin Gerdes

Keyword(s):

Myocardial Infarction ◽

Left Ventricular ◽

Experimental Myocardial Infarction ◽

Lv Function ◽

Sprague Dawley ◽

Lv Dysfunction ◽

Long Term Effect ◽

Sprague Dawley Rats ◽

Lv Remodeling

It has been shown that hypothyroidism may lead to delayed wound healing after experimental myocardial infarction (MI) in rats and increased infarct size in dogs. However, the long-term effect of hypothyroidism on left ventricular (LV) remodeling after MI has not been determined. Adult female Sprague-Dawley rats with and without surgical thyroidectomy (TX) were used in the study. Four weeks after TX, MI or sham MI was performed on TX and non-TX rats. Rats from all groups were examined 4 wk later. Four weeks after TX, hypothyroid-induced LV dysfunction was confirmed by echocardiography. In terminal experiments 4 wk after MI, TX sham-MI rats showed smaller hearts and impaired LV function compared with non-TX sham-MI controls. TX + MI rats showed smaller hearts with bigger infarct areas, higher LV end-diastolic pressures, and greater impairment of relaxation (−dP/d t) compared with non-TX MI rats. Relative changes after MI between TX and non-TX rats for most other hemodynamic and echocardiographic indexes were similar. These results suggest that preexisting hypothyroidism exaggerates post-MI remodeling and worsens LV function, particularly diastolic function.

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Acute recoordination rather than functional hemodynamic improvement determines reverse remodelling by cardiac resynchronisation therapy

The International Journal of Cardiovascular Imaging ◽

10.1007/s10554-021-02174-7 ◽

2021 ◽

Author(s):

Philippe C. Wouters ◽

Geert E. Leenders ◽

Maarten J. Cramer ◽

Mathias Meine ◽

Frits W. Prinzen ◽

...

Keyword(s):

Systolic Function ◽

Cardiac Resynchronisation Therapy ◽

Left Ventricular ◽

Lv Function ◽

Peak Strain ◽

Cardiac Resynchronisation ◽

Reverse Remodelling ◽

Resynchronisation Therapy ◽

Lv Systolic Function

AbstractPurpose: Cardiac resynchronisation therapy (CRT) improves left ventricular (LV) function acutely, with further improvements and reverse remodelling during chronic CRT. The current study investigated the relation between acute improvement of LV systolic function, acute mechanical recoordination, and long-term reverse remodelling after CRT. Methods: In 35 patients, LV speckle tracking longitudinal strain, LV volumes & ejection fraction (LVEF) were assessed by echocardiography before, acutely within three days, and 6 months after CRT. A subgroup of 25 patients underwent invasive assessment of the maximal rate of LV pressure rise (dP/dtmax,) during CRT-implantation. The acute change in dP/dtmax, LVEF, systolic discoordination (internal stretch fraction [ISF] and LV systolic rebound stretch [SRSlv]) and systolic dyssynchrony (standard deviation of peak strain times [2DS-SD18]) was studied, and their association with long-term reverse remodelling were determined. Results: CRT induced acute and ongoing recoordination (ISF from 45 ± 18 to 27 ± 11 and 23 ± 12%, p < 0.001; SRS from 2.27 ± 1.33 to 0.74 ± 0.50 and 0.71 ± 0.43%, p < 0.001) and improved LV function (dP/dtmax 668 ± 185 vs. 817 ± 198 mmHg/s, p < 0.001; stroke volume 46 ± 15 vs. 54 ± 20 and 52 ± 16 ml; LVEF 19 ± 7 vs. 23 ± 8 and 27 ± 10%, p < 0.001). Acute recoordination related to reverse remodelling (r = 0.601 and r = 0.765 for ISF & SRSlv, respectively, p < 0.001). Acute functional improvements of LV systolic function however, neither related to reverse remodelling nor to the extent of acute recoordination. Conclusion: Long-term reverse remodelling after CRT is likely determined by (acute) recoordination rather than by acute hemodynamic improvements. Discoordination may therefore be a more important CRT-substrate that can be assessed and, acutely restored.

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Effects of avertin versus xylazine-ketamine anesthesia on cardiac function in normal mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.281.5.h1938 ◽

2001 ◽

Vol 281 (5) ◽

pp. H1938-H1945 ◽

Cited By ~ 70

Author(s):

Chari Y. T. Hart ◽

John C. Burnett ◽

Margaret M. Redfield

Keyword(s):

Cardiac Function ◽

Diastolic Pressure ◽

Systolic Function ◽

Pressure Rise ◽

Left Ventricular ◽

Lv Function ◽

Ketamine Anesthesia ◽

The Difference ◽

And Function ◽

Derivatives Of

Anesthetic regimens commonly administered during studies that assess cardiac structure and function in mice are xylazine-ketamine (XK) and avertin (AV). While it is known that XK anesthesia produces more bradycardia in the mouse, the effects of XK and AV on cardiac function have not been compared. We anesthetized normal adult male Swiss Webster mice with XK or AV. Transthoracic echocardiography and closed-chest cardiac catheterization were performed to assess heart rate (HR), left ventricular (LV) dimensions at end diastole and end systole (LVDd and LVDs, respectively), fractional shortening (FS), LV end-diastolic pressure (LVEDP), the time constant of isovolumic relaxation (τ), and the first derivatives of LV pressure rise and fall (dP/d t max and dP/d t min, respectively). During echocardiography, HR was lower in XK than AV mice (250 ± 14 beats/min in XK vs. 453 ± 24 beats/min in AV, P < 0.05). Preload was increased in XK mice (LVDd: 4.1 ± 0.08 mm in XK vs. 3.8 ± 0.09 mm in AV, P < 0.05). FS, a load-dependent index of systolic function, was increased in XK mice (45 ± 1.2% in XK vs. 40 ± 0.8% in AV, P < 0.05). At LV catheterization, the difference in HR with AV (453 ± 24 beats/min) and XK (342 ± 30 beats/min, P < 0.05) anesthesia was more variable, and no significant differences in systolic or diastolic function were seen in the group as a whole. However, in XK mice with HR <300 beats/min, LVEDP was increased (28 ± 5 vs. 6.2 ± 2 mmHg in mice with HR >300 beats/min, P < 0.05), whereas systolic (LV dP/d t max: 4,402 ± 798 vs. 8,250 ± 415 mmHg/s in mice with HR >300 beats/min, P < 0.05) and diastolic (τ: 23 ± 2 vs. 14 ± 1 ms in mice with HR >300 beats/min, P < 0.05) function were impaired. Compared with AV, XK produces profound bradycardia with effects on loading conditions and ventricular function. The disparate findings at echocardiography and LV catheterization underscore the importance of comprehensive assessment of LV function in the mouse.

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