Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Survival After Implantable Cardioverter-Defibrillator Implantation in the Elderly
- Multi-Institutional Study of Implantable Defibrillator Lead Performance in Children and Young Adults: Results of the Pediatric Lead Extractability and Survival Evaluation (PLEASE) Study
- Serum Proprotein Convertase Subtilisin/Kexin Type 9 and Cell Surface Low-Density Lipoprotein Receptor: Evidence for a Reciprocal Regulation
- Economic Evaluation of Percutaneous Left Atrial Appendage Occlusion, Dabigatran, and Warfarin for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation
- Cost-Effectiveness of Ventricular Assist Device Therapy as a Bridge to Transplantation Compared With Nonbridged Cardiac Recipients
- Prognostic Value of the Index of Microcirculatory Resistance Measured After Primary Percutaneous Coronary Intervention
- Defective Extracellular Pyrophosphate Metabolism Promotes Vascular Calcification in a Mouse Model of Hutchinson-Gilford Progeria Syndrome That Is Ameliorated on Pyrophosphate Treatment
- Info & Metrics
Survival After Implantable Cardioverter-Defibrillator Implantation in the Elderly
The benefit of implantable cardioverter-defibrillators (ICDs) among elderly patients is controversial and may be attenuated by nonarrhythmic death. An estimated 28% of those deemed potentially eligible for ICD implantation by conventional criteria are octogenarians. The Ontario ICD registry is a large, prospective, inclusive database designed to evaluate adjudicated clinical and device-related outcomes after ICD implantation. We examined 5399 primary and secondary prevention ICD recipients between February 2003 and September 2010 to determine the effect of age on mortality, hospitalization, device therapy, and complications. Among primary prevention ICD recipients aged 18 to 49, 50 to 59, 60 to 69, 70 to 79, and ≥80 years, mortality increased significantly with age, as follows: 2.1, 3.0, 5.4, 6.9, and 10.2 deaths per 100 person-years, respectively. Secondary prevention ICD recipients also demonstrated increasing mortality, as follows: 2.2, 3.8, 6.1, 8.7, and 15.5 deaths per 100 person-years. However, rates of appropriate shock were similar across age groups, with a mean of 5.1 and 12.0 events per 100 person-years for primary and secondary prevention cohorts, respectively. Competing risk analysis verified an increase in all-cause mortality but no significant decline in appropriate shocks with advanced age. Furthermore, inappropriate therapy and complications were similar regardless of age. These results suggest that decisions regarding ICD candidacy should not be based on age alone. Cardiovascular and noncardiovascular hospitalizations were elevated in the elderly, reflecting a greater impact of comorbidities. Consideration of prognostic factors that predict mortality in conjunction with individualized clinical judgment will help to identify older patients who are more likely to benefit from ICD implantation. See p 2383.
Multi-Institutional Study of Implantable Defibrillator Lead Performance in Children and Young Adults: Results of the Pediatric Lead Extractability and Survival Evaluation (PLEASE) Study
This is a prospective multicenter study of 848 pediatric and congenital patients undergoing implantable cardioverter-defibrillator placement. The overall prevalence of implantable cardioverter-defibrillator lead failure was 14%. In particular, Sprint Fidelis leads showed a 9.2% yearly failure rate, 4-fold higher than that of all other leads in the study and significantly higher than published Fidelis lead failure rates in adult patients. This higher failure rate highlights the biophysical difference between pediatric and adult patients and raises caution about the cross-applicability of lead performance data between different age groups. Young age at implantation was also found to be associated with lead failure, showing an incremental risk in the <12-year-old and <8-year-old groups. Young age at implantation is a potentially modifiable clinical variable, and route of implantation should be considered when a young patient is evaluated for implantable cardioverter-defibrillator placement. Lead extraction was performed in the great majority of failed leads. Older lead age was identified as a risk factor for requiring a technically advanced extraction technique, and major procedural complications were relatively common. The findings in this study emphasize the high risk of lead failure in pediatric patients with an augmented risk in recalled thin leads such as Fidelis. The compounded lifetime morbidity from implantable cardioverter-defibrillator system failures in pediatric patients has critical implications and remains a major concern. See p 2393.
Serum Proprotein Convertase Subtilisin/Kexin Type 9 and Cell Surface Low-Density Lipoprotein Receptor: Evidence for a Reciprocal Regulation
We show novel posttranscriptional regulatory mechanisms determining serum levels and function of proprotein convertase subtilisin/kexin type 9 (PCSK9) : clearance via the low-density lipoprotein (LDL) receptor (LDLR) and transport on LDL in a quantitatively significant but less active form. Although PCSK9 is known to regulate LDLR levels, we report here that the reverse is also true and that the main exit route for serum PCSK9 is via LDLR. Thus, LDLR mutations may have larger effects on LDL metabolism if they affect not only LDL internalization but also PCSK9 clearance. We foresee a clinical scenario in which LDLR mutations that affect PCSK9 clearance in addition to LDL clearance (eg, receptor negative) can aggravate hypercholesterolemia via the effect of accumulated PCSK9, resulting from defective clearance, on the normal LDLR allele product. Along this line of thinking, it is also possible to forecast hypercholesterolemia resulting from an LDLR mutation that only causes defective PCSK9 clearance. It is interesting that carriers of LDLR-negative mutations have indeed been reported to show significantly higher LDL levels compared with carriers of dysfunctional LDLR mutations. Our finding that about one third of serum PCSK9 is part of LDL and is in a monomeric, less active form suggests that peripheral distribution and function of this regulator of LDLR levels are influenced by the lipoprotein that acts as a canonical ligand for LDLR. Maneuvers that increase the PCSK9 content of LDL in serum may allow us to broaden the search for inhibitory strategies of PCSK9 action, currently limited to blocking the interaction between PCSK9 and LDLR via antibodies. See p 2403.
Economic Evaluation of Percutaneous Left Atrial Appendage Occlusion, Dabigatran, and Warfarin for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation
The increasing prevalence of atrial fibrillation will pose a significant public health burden related to the increased risk of stroke. Warfarin therapy has been proven to reduce stroke risk in nonvalvular atrial fibrillation; however, it confers an increased risk of bleeding, has a narrow therapeutic range, and necessitates frequent monitoring. Novel oral anticoagulants and percutaneous left atrial appendage occlusion are challenging the current paradigm for stroke prevention in patients with nonvalvular atrial fibrillation, because these novel approaches may provide stroke protection while reducing the risk of bleeding compared with warfarin. Currently, no direct head-to-head comparisons of these novel therapies exist. As such, we constructed a decision-analytic model that incorporated all available evidence to assess the balance between the potential benefits and trade-offs of these novel strategies compared with warfarin. Our work demonstrated that warfarin therapy has the lowest quality-adjusted life years at 4.55, followed by the novel oral anticoagulant dabigatran at 4.64 quality-adjusted life years and left atrial appendage occlusion at 4.68 quality-adjusted life years. The average lifetime costs were $21 429 for a patient taking warfarin, $25 760 for a patient taking dabigatran, and $27 003 for a patient treated by left atrial appendage occlusion. Our results suggest that a strategy of left atrial appendage occlusion is preferable to dabigatran therapy. These findings are important because they may guide policy makers to critically evaluate the merits of each approach before adoption and provide clinical researchers with direction for future research in the field of stroke prevention in nonvalvular atrial fibrillation. See p 2414.
Cost-Effectiveness of Ventricular Assist Device Therapy as a Bridge to Transplantation Compared With Nonbridged Cardiac Recipients
Current treatment options for advanced heart failure patients include heart transplantation and ventricular assist device (VAD) implantation. The median posttransplantation survival is 10 years. However, only 45% to 65% of patients on the waiting list receive an organ, and the mortality rate for those patients who remain on the list is 35% at 1 year. One-year survival of VAD patients is 83%; however, VAD therapy is associated with complications, and follow-up remains too short to draw conclusions about long-term outcomes. The benefits and risks associated with both therapies and the lack of comparative studies make it difficult to confidently determine which approach is best based on individual patient characteristics. Therefore, we performed a cost-effectiveness analysis to evaluate the clinical benefits and costs associated with VAD therapy compared with nonbridged heart transplantation in transplant-eligible patients with advanced heart failure. The results from the model showed that VAD therapy is associated with increased survival and increased cost in high-, medium-, and even low-risk patients. The cost-effectiveness ratio of VAD therapy compared with heart transplantation at a 20-year time horizon was $84 964 per life year in high-risk patients, $99 039 per life year in medium-risk patients, and $119 574 per life year in low-risk patients. Subgroup analyses indicated that the cost-effectiveness ratio was substantially modified in special circumstances, considering risk of post-VAD and transplantation complications, waiting time, renal dysfunction, and patient age. These results will help healthcare providers perform informed decision making to improve outcomes and reduce costs associated with the management of patients with advanced heart failure. See p 2424.
Prognostic Value of the Index of Microcirculatory Resistance Measured After Primary Percutaneous Coronary Intervention
Coronary microvascular damage at the time of ST-segment elevation myocardial infarction portends a worse prognosis. The Index of Microcirculatory Resistance is a quantitative, reproducible, and relatively straightforward wire-based method for measuring microvascular function in the cardiac catheterization laboratory at the time of ST-segment elevation myocardial infarction, which is independent of hemodynamic changes and specific for the microvasculature. The Index of Microcirculatory Resistance has been shown previously to predict the size of a myocardial infarction and the recovery of left ventricular function over time. In this study, we show that the Index of Microcirculatory Resistance measured after primary percutaneous coronary intervention in 253 patients with ST-segment elevation myocardial infarction is an independent predictor of death and the need for rehospitalization for congestive heart failure during 2.8 years of follow-up, whereas other common measures of microvascular function were not. The Index of Microcirculatory Resistance appears to be a useful method for identifying patients with ST-segment elevation myocardial infarction at high risk for adverse events who might benefit from novel strategies aimed at recovery of microvascular function. See p 2436.
Defective Extracellular Pyrophosphate Metabolism Promotes Vascular Calcification in a Mouse Model of Hutchinson-Gilford Progeria Syndrome That Is Ameliorated on Pyrophosphate Treatment
Progerin is a mutant form of lamin A responsible for Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disorder featuring excessive vascular calcification (VC). However, calcium dysfunction is understudied in this disease. Here, we have shown that progerin-expressing LmnaG609G/+ mice, which mimic the main clinical manifestations of HGPS, develop excessive VC. Moreover, primary vascular smooth muscle cells from LmnaG609G/+ mice exhibit increased tissue-nonspecific alkaline phosphatase and apyrase 1/eNTPD1 and reduced mitochondrial ATP synthesis and extracellular ATP accumulation. Accordingly, LmnaG609G/+ vascular smooth muscle cells show defective production and extracellular accumulation of pyrophosphate, a major inhibitor of VC. We also found increased alkaline phosphatase activity and reduced ATP and pyrophosphate levels in plasma of LmnaG609G/+ mice. Pyrophosphate administration to severely ill progeroid LmnaG609G/G609G mice carrying the LMNA mutation in homozygosis inhibited VC but did not improve body weight or mortality. Because HGPS patients carry the LMNA mutation in heterozygosis, future studies are warranted in very young heterozygous LmnaG609G/+ mice to ascertain whether chronic treatment with pyrophosphate starting early in life cannot only inhibit VC but also improve the general health and life span of progeroid mice. Moreover, it will be of interest to investigate whether treatment of progeroid mice with pyrophosphate in combination with tissue-nonspecific alkaline phosphatase or PHOSPHO1 inhibitors and farnesyl transferase inhibitors and statins, which are currently under evaluation in clinical trials of HGPS, is more beneficial than current strategies. Because progerin progressively accumulates in the vascular tissue of non-HGPS individuals, these studies should shed light into VC associated with both premature and physiological aging. See p 2442.
- © 2013 American Heart Association, Inc.
- Survival After Implantable Cardioverter-Defibrillator Implantation in the Elderly
- Info & Metrics