Bifocal left ventricular stimulation or the optimal left ventricular stimulation site in cardiac resynchronization therapy: a pressure-volume loop study.

AIMS: Several implantation strategies have been proposed to improve response to cardiac resynchronization therapy (CRT), including bifocal left ventricular (LV) stimulation and optimal single-LV lead placement. This study aimed to compare these two strategies during invasive pressure-volume (PV) loop measurements. METHODS AND RESULTS: Thirty-three patients eligible for CRT were included [21 (64%) men, 20 (61%) ischaemic aetiology, QRS 155 ± 23 ms], and underwent cardiac magnetic resonance (CMR) imaging and invasive PV loop measurements. Left ventricular pump function was characterized by stroke work (SW) and dP/dtmax (5.1 ± 3.4 L mmHg and 856 ± 190 mmHg/s, respectively). Haemodynamic response was assessed during stimulation at single-LV sites and during bifocal LV [anterolateral and posterolateral (PL)] stimulation. Response during bifocal LV stimulation was not significantly higher compared with standard PL pacing (SW; ß = 9.4 ± 5.4, P = 0.080; dP/dtmax, ß = 0.2 ± 1.9, P = 0.922). However, mean pump function improvement was significantly higher during stimulation at the optimal LV site compared with bifocal LV stimulation (SW; ß = 12.7 ± 5.1, P = 0.012; dP/dtmax, ß = 3.3 ± 1.2, P = 0.020). Myocardial tissue properties were assessed by CMR tissue tagging. Mechanical activation at the optimal LV site was significantly more delayed compared with the worst LV site (431 ± 93 ms vs. 326 ± 127 ms; P = 0.004). CONCLUSION: Stimulation at the optimal LV site showed a significantly higher pump function improvement compared with bifocal LV stimulation. Mechanical activation at the optimal LV site was significantly more delayed compared with the non-optimal LV site. In general, these results suggest that implantation of a second LV lead yields no additional benefit over implantation of one optimally placed LV lead. However, a bifocal approach might be beneficial in the individual patient.

Scar tissue-guided left ventricular lead placement for cardiac resynchronization therapy in patients with ischemic cardiomyopathy: an acute pressure-volume loop study.

BACKGROUND: Response to cardiac resynchronization therapy (CRT) is hampered by the extent and location of left ventricular (LV) scar tissue. It is commonly advised to avoid scar tissue while placing the LV lead. However, whether individual patients benefit from this strategy remains unclear. METHODS: Thirty-two CRT candidates with ischemic cardiomyopathy were enrolled from 2 successive clinical trials (TBS and E-pot study). Magnetic resonance imaging with late contrast enhancement was performed to assess location, degree and transmurality of LV scar tissue. Patients underwent invasive pressure-volume loop measurements to assess acute LV pump function changes during pacing at posterolateral (PL) and anterolateral LV sites. RESULTS: In the study population (26 [81%] men, ejection fraction [EF] 22% ± 8%, QRS 149 ± 20 milliseconds), baseline mean stroke work (SW) and dP/dtmax were 4.4 ± 2.2 L∙mmHg and 849 ± 212 mmHg/s, respectively. The extent of scar tissue was inversely related to the acute increase in SW during pacing (R = -0.53, P = .002). Stimulating PL scar tissue resulted in deterioration of pump function (∆SW -17% ± 17%, P = .018), whereas pacing PL viable tissue led to an increase in pump function (∆SW +62% ± 51%, P < .001). Switching from pacing at the location of scar tissue, irrespective of the scar location, to viable tissue showed a significant increase in SW (-8% ± 20% vs +20 ± 40, P = .004). CONCLUSIONS: The extent of LV scar tissue is inversely related to acute pump function improvement during CRT. Pacing at the location of (transmural) scar tissue at any site of the LV will generally deteriorate LV pump function. Placing the LV lead over viable myocardium significantly improves pump function as compared with pacing at the location of scar tissue in patients with ischemic cardiomyopathy.

Multicenter analyses demonstrate significant clinical effects of minor histocompatibility antigens on GvHD and GvL after HLA-matched related and unrelated hematopoietic stem cell transplantation.

The effect of minor H antigen mismatching on the occurrence of graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) after HLA-matched hematopoietic stem cell transplantation (HSCT) has mainly been demonstrated in single-center studies. Yet, the International Histocompatibility and Immunogenetics Workshops (IHIW) provide a collaborative platform to execute crucial large studies. In collaboration with 20 laboratories of the IHIW, the roles of 10 autosomal and 10 Y chromosome-encoded minor H antigens were investigated on GvHD and relapse incidence in 639 HLA-identical related donor (IRD) and 210 HLA-matched unrelated donor (MUD) HSCT recipients. Donor and recipient DNA samples were genotyped for the minor H antigens HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, SP110, PANE1, UGT2B17, and HY. The correlations with the primary outcomes GvHD (acute or chronic GvHD), survival, and relapse were statistically analyzed. The results of these multicenter analyses show that none of the HLA class I-restricted HY antigens were found to be associated with any of the primary outcomes. Interestingly, of the HLA class II-restricted HY antigens analyzed, HLA-DQ5 positive recipients showed a significantly increased GvHD-free survival in female-to-male HSCT compared with male-to-female HSCT (P = .013). Yet, analysis of the overall gender effect, thus independent of the known HY antigens, between the gender groups demonstrated an increased GvHD incidence in the female-to-male transplantations (P < .005) and a decreased GvHD-free survival in the female-to-male transplantations (P < .001). Of all autosomally encoded minor H antigens, only mismatching for the broadly expressed minor H antigen HA-8 increased the GvHD incidence in IRD HSCT (Hazard ratio [HR] = 5.28, P < .005), but not in MUD HSCT. Most striking was the influence of hematopoietic restricted minor H antigens on GvL as mismatching for hematopoietic minor H antigens correlated with lower relapse rates (P = .078), higher relapse-free survival (P = .029), and higher overall survival (P = .032) in recipients with GvHD, but not in those without GvHD. In conclusion, the significant GvHD effect of the broadly expressed minor H antigen HA-8 favors matching for HA-8 in IRD, but not in MUD, patient/donor pairs. The GvHD-GvL association demonstrating a significant lower relapse in hematopoietic minor H antigen mismatched patient/donor pairs underlines their clinical applicability for adoptive immunotherapy, enhancing the GvL effect in a GvHD controllable manner.

Phenotype frequencies of autosomal minor histocompatibility antigens display significant differences among populations.

Minor histocompatibility (H) antigens are allogeneic target molecules having significant roles in alloimmune responses after human leukocyte antigen-matched solid organ and stem cell transplantation (SCT). Minor H antigens are instrumental in the processes of transplant rejection, graft-versus-host disease, and in the curative graft-versus-tumor effect of SCT. The latter characteristic enabled the current application of selected minor H antigens in clinical immunotherapeutic SCT protocols. No information exists on the global phenotypic distribution of the currently identified minor H antigens. Therefore, an estimation of their overall impact in human leukocyte antigen-matched solid organ and SCT in the major ethnic populations is still lacking. For the first time, a worldwide phenotype frequency analysis of ten autosomal minor H antigens was executed by 31 laboratories and comprised 2,685 randomly selected individuals from six major ethnic populations. Significant differences in minor H antigen frequencies were observed between the ethnic populations, some of which appeared to be geographically correlated.

Usefulness of a pacing guidewire to facilitate left ventricular lead implantation in cardiac resynchronization therapy.

BACKGROUND: Intraoperative measurements of left ventricular (LV) pacing and sensing values were assessed using a novel 0.014-inch guidewire (Visionwire, Biotronik GmbH, Berlin, Germany) enabling pacing and sensing at the distal tip before final LV lead implantation. METHODS: Twenty-two consecutive patients selected for cardiac resynchronization therapy were studied. RESULTS: Significant correlation was found between the LV pacing threshold as assessed by the Visionwire and values after final LV lead implantation (r = 0.92, P < 0.001). Correlation for LV sensing was also significant (r = 0.72, P < 0.001). No significant correlation was present with respect to phrenic nerve stimulation. However, no phrenic nerve stimulation at 10 V/0.5 ms using the Visionwire identified 88% of patients without phrenic nerve stimulation at 10 V/0.5 ms with subsequent LV lead measurements. CONCLUSION: This technique may facilitate transvenous LV lead implantation by preventing implantation in a unsuitable target vessel with respect to pacing and sensing values or phrenic nerve stimulation, thereby reducing procedure and fluoroscopy time.

Mode of death in Shapiro syndrome: a case report.

BACKGROUND: Shapiro syndrome is extremely rare and is characterized by the triad of spontaneous periodic hypothermia, hyperhidrosis and agenesis of the corpus callosum, resulting in neurological and psychological disorders. The exact mechanism of this syndrome is unknown and treatment consists of controlling the periodic attacks. This case report describes a case of Shapiro syndrome presenting with ventricular fibrillation (VF) who was treated with dual chamber implantable cardioverter defibrillator (ICD) therapy. CASE SUMMARY: A 45-year-old man, suffering from Shapiro syndrome with frequent hypothermic attacks, was admitted to the emergency department with an out of hospital cardiac arrest caused by VF due to hypothermia. To prevent cardiac death during future hypothermic attacks with VF, the patient was treated with a dual chamber ICD. Within 1 month after ICD implantation the patient had two events of ventricular tachycardia/VF during hypothermia, which were both successfully terminated by an ICD shock. One year after ICD implantation the patient suffered from an uncontrolled urinary tract infection and the patient passed away. Post-mortem interrogation of the ICD did not reveal further episodes of VF and showed a higher supraventricular heartrate in the last days before his death, probably due to a sinus tachycardia driven by the infection. It was concluded that the most likely cause of death was an uncontrolled sepsis. DISCUSSION: The current case showed that ICD therapy can be successful in treating VF episodes in patients with unexpected periods of hypothermia.

Recurrent ventricular fibrillation caused by coronary artery spasm leading to implantable cardioverter defibrillator implantation.

Coronary artery spasm has been known to induce ischaemia and ventricular arrhythmias. We present a case of recurrent ventricular fibrillation caused by spasm-associated transmural myocardial ischaemia. During an intra-coronary acetylcholine provocation test, severe coronary spasm could be induced. The patient was treated with a hybrid approach of medication and an implantable defibrillator.

Prediction of long-term outcome of cardiac resynchronization therapy by acute pressure-volume loop measurements.

AIMS: Invasive assessment of acute haemodynamic response to biventricular pacing has been proposed as a tool to determine individual response and to optimize the effects of CRT. However, the long-term results of this approach have been poorly studied. The present study relates acute haemodynamic effects of CRT to long-term outcome. METHODS AND RESULTS: Forty-one patients were analysed in the present study. During temporary biventricular pacing before implantation, acute changes in LV pump function were assessed by pressure-volume loop measurements and related to long-term response after CRT. In the study population [30 (71%) men, NYHA class 2.9 ± 0.4, EF 28 ± 7%, QRS 150 ± 25 ms], baseline mean stroke work (SW) and dP/dt(max) were 4.6 ± 2.6 L × mmHg and 874 ± 259 mmHg/s, respectively. During biventricular pacing, mean SW and dP/dt(max) increased significantly by 43 ± 39% (+ 2.2 ± 2.4 L × mmHg, P < 0.001) and 13 ± 18% (+ 96 ± 136 mmHg/s, P < 0.001), respectively. In long-term responders (n = 29, 71%) compared with non-responders (n = 12, 29%), the acute increase in SW was significantly higher (+57 ± 33% vs. + 10 ± 30%, P < 0.001), whereas the acute increase in dP/dt(max) was not significantly different between responders and non-responders (+ 15 ± 18% vs. 6 ± 15%, P = 0.139). Receiver operating characteristic (ROC) curve analysis indicated that SW was superior to dP/dt(max), QRS duration and LV dyssynchrony in prediction of response to CRT. A cut-off value for SW of 20% yielded a sensitivity of 90% and specificity of 75% to predict reverse remodelling at 6 months. CONCLUSION: Invasive assessment of acute haemodynamics is a reliable tool to determine individual response to CRT. An acute increase in SW predicts long-term response to CRT with a higher accuracy than an acute increase in dP/dt(max), baseline QRS duration, and degree of LV mechanical dyssynchrony.

Effects of QRS duration and pacing location on pressure-volume loop evaluation of cardiac resynchronization therapy in end-stage heart failure.

Cardiac resynchronization therapy (CRT) decreases the morbidity and mortality in patients with end-stage heart failure. However, patient selection remains challenging, because a considerable 30% to 50% do not respond. Controversy exists on the cutoff values for the QRS duration and the optimal lead location. The present study relates these parameters on an individual basis to acute pump function improvement using invasively obtained pressure-volume loops. Fifty-seven patients with symptomatic end-stage heart failure were included in our temporary biventricular stimulation study and were grouped according to the QRS duration (QRS <20 ms, QRS ≥120 ms but <150 ms, and QRS ≥150 ms). All patients underwent pressure-volume loop assessment of the response to biventricular pacing, comparing the baseline measurements to both right ventricular apex pacing combined with a left ventricular lead in the posterolateral and anterolateral region of the LV. Group analysis during conventional (posterolateral and right ventricular apex) CRT did not show improvement in stroke work and dP/dt(max) (-2%, p = NS; and -7%; p <0.001) in the narrow QRS group but a significant increase in the intermediate (+27%, p = 0.020, and +5%, p = 0.044) and wide (+48%, p = 0.002, and +18%, p <0.001) QRS groups. CRT using the anterolateral and right ventricular apex configuration evoked a consistently lower response compared to posterolateral and right ventricular apex, resulting in a significant hemodynamic deterioration in the narrow QRS group. However, analysis on an individual basis identified 25% of patients with narrow QRS duration showing possible hemodynamic benefit from CRT compared to 83% of patients with intermediate and wide QRS combined. In contrast, 15% of patients had deterioration by conventional (posterolateral right ventricular apex) CRT in the intermediate and wide QRS groups compared to 31% in the narrow QRS group; 19% of patients could be improved by lead placement in the anterolateral rather than the posterolateral region. In conclusion, the acute hemodynamic response to CRT is generally in line with the long-term results from large randomized trials; however, the individual variation is large. The temporary biventricular stimulation protocol might aid in individual patient selection and in research aiming at a reduction of nonresponders and improvement in lead positioning.

A uniform genomic minor histocompatibility antigen typing methodology and database designed to facilitate clinical applications.

BACKGROUND: Minor Histocompatibility (H) antigen mismatches significantly influence the outcome of HLA-matched allogeneic stem cell transplantation. The molecular identification of human H antigens is increasing rapidly. In parallel, clinical application of minor H antigen typing has gained interest. So far, relevant and simple tools to analyze the minor H antigens in a quick and reliable way are lacking. METHODOLOGY AND FINDINGS: We developed a uniform PCR with sequence-specific primers (PCR-SSP) for 10 different autosomal minor H antigens and H-Y. This genomic minor H antigen typing methodology allows easy incorporation in the routine HLA typing procedures. DNA from previously typed EBV-LCL was used to validate the methodology. To facilitate easy interpretation for clinical purposes, a minor H database named dbMinor (http://www.lumc.nl/dbminor) was developed. Input of the minor H antigen typing results subsequently provides all relevant information for a given patient/donor pair and additional information on the putative graft-versus-host, graft-versus-tumor and host-versus-graft reactivities. SIGNIFICANCE: A simple, uniform and rapid methodology was developed enabling determination of minor H antigen genotypes of all currently identified minor H antigens. A dbMinor database was developed to interpret the genomic typing for its potential clinical relevance. The combination of the minor H antigen genomic typing methodology with the online dbMinor database and applications facilitates the clinical application of minor H antigens anti-tumor targets after stem cell transplantation.