An Engineering Model of Dynamic Cardiomyoplasty. I.

Dynamic cardiomyoplasty (DCM) is an emerging surgical procedure for heart failure in which the patient's latissimus dorsi (LD) muscle is wrapped around the heart and stimulated to contract in synchrony with the heartbeat as a cardiac assist measure. A 6 week training protocol of progressive electrical stimulation renders the normally fatigueable skeletal muscle fatigue-resistant and suitable for chronic stimulation. To date, over 500 procedures have been performed in worldwide clinical trials. Investigators typically report symptomatic improvement and modest hemodynamic improvement in patients. Controversy exists regarding the exact mechanism of DCM. To test the hypothesis that DCM augments cardiac stroke volume through improvement in systolic function, we formulated an engineering model of dynamic cardiomyoplasty to predict stroke volume. The heart and the LD were modeled as nested (series) elastance chambers, and the vasculature was represented by a two-element Windkessel model. Using five healthy goats, we verified model predictions of stroke volume for both stimulator ON beats (y=1.00x–0.08, r=0.87, p < 0.0001) and OFF beats (y=1.01x+1.06, r=0.91, p < 0.0001), where x and y are the measured and predicted stroke volumes, respectively. The model confirms that using untrained latissimus dorsi applied to the normal myocardium produces only moderate increases in stroke volume and suggests that future research should focus on increasing LD strength after training.     

Cardiomyoplasty: long-term results in ischemic cardiomyopathy

INTRODUCTION: Cardiomyoplasty was introduced into clinical practice in 1985 by Alain Carpentier. Since then, the procedure has been performed on more than 400 patients worldwide. The latissimus dorsi muscle is prepared maintaining the vascular supply, then the muscle flap is wrapped around the heart and connected to a cardiomyostimulator. The muscle is later stimulated synchronously with ventricular systole to augment the cardiac contractility. METHODS: To evaluate the long-term outcome of cardiomyoplasty, we investigated 3 patients electively undergoing this procedure in our hospital. All of these patients (2 male, 1 female) had severe chronic heart failure which did not respond to optimal medical treatment. The mean follow-up time was 42 months (range 24 - 60). All patients showed symptoms corresponding to NYHA class III, and one patient intermittently showed class IV despite conventional medical therapy. Patients were evaluated at 6-month intervals for 2 years with right heart catheterization, radionuclide scans, echocardiography, as well as questionnaires for assessing quality of life. RESULTS: There was no operative mortality. One patient experienced sudden death 2 years after operation. There were no significant changes in hemodynamic variables at 6, 12 or 24 months after surgery, respectively. Left ventricular ejection fraction increased from 20.0 ( 9.2 to 40.0 +/- 7.1 % (p = 0.05) 1 year after operation. Considerable improvement of symptoms was seen in all, and 1 patient returned to work. NYHA-class decreased from 3.1 to 2.0 (p = 0.02). CONCLUSIONS: Following cardiomyoplasty, patients may exhibit impressive clinical improvement with less striking changes of objective hemodynamic parameters. Thus, in our patients, dynamic cardiomyoplasty improves quality of life. We do not consider this treatment to be an alternative to heart transplantation. It does, however, provide a therapeutic option for patients for whom transplantation is contraindicated.     

Cardiocirculatory bio-assist: is it time to reconsider demand dynamic cardiomyoplasty? Review and future perspectives

In the last 15 years, dynamic cardiomyoplasty has remained an experimental procedure even after the enthusiastic short- and mid-term results, mainly because of the disappointing long-term outcome caused by muscular degeneration secondary to chronic continuous electrical stimulation of the latissimus dorsi. In Italy, a group of muscular pathologists, cardiologists, and cardiac surgeons conducted an experiment of an activity-rest stimulation protocol in humans that should avoid complete transformation of the skeletal muscle, maintaining its properties overtime. This "demand" stimulation protocol gave good results, improving New York Heart Association class, ejection fraction value, and survival. Even though dynamic cardiomyoplasty was excluded from the recent international guidelines for the management of heart failure, the discussion on the ability of this unique kind of cardiocirculatory bio-assistance is due to be reopened, thanks to the results of the new stimulation protocol. Heart transplantation, circulatory supporting devices, multisite stimulation therapy, and the total artificial heart are not always and in all countries the best solutions: the great economic cost, the numerous contraindications, the need for immunosuppression and antithrombotic therapy, and the troublesome follow up constitute important drawbacks. For patients in whom transplant surgery cannot be performed, as well as in developing countries, the nonprohibitively expensive demand dynamic cardiomyoplasty may still play a role.     

Dynamic cardiomyoplasty decreases myocardial workload as assessed by tissue tagged MRI

The effects of dynamic cardiomyoplasty (CMP) on global and regional left ventricular (LV) function in end-stage heart failure still remain unclear. MRI with tissue-tagging is a novel tool for studying intramyocardial motion and mechanics. To date, no studies have attempted to use MRI to simultaneously study global and regional cardiac function in a model of CMP. In this study, we used MRI with tissue-tagging and a custom designed MR compatible muscle stimulating/pressure monitoring system to assess long axis regional strain and displacement variations, as well as changes in global LV function in a model of dynamic cardiomyoplasty. Three dogs underwent rapid ventricular pacing (RVP; 215 BPM) for 10 weeks; after 4 weeks of RVP, a left posterior CMP was performed. After 1 year of dynamic muscle stimulation, the dogs were imaged in a 1.5 T clinical MR scanner. Unstimulated and muscle stimulated tagged long axis images were acquired. Quantitative 2-D regional image analysis was performed by dividing the hearts into three regions: apical, septal, and lateral. Maximum and minimum principal strains (lambda, and lambda2) and displacement (D) were determined and pooled for each region. MR LV pressure-volume (PV) loops were also generated. Muscle stimulation produced a leftward shift of the PV loops in two of the three dogs, and an increase in the peak LV pressure, while stroke volume remained unchanged. With stimulation, lambda1 decreased significantly (p<0.05) in the lateral region, whereas lambda2 increased significantly (p<0.05) in both the lateral and apical regions, indicating a decrease in strain resulting from stimulation. D only increased significantly (p<0.05) in the apical region. The decrease in strain between unassisted and assisted states indicates the heart is performing less work, while maintaining stroke volume and increasing peak LV pressure. These findings demonstrate that the muscle wrap functions as an active assist, decreasing the workload of the heart, while preserving total pump performance.     

Histopathological findings in skeletal muscle used in human dynamic cardiomyoplasty

Patients submitted to dynamic cardiomyoplasty had an initial clinical improvement followed by a decrease in cardiac failure indices. A histopathological study of the skeletal muscle was undertaken to explain this. Latissimus dorsi fragments from 15 patients submitted to dynamic cardiomyoplasty in a 1:1 (heart beat:muscle stimulation) conditioning were analysed by light microscopy. The interval between surgery and obtaining the specimens (13 from necropsies, two from heart transplants) ranged from 37 days to 6 years. Nuclear clumps and internalization, the presence of round fibres, inflammation, and fibrosis were analysed semi-quantitatively; the thickness of muscle fibres and the percentage of tissue fat were measured by image analysis. The quantitative data were also compared, in 12 cases, with gender- and age-matched necropsy controls. The mean thickness of muscle fibres in cases and controls was 27.21+/-5.33 and 40.84+/-9.42 microm, respectively (p=0.001). The percentage of tissue fat in cases and controls was 12.04+/-12.66% and 0.93+/-0.91%, respectively (p=0.008). The duration of grafts correlated positively with the quantity of nuclear clumps (R=0.80, p<0.001) and round fibres (R=0.53, p=0.04), as well as with the percentage of tissue fat (R=0.68, p=0.005). Accordingly, a negative correlation was found between the duration of grafts and the mean diameter of fibres, characterizing muscle atrophy (R=-0.66, p=0.01). The longer the post-surgical period, the more intense the degenerative lesions. This study shows that skeletal muscle used in human dynamic cardiomyoplasty may atrophy and be replaced by fat when stimulation is synchronized to every cardiac beat. These findings could play a role in explaining the long-term results of this surgical procedure.     

Dynamic cardiomyoplasty in a patient with end-stage cardiomyopathy.

Dynamic cardiomyoplasty is a relatively new surgical procedure by which a transformed fatigue-resistant skeletal muscle wrapped around the heart is stimulated to contract in synchrony with it, thereby augmenting the ventricular functions of a failing heart. We performed a cardiomyoplasty with latissimus dorsii (LD) in a patient who was refused the heart transplant programme because of pulmonary hypertension and psychosocial contraindications. The patient was 34 years old, functional class grade IV of the New York Heart Association (NYHA), with a three-month history, due to ischemic cardiomyopathy with multiple vessels affected, 10% ejection fraction, arteriolar pulmonary resistance of 7.5 U Wood. Cardiomyoplasty was performed after training the LD muscle for four weeks. One week later the pacemaker was programmed in a DDD mode: amplitude 3.75 V, pulse duration 0.50 ms, AV delay 175 ms. The patient reached functional class grade I-II (NYHA). Inotrope support was discontinued and great clinical improvement was noted. The ejection fraction rose from 10% to 30%. Echocardiographic left ventricular outflow tract velocity increased from 0.33 m/s to 0.60 m/s. These values were compared with radionuclide angiocardiography and echocardiography evaluations. The great clinical improvement and positive changes in left ventricular parameters suggest that cardiomyoplasty is useful in the treatment of some cases of dilated or ischemic cardiomyopathy as an alternative to heart transplantation. Long term follow-up is necessary to evaluate this procedure.     

Trans-coronary transplantation may be an optimal route in cellular cardiomyoplasty with stem cells

Myocardial infarction is the leading cause of congestive heart failure and death in the industrialized world. However, the intrinsic repair mechanism of the injured heart and current therapeutic means are inadequate to regenerate lost myocardium. Recent interests focused on cellular cardiomyoplasty which is an outside intervention to support the reparative process in the heart through transplantation of stem/progenitor cells. Cellular myocardioplasty with stem cells is a possible option to reverse the adverse hemodynamic and neurohormonal imbalance after myocardial infarction. Experimental studies and clinical trials suggest that cellular cardiomyoplasty with stem/progenitor cells may improve cardiac function and prevent ventricular remodeling of the injured heart. Although the mechanisms are still in intensive debate, cellular cardiomyoplasty with stem cells has already been introduced into the clinical settings. However, it is an important challenge how donor cells are delivered to the targeted area. In early studies in animals, intramyocardial injection of stem cells after thoracotomy is the main transplantation route which is not suitable to most patients in clinical settings. Then the catheter-based infusion of stem cells is clinically introduced and rapidly developed because of its safety, convenience and micro-invasion. We hypothesize that catheter-based transplantation with stem cells may be a promising means to treat ischemic heart diseases in the future in clinical settings.     

Motor hand recovery after stroke. Prognostic yield of early transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) was performed in 20 patients within the first days after stroke. Motor evoked potentials (MEPs) were bilaterally recorded over thenar eminence muscles, and central motor conduction time (CMCT), amplitude of the MEPs (A%M) and threshold intensity compared between both sides. Six months later the patients were reexamined. Within the first days after stroke the obtention of MEPs at rest or during voluntary muscle activation have a favorable prognostic value. All patients with early response by TMS reached a good motor function in the following months. The follow-up showed that the electrophysiological improvement was closely related to clinical recovery of the hand function. However, even in cases with a good recovery, the CMCT and, mainly, the A%M, may be significantly different related to those in normal hand. TMS may be an early and valuable prognostic indicator of hand function recovery after stroke, and their prognostic yield is higher than clinical evaluation and CT study. TMS is a quantifiable method of motor disability and may have practical application in the management and rehabilitation therapy in stroke patients.     

Survival after stroke. Risk factors and determinants in the Copenhagen Stroke Study

The eight papers included in this doctoral thesis were made during my position as a clinical research assistant at the Department of Neurology, Bispebjerg Hospital. All papers are based on the Copenhagen Stroke Study, which comprises a cohort of 1197 patients with acute stroke admitted to a single stroke unit and recruited from a well-defined area in Copenhagen, Denmark. This thesis focuses on the survival after stroke in relation to several baseline clinical characteristics and risk factors for cardiovascular disease. The thesis comes in three sections with regard to whether factors or clinical characteristics are permanent, potentially modifiable, or possible to change. The relative importance of the factors and clinical characteristics are discussed in relation to short-, intermediate-, and long-term survival after stroke. The results from the Copenhagen Stroke Study are compared to the results from other community-based or population-based studies. The two most prominent factors that determine both short- and long-term survival after stroke are age and stroke severity at onset. Advancing age and increasing severity are perceptively negatively correlated to survival. In some cases emerging therapies such as thrombolytic therapy and hypothermia may alleviate the burden of stroke severity, but this is not the case for the majority of stroke patients. The necessity to measure stroke severity with a validated stroke scale when comparing stroke patients in randomized clinical trials or population-based surveys is emphasized. For factors such as sex, and most cardiovascular risk factors further studies are necessary to clarify the relation to survival because studies disagree. Conclusions from studies of the relation between survival and alcohol intake are still debatable, mostly because of diverging definitions of the intensity of exposure. Smoking is uniformly associated with a poorer survival after stroke. Stroke unit treatment improves both short- and longterm survival regardless of stroke type, severity, age, and cardiovascular risk factor profile.     

Dehydroascorbic acid for the treatment of acute ischemic stroke

In animal models of acute ischemic stroke, intravenous dehydroascorbic acid (DHAA), unlike ascorbic acid (AA), readily enters brain and is converted in both normal and ischemic brain into protective ascorbic acid. When given parenterally DHAA minimizes infarct volume and facilitates functional recovery. I hypothesize the same effect will occur in humans with acute ischemic stroke. Efficacy in reducing infarct volume is demonstrable in mice and rats even when DHAA is infused three hours after the experimental infarct. Moreover, there is fivefold mechanistic rational for DHA beside excellent pharmacokinetics and rapid penetration of brain and conversion to protective AA: (1) in ischemic brain, there is a precipitous decline in AA which can be reversed by intravenous DHAA; (2) after reduction of DHAA to AA in both normal and ischemic brain, AA can reduce oxidized vitamin E and glutathione, other protectors of brain against damaging reactive oxygen species which build up in ischemic brain; (3) AA itself can protect brain against damaging reactive oxygen species; (4) AA is an essential cofactor for several enzymes in brain including ten-eleven translocase-2 which upregulates production of protective molecules like brain-derived neurotrophic factor; and (5) DHAA after conversion to AA prevents both lipid oxidation and presumably oxidation of other labile substances (e.g., dopamine) in ischemic brain. In terms of safety, based on all available animal information, DHAA is safe in the proposed dosing regimen. For human clinical trials, the methodology for conducting the proposed animal safety, clinical pharmacology and phase II efficacy studies is straightforward. Finally, if DHAA preserved brain substance and function in humans, it could be employed in pre-hospital stroke patients.     

Preclinical animal studies in ischemic stroke: Challenges and some solutions

Despite the impressive efficacies demonstrated in preclinical research, hundreds of potentially neuroprotective drugs have failed to provide effective neuroprotection for ischemic stroke in human clinical trials. Lack of a powerful animal model for human ischemic stroke could be a major reason for the failure to develop successful neuroprotective drugs for ischemic stroke. This review recapitulates the available cerebral ischemia animal models, provides an anatomical comparison of the circle of Willis of each species, and describes the functional assessment tests used in these ischemic stroke models. The distinct differences between human ischemic stroke and experimental stroke in available animal models is explored. Innovative animal models more closely resembling human strokes, better techniques in functional outcome assessment and better experimental designs generating clearer and stronger evidence may help realise the development of truly neuroprotective drugs that will benefit human ischemic stroke patients. This may involve use of newer molecules or revisiting earlier studies with new experimental designs. Translation of any resultant successes may then be tested in human clinical trials with greater confidence and optimism.     

Interaction of interval-force relationship with aortic pressure and stroke volume.

The modification by aortic pressure and stroke volume of the response in cardiac performance to increases in heart rate (interval-force relationship) has not been previously studied. To investigate this interaction, 30 adrenergically blocked anesthetized dogs on right heart bypass were studied. At constant low aortic pressure and stroke volume, increasing heart rate (over the entire range 60-180) is associated with a continuously increasing stroke power, decreasing systolic ejection period, and an unchanging left ventricular end-diastolic pressure and circumference. At increased aortic pressure or stroke volume at low rates (60-120), increases in heart rate were associated with an increased performance. However, at increased aortic pressure or stroke volume at high rates (120-180), increases in heart rate were associated with a leveling or decrease in performance. Thus, an increase in aortic pressure or stroke volume results in an accentuation of the improvement in cardiac performance observed with increases in heart rate, but this response is limited to a low heart rate range. Therefore, the hemodynamic response to given increases in heart rate is critically dependent on aortic pressure and stroke volume.     

Intermittent hypoxia and vascular function: implications for obstructive sleep apnoea

Obstructive sleep apnoea (OSA) has been implicated as a risk factor for the development of hypertension, stroke and myocardial infarction. The main cause of cardiovascular and cerebrovascular disease in OSA is thought to be exposure to intermittent hypoxia, which can lead to oxidative stress, inflammation, atherosclerosis, endothelial dysfunction and hypertension. These proposed mechanisms have been drawn from basic research in animal and human models of intermittent hypoxia in addition to clinical investigation of patients with OSA. This review outlines the association between OSA and vascular disease, describes basic mechanisms that may be responsible for this association and compares the results from studies of OSA subjects with those in experimental models of intermittent hypoxia.     

Lesions Responsible for Impaired Visual Perception in Poststroke Patients Using Voxel‐Based Lesion Symptom Mapping

We aimed to clarify the clinical characteristics that affect visual perception (VP) and elucidate lesion locations correlated with impaired VP. We reviewed 61 patients with stroke. Clinical assessments of a motor‐free VP test were used to evaluate VP after stroke. Regression analyses were performed to examine predictors of impaired VP. We generated statistical maps of lesions related to impaired VP using voxel‐based lesion symptom mapping (VLSM). The group of patients who had right hemispheric lesions had significantly low VP function. In a regression model, impaired VP was predicted by cognitive function, age, lesion volume, and right hemispheric lesion. Using VLSM, we found lesion location associated with impaired VP after adjusting for age, lesion volume, and Korean version of mini mental status exam. The results showed a lesion pattern with predominant distribution in the right parietal lobe and deep white matter. Age, lesion volume, and cognitive impairment affected the results of VP tests. Even after adjustments, we found that lesions responsible for impaired VP were located in the right parietal lobe and deep white matter. This result confirmed right hemispheric dominance for VP using VLSM. Clin. Anat. 32:689–696, 2019. © 2019 Wiley Periodicals, Inc.     

Limitations of a convolution method for modeling geometric uncertainties in radiation therapy. I. The effect of shift invariance

Convolution methods have been used to model the effect of geometric uncertainties on dose delivery in radiation therapy. Convolution assumes shift invariance of the dose distribution. Internal inhomogeneities and surface curvature lead to violations of this assumption. The magnitude of the error resulting from violation of shift invariance is not well documented. This issue is addressed by comparing dose distributions calculated using the Convolution method with dose distributions obtained by Direct Simulation. A comparison of conventional Static dose distributions was also made with Direct Simulation. This analysis was performed for phantom geometries and several clinical tumor sites. A modification to the Convolution method to correct for some of the inherent errors is proposed and tested using example phantoms and patients. We refer to this modified method as the Corrected Convolution. The average maximum dose error in the calculated volume (averaged over different beam arrangements in the various phantom examples) was 21% with the Static dose calculation, 9% with Convolution, and reduced to 5% with the Corrected Convolution. The average maximum dose error in the calculated volume (averaged over four clinical examples) was 9% for the Static method, 13% for Convolution, and 3% for Corrected Convolution. While Convolution can provide a superior estimate of the dose delivered when geometric uncertainties are present, the violation of shift invariance can result in substantial errors near the surface of the patient. The proposed Corrected Convolution modification reduces errors near the surface to 3% or less.     

New advances in dynamic cardiomyoplasty: Doppler flow wire shows improved cardiac assistance in demand protocol

No data have been published on real cardiac assistance with demand dynamic cardiomyoplasty. We tested the utility of a Doppler flow wire in measuring beat by beat aortic flow velocity and evaluating cardiac assistance in demand cardiomyoplasty patients. The technique was tested in seven patients (M/W = 6/1; age, 57.1+/-6.2 years; atrial fibrillation/ sinus rhythm = 1/6; New York Heart Association [NYHA] classification = 1.4+/-0.5). Measurements were done using a 0.018 inch peripheral Doppler flow wire advanced through a 5 French arterial femoral sheath. Three 1 minute periods with the stimulator off, and three 1 minute periods with clinical stimulation were recorded. We measured peak aortic flow velocity in all beats. Latissimus dorsi mechanogram was simultaneously recorded. Comparison between preoperative and follow-up data showed significantly higher values of tetanic fusion frequency and ejection fraction at follow-up, whereas mean NYHA class was significantly lower. Statistical analysis showed an increase in aortic flow velocity not only in the assisted versus rest period, but also in assisted versus unassisted beats (8.42+/-6.98% and 7.55+/-3.07%). A linear correlation was found between increase in flow velocity and latissimus dorsi wrap tetanic fusion frequency (r2 = 0.53). In demand dynamic cardiomyoplasty, systolic assistance is significant and correlated to the latissimus dorsi speed of contraction; a demand stimulation protocol maintains muscle properties and increases muscle performance.     

Kubicek每搏心输出量计算公式的三维有限元仿真研究

我们从 Kubicek模型三维有限元仿真的角度对 Kubicek每搏心输出量计算公式的临床应用价值进行了研究。在计算机仿真研究中 ,我们对比了模型仿真结果、具体采用 Kubicek每搏心输出量计算公式所得结果以及所设模型的理论计算结果。仿真结果表明 :模型中阻抗改变与主动脉中血液容积改变之间存在着近似的线性关系 ,证明了 Kubicek每搏心输出量计算公式具有一定的临床应用价值 ,同时也为心阻抗血流图基础理论提供了新的研究途径。     

Frequency and clinical, neuropsychological and neuroimaging correlates of apathy following stroke - the Sydney Stroke Study

BACKGROUND: The frequency and clinical, neuropsychological and neuroimaging correlates of apathy in patients who have had a stroke are inadequately defined.METHOD: A total of 167 consecutive patients admitted to the stroke units of two university hospitals after an ischaemic stroke and 109 controls received extensive medical, psychiatric and neuropsychological assessments; a subset received a magnetic resonance imaging (MRI) scan. The groups were matched for sex and age. Patients were assessed 3-6 months after their stroke. The sample for this study comprised 135 patients and 92 controls who completed the Apathy Evaluation Scale (AES).RESULTS: Apathy was present in 26.7% of stroke patients compared to 5.4% of controls. Apathetic stroke patients were older, more functionally dependent and had lower Mini-Mental State Examination (MMSE) scores than those without apathy. Apathy was not associated with risk factors for cerebrovascular disease or stroke severity. There was a weak but significant correlation between apathy and self-reported depression but not with clinician-rated depression. Neuropsychologically, after correction for age, premorbid intelligence (IQ) and depression, apathy was associated with reduced attention and speed of information processing. On neuroimaging there were trends for associations of apathy with the extent of hyperintensities in the right hemisphere and right fronto-subcortical circuit, but not with total stroke volume or number of strokes.CONCLUSIONS: Apathy is common following a cerebrovascular event. Presence of apathy may be related to older age and right fronto-subcortical pathway pathology, rather than stroke severity. It is associated with functional impairment and cognitive deficits.     

Chronic basal meningitis and vasculitis in acquired immunodeficiency syndrome. A possible role for human immunodeficiency virus

We describe the clinical and postmortem findings in a 57-year-old man with human immunodeficiency virus who presented with neurologic symptoms attributed to stroke. In addition to multiple foci of ischemic necrosis, pathologic examination of the brain showed chronic basal meningitis and vasculitis. No microorganisms were found. The association of meningitis and vasculitis in patients with acquired immunodeficiency syndrome is unusual and the possibility that these conditions may be due to primary human immunodeficiency virus infection is raised.