Challenging Case of Transcatheter Mitral Valve-in-Valve-in-Valve Replacement.

BACKGROUND A 39-year-old man with a complex valvular history of recurrent methicillin-resistant Staphylococcus aureus endocarditis with 2 surgical mitral valve replacements (in 2016 and 2017) followed by transcatheter mitral valve replacement (in 2019) presented with orthopnea, paroxysmal nocturnal dyspnea, chest pain, cough, and progressively worsening dyspnea on exertion. CASE REPORT Extensive workup was performed, including transesophageal echocardiogram, which revealed a malfunctioning, severely stenotic bioprosthetic valve. Left and right heart catheterization revealed mild non-obstructive coronary artery disease and severe pulmonary hypertension. Given the patient's complex medical history, he was deemed to be at an elevated risk for repeat sternotomy and repeat valve replacement surgery. Therefore, he underwent a percutaneous transcatheter mitral valve replacement with a 26-mm SAPIEN 3 Edwards valve placed within the previous 29-mm SAPIEN valve. Post-procedural imaging revealed a well-placed valve with an improved mitral valve gradient. CONCLUSIONS This is one of the few rare cases of mitral valve-in-valve via a transcatheter mitral valve replacement approach with successful deployment of a SAPIEN 3 tissue heart valve. The patient experienced significant reversal of heart failure symptoms and improved exertional tolerance following deployment of the valve and was eventually discharged home in a stable condition.

Protease-activated receptor-1 antagonists: focus on SCH 530348.

Currently available antiplatelet agents have shown improved short- and long-term clinical outcomes but are associated with increased bleeding risk, and the rates of recurrent ischemic events still remain high. Selective inhibition of protease-activated receptor-1 for thrombin represents a potential novel strategy to reduce ischemic events without increasing the risk of bleeding. Two protease-activated receptor-1 antagonists are currently being evaluated in clinical trials: SCH 530348 and E5555. Results of phase II trials have shown that SCH 530348, when added to standard antiplatelet therapy, was well tolerated and not associated with increased bleeding risk. Two large-scale phase III trials assessing the efficacy of SCH 530348 in addition to the standard of care are currently ongoing. This review provides an outline of the current status of understanding on platelet thrombin-receptor antagonist SCH 530348, focusing on its pharmacologic properties and clinical development.

Endothelin-1 gene and endothelin receptor A gene polymorphisms in severe pulmonary hypertension associated with rheumatic mitral valve disease.

INTRODUCTION: Endothelin-1 (ET-1) gene polymorphisms are implicated in pathogenesis of idiopathic pulmonary arterial hypertension. METHODS: We studied ET-1 (Lys198Asn and 3A/4A) and endothelin receptor A (ETA) gene (His323His) polymorphisms in 123 subjects with pulmonary hypertension associated with rheumatic mitral valve disease (PH-MVD) and 123 healthy controls. RESULTS: The mutant homozygous Asn/Asn genotype in Lys198Asn and T/T genotype in His323His polymorphism was more prevalent in the PH-MVD group. Presence of Asn/Asn genotype was significantly associated with an increased risk (odds ratio 3.9). CONCLUSIONS: ET-1 and ETA gene polymorphisms are prevalent in the PH-MVD group suggesting that they may predispose to the development of PH.

Left atrial function by two-dimensional speckle tracking echocardiography in patients with severe rheumatic mitral stenosis and pulmonary hypertension.

We studied left atrial (LA) function in severe rheumatic mitral stenosis (MS) patients using two-dimensional speckle tracking echocardiography (STE). Eighty patients with isolated severe MS in sinus rhythm and 40 controls underwent comprehensive echocardiography including STE derived LA strain [reservoir strain (LASr), conduit strain (LAScd) and contractile strain (LASct)]. The mean MVA was 0.93 ± 0.21 cm2. The mean values of LASr (14.73 ± 8.59%), LAScd (-7.61 ± 4.47%) and LASct (-7.16 ± 5.15%) in patients were significantly lower (p < 0.001) vs. controls 44.11 ± 10.44%, -32.45 ± 7.63%, -11.85 ± 6.77% respectively and showed decreasing trend with increasing MS severity and higher NYHA class. In conclusion, LA dysfunction is prevalent in severe MS irrespective of NYHA functional class.

Gender differences in genotypic distribution of endothelin-1 gene and endothelin receptor A gene in pulmonary hypertension associated with rheumatic mitral valve disease.

INTRODUCTION: The female gender is a risk factor for idiopathic pulmonary arterial hypertension. However, it is unknown whether females with rheumatic mitral valve disease are more predisposed to develop pulmonary hypertension compared to males. AIM: We aimed to investigate whether there was a difference in genotypic distribution of endothelin-1 (ET-1) and endothelin receptor A (ETA) genes between female and male patients of pulmonary hypertension associated with rheumatic mitral valve disease (PH-MVD). METHODS: We compared prevalence of ET-1 gene (Lys198Asn) and ETA gene (His323His) polymorphisms according to gender in 123 PH-MVD subjects and 123 healthy controls. RESULTS: The presence of mutant Asn/Asn and either mutant Asn/Asn or heterozygous Lys/Asn genotypes of Lys198Asn polymorphism when compared to Lys/Lys in females showed significant association with higher risk (odds ratio [OR] 4.5; p =0.007 and OR 2.39; p =0.02, respectively). The presence of heterozygous C/T and either mutant T/T or heterozygous C/T genotypes of His323His polymorphism when compared to wild C/C genotype in females showed a significant association with higher risk (OR 1.96; p =0.047 and OR 2.26; p =0.01, respectively). No significant difference was seen in genotypic frequencies in males between PH-MVD subjects and controls. Logistic regression analysis showed that mutant genotype Asn/Asn (p =0.007) and heterozygous genotype Lys/Asn of Lys198Asn polymorphism (p =0.018) were independent predictors of development of PH in females. CONCLUSIONS: ET-1 and ETA gene polymorphisms were more prevalent in females than males in PH-MVD signifying that females with rheumatic heart disease may be more susceptible to develop PH.

Mechanisms underlying pleiotropic effects of statins.

Statins are the most efficacious hypolipidemic drugs available. Numerous meta-analyses of clinical trials have provided unequivocal evidence that statins are effective and safe in preventing cardiovascular morbidity and mortality in patients with and without pre-existing ischemic heart disease. With widespread usage of statins, its actions other than that of lipid-lowering have started to emerge. Although the effects of statins were initially attributed to a reduction in lipid levels, many benefits are now considered to stem from effects other than lipid modulation. In this review, we describe the mechanisms of these pleiotropic effects and the pathways involved in these effects.

Clopidogrel resistance.

Clopidogrel resistance is an emerging clinical scenario, as antiplatelet therapy has become the cornerstone of modern cardiovascular treatment. This leads to an increase in stent thromboses and recurrent ischemic events which add to the health care costs, and increased periprocedural morbidity and mortality. Management of clopidogrel resistance is challenging as there are no standardized guidelines. The arrival of newer antiplatelet drugs and the detection of genetic polymorphisms in susceptible populations may have an impact on the management. Further trials are needed regarding the target population who should be screened for clopidogrel resistance, a standardized diagnostic test to detect clopidogrel resistance, the role of pharmacogenetics, and the need for tailored therapeutic options for a patient with clopidogrel resistance.

Major adverse cardiac events at long-term follow-up in patients treated with single versus multiple stents during single-vessel percutaneous coronary intervention.

BACKGROUND: Although insertion of multiple stents into a single coronary vessel during single-vessel percutaneous coronary intervention (PCI) is common, there are no data on long-term occurrence of major adverse cardiac events (MACE) in patients treated with multiple stents versus a single stent. METHODS: The incidence of MACE (death, myocardial infarction, or target vessel revascularization) during long-term follow-up was investigated in 634 patients who underwent single-vessel PCI. Of the 634 patients, 319 (50%) had a single stent, and 315 (50%) had multiple stents inserted. Stepwise Cox regression analyses were performed to identify significant independent prognostic factors for MACE. RESULTS: At 47-month follow-up, MACE occurred in 61 of 319 patients (19%) who had a single stent versus in 57 of 315 patients (18%) who had multiple stents (P not significant). Significant independent predictors of MACE were use of vein grafts (hazard ratio = 1.94; 95% CI, 1.24-3.03; P = 0.0038) and use of drug-eluting stents (hazard ratio = 0.49; 95% CI, 0.34-0.72; P = 0.0002). CONCLUSIONS: At long-term follow-up of single-vessel PCI, the incidence of MACE was similar in patients with multiple or single stents inserted even after controlling for the length of stents.

Effect of statins on fasting plasma glucose in diabetic and nondiabetic patients.

BACKGROUND: The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) reduce serum cholesterol level and cardiovascular morbidity and mortality. However, the effect of statins on glucose metabolism is unclear. Some studies have suggested that statins may cause hyperglycemia by increasing calcium concentration in the islet cells leading to decrease in insulin release or by decreasing GLUT 4-mediated peripheral glucose uptake. METHODS: We analyzed the data in 345,417 patients (mean age 61 +/- 15 years, 94% males, 6% diabetic, 20% statin users) from the Veterans Affairs VISN 16 database. We studied change in fasting plasma glucose (FPG) in this population over a mean time of 2 years between the first available measurement and the last measurement form the most recent recorded visit. Data were limited to patients who had 2 FPG measurements. Diagnosis of diabetes had to be present before the first FPG measurement. RESULTS: Among patients without diabetes, FPG increased with statin use from 98 mg/dL to 105 mg/dL, and among nonstatin users, FPG increased from 97 mg/dL to 101 mg/dL (increase in FPG with statin use P < 0.0001). Among patients with diabetes, FPG increased with statin use from 102 mg/dL to 141 mg/dL, and among nonstatin users, FPG increased from 100 mg/dL to 129 mg/dL (increase in FPG with statin use; P < 0.0001). After adjustment for age and use of aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors, the change in FPG in nondiabetic statin users was 7 mg/dL (vs 5 mg/dL in nonstatin users, P < 0.0001) and for diabetic statin users it was 39 mg/dL (vs 32 in nonstatin users, P < 0.0001). CONCLUSIONS: Statin use is associated with a rise of FPG in patients with and without diabetes. This relationship between statin use and rise in FPG is independent of age and use of aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors.

Relation of cardiac troponin I levels with in-hospital mortality in patients with ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.

Troponin I levels were drawn within 24 hours of stroke in 161 of 175 patients (92%) with ischemic stroke, 94 of 107 patients (88%) with intracerebral hemorrhage, and 96 of 96 patients (100%) with subarachnoid hemorrhage. A troponin level >0.4 ng/ml was considered increased. In patients with ischemic stroke, in-hospital mortality occurred in 15 of 23 patients (65%) with increased troponin I compared with 6 of 138 patients (4%) with normal troponin I (p <0.001). In patients with intracerebral hemorrhage, in-hospital mortality occurred in 9 of 14 patients (64%) with increased troponin I compared with 22 of 80 patients (28%) with normal troponin I (p <0.005). In patients with subarachnoid hemorrhage, in-hospital mortality occurred in 8 of 20 patients (40%) with increased troponin I compared with 8 of 76 patients (11%) with normal troponin I (p <0.005). In conclusion, patients with ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage with elevated troponin I levels have increased in-hospital mortality.

Effect of statins on the development of renal dysfunction.

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) decrease serum cholesterol. Dyslipidemia is believed to be associated with the development of renal dysfunction. It was postulated that statins may reduce the development of renal dysfunction. The effect of statin use on the development of renal dysfunction in 197,551 patients (Department of Veterans Affairs, Veterans Integrated Service Network 16 [VISN16] database) was examined. Of these patients, 29.5% (58,332 patients) were statin users and 70.5% (139,219 patients) were not. Development of renal dysfunction was defined as doubling of baseline creatinine or increase in serum creatinine > or =0.5 mg/dl from the first to last measurement with a minimum of 90 days in between. During 3.1 years of follow-up, 3.4% of patients developed renal dysfunction. After adjustment for demographics, diabetes mellitus, smoking, hypertension, and other medications (mainly angiotensin-converting enzyme inhibitors, calcium channel blockers, and aspirin), use of statins decreased the odds of developing renal dysfunction by 13% (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.82 to 0.92, p <0.0001). The beneficial effect of statins appeared to be independent of the decrease in cholesterol. Other variables that affected the development of renal dysfunction were age (OR 1.04, 95% CI 1.03 to 1.04, p <0.0001), diabetes (OR 1.77, 95% CI 1.68 to 1.86, p <0.0001), hypertension (OR 1.11, 95% CI 1.02 to 1.2, p = 0.0153), and smoking (OR 1.12, 95% CI 1.02 to 1.24, p = 0.0244). In conclusion, statin use may retard the development of renal dysfunction. The beneficial effect of statins in preventing the development of renal dysfunction appears to be independent of their lipid-lowering effect.

Percutaneous intervention on the saphenous vein bypass grafts--long-term outcomes.

BACKGROUND/OBJECTIVE: In this era of drug eluting stents (DES), the long-term outcome of percutaneous intervention (PCI) on saphenous venous grafts (SVG) is unknown. The objective of the study was to compare the long-term outcomes of DES versus bare metal stent (BMS) in this population and to determine the predictors of outcomes. METHODS: We reviewed the medical records of all patients who had PCI performed during January 2003 to February 2005 to obtain data cardiac risk factors, medications at discharge, angiographic details and outcomes. RESULTS: One hundred and nine patient had PCI to SVG; of these, 37 patients received DES and the remaining had BMS. Over a mean follow-up of 33 months, the PCI using DES was associated with 30% restenosis, 35% target vessel revascularization (TVR) and major adverse cardiac event (MACE) rate of 46% versus 35% restenosis, 38% TVR and 50% MACE rate with BMS. There was no significant difference in long-term outcome with DES as compared to BMS. CONCLUSION: There was no difference in the long-term outcomes of PCI on SVG irrespective of the type of stent used.

Present status of coronary bifurcation stenting.

Percutaneous coronary intervention (PCI) for bifurcation lesions is technically limited by the risk of side branch occlusion. In comparison with nonbifurcation interventions, bifurcation interventions have a lower rate of procedural success, higher procedural costs and a higher rate of clinical and angiographic restenosis. The recent introduction of drug-eluting stents (DES) has resulted in reduced incidence of main vessel restenosis compared with historical controls. However, side-branch ostial residual stenosis and long-term restenosis still remain problematic. In the era of DES, techniques employing two stents have emerged that allow stenting of the large side branch in addition to the main artery. Stenting of the main vessel with provisional side branch stenting seems to be the prevailing approach. This paper reviews outcome data with different treatment modalities for this complex lesion with particular emphasis on the use of DES as well as potential new therapeutic approaches.

Prevalence of obstructive coronary artery disease in patients with and without prior stroke undergoing coronary angiography for suspected coronary artery disease.

This study was conducted to investigate the prevalence and severity of obstructive coronary artery disease (CAD) in 64 men and 38 women (mean age 71+/-9 years) with previous stroke and in 102 age- and gender-matched patients with similar coronary risk factors without previous stroke who underwent coronary angiography for chest pain. Obstructive CAD was present in 100 of 102 patients (98%) with previous stroke and in 84 of 102 (82%) patients without previous stroke (p<0.001). Obstructive 3-vessel CAD was present in 56 of 102 patients (55%) with previous stroke and in 35 of 102 patients (34%) without previous stroke (p<0.005). The prevalence of 2-vessel CAD and of 1-vessel CAD was not significantly different between patients with and without previous stroke. In conclusion, patients with previous stroke have a significantly higher prevalence of obstructive CAD and of obstructive 3-vessel CAD than age- and gender-matched patients with similar coronary risk factors without previous stroke who undergo coronary angiography for chest pain.

Predictors of in-stent restenosis and patient outcome after percutaneous coronary intervention in patients with diabetes mellitus.

Diabetics have a significantly higher incidence of major adverse cardiac events (MACEs) and in-stent restenosis (ISR) than nondiabetics after percutaneous coronary intervention (PCI). Predictors of MACEs and ISR are uncertain in diabetics. In recent studies, microalbuminuria and proliferative retinopathy have been believed to relate to progressive coronary atherosclerosis. We retrospectively studied 191 consecutive patients (mean age 65 +/- 9 years) with diabetes who underwent PCI to determine predictors of ISR and MACEs (defined as cumulative incidence of myocardial infarction, revascularization, or death from cardiovascular cause), with special reference to microalbuminuria and proliferative retinopathy. Of 191 patients, 106 (56%) had a follow-up coronary angiogram at 16 +/- 2 months. Of these 106 patients, 66 (62%) developed ISR. In the multivariate model, microalbuminuria or proliferative retinopathy did not achieve significant association with ISR. Serum high-density lipoprotein cholesterol levels were significantly associated with a lower incidence of ISR (odds ratio [OR] 0.928, 95% confidence interval [CI] 0.876 to 0.983, p = 0.011) and MACEs (OR 0.96, 95% CI 0.931 to 1.000, p = 0.048). Use of drug-eluting stents also had a negative association with ISR (OR 0.171, 95% CI 0.05 to 0.585, p = 0.004). Renal insufficiency was associated with higher MACEs (OR 3.19, 95% CI 1.45 to 7.031, p = 0.0039). In conclusion, serum high-density lipoprotein cholesterol levels were inversely associated with ISR or MACEs.

Inflammatory markers, angiographic severity of coronary artery disease, and patient outcome.

Serum levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) have been shown to be predictors of adverse outcomes in patients with coronary artery disease (CAD). We hypothesized that measurement of inflammatory markers could predict atherosclerotic burden and major adverse cardiac events (MACEs). We prospectively measured hs-CRP, IL-6, and TNF-alpha in 249 patients who were admitted with acute chest pain and underwent coronary angiography. We analyzed the relation between serum levels of inflammatory markers and angiographic severity of CAD. A follow-up at 6 months was conducted to assess MACEs, defined as a cumulative of myocardial infarction, all-cause death, or coronary revascularization (percutaneous coronary intervention or coronary artery bypass surgery). After adjusting for conventional CAD risk factors (age, gender, diabetes, hypertension, smoking, and hypercholesterolemia), there was no association between inflammatory markers (hs-CRP, IL-6, and TNF-alpha) and angiographic severity of CAD. There was a significant positive correlation between age, male gender, diabetes mellitus, and hypercholesterolemia with atherosclerotic burden determined by angiography. There was no significant positive association between MACEs and hs-CRP, IL-6, or TNF-alpha level in unadjusted and adjusted models. In conclusion, in patients hospitalized with chest pain, we found no association of serum levels of hs-CRP, IL-6, or TNF-alpha with coronary atherosclerotic burden or MACEs at 6 months after adjustment for traditional CAD risk factors.

Common carotid artery wall thickness and external diameter as predictors of prevalent and incident cardiac events in a large population study.

BACKGROUND: Arterial diameters enlarge in response to wall thickening, plaques, and many atherosclerotic risk factors. We hypothesized that right common carotid artery (RCCA) diameter would be independently associated with cardiac disease and improve risk discrimination. METHODS: In a middle-aged, biracial population (baseline n = 11225), we examined associations between 1 standard deviation increments of baseline RCCA diameter with prevalent myocardial infarction (MI) and incident cardiac events (MI or cardiac death) using logistic regression and Cox proportional hazards models, respectively. Areas under the receiver operator characteristic curve (AUC) were used to estimate model discrimination. RESULTS: MI was present in 451 (4%) participants at baseline (1987-89), and incident cardiac events occurred among 646 (6%) others through 1999. Adjusting for IMT, RCCA diameter was associated with prevalent MI (female OR = 2.0, 95%CI = 1.61-2.49; male OR = 1.16, 95% CI = 1.04-1.30) and incident cardiac events (female HR = 1.75, 95% CI = 1.51-2.02; male HR = 1.27, 95% CI = 1.15-1.40). Associations were attenuated but persisted after adjustment for risk factors (not including IMT) (prevalent MI: female OR = 1.73, 95% CI = 1.40-2.14; male OR = 1.14, 95% CI = 1.02-1.28, and incident cardiac events: female HR = 1.26, 95% CI = 1.08-1.48; male HR = 1.19, 95% CI = 1.08-1.32). After additional adjustment for IMT, diameter was associated with incident cardiac events in women (HR = 1.18, 95% CI = 1.00-1.40) and men (HR = 1.17, 95% CI = 1.06-1.29), and with prevalent MI only in women (OR = 1.73; 95% CI = 1.37-2.17). In women, when adjustment was limited, diameter models had larger AUC than other models. CONCLUSION: RCCA diameter is an important correlate of cardiac events, independent of IMT, but adds little to overall risk discrimination after risk factor adjustment.

Implantable cardioverter defibrillators for prevention of sudden cardiac death.

Despite the multiple advances in the field of cardiovascular medicine, the incidence of sudden cardiac death (SCD) continues to rise. Of all SCDs, <25% occur in individuals deemed at high risk by current risk-stratification algorithms; hence, these risk-stratification algorithms are not satisfactory. Until better markers are identified to risk stratify patients, we will see an increasing use of implantable cardioverter defibrillators (ICDs). However, even with the increase in defibrillator use, the impact on overall incidence of SCD may only be modest, as many individuals experience SCD as the first manifestation of cardiovascular disease. Another important challenge is widespread availability of automated external defibrillators and effective utilization of public access defibrillation programs for timely and appropriate management of out-of-hospital victims with cardiac arrest. This review discusses the current understanding on SCD, risk stratification, and management aimed at reducing SCD, particularly with the use of ICDs.

Value of CRP in coronary risk determination.

Initial studies showed that C-reactive protein (CRP) may have a role in the genesis of atherosclerotic lesions and as a novel biomarkers of patients at risk of developing coronary heart disease (CHD) events. Most of these studies had methodologic limitations, and recent data contradict these findings and suggest that inflammatory markers, such as CRP, have limited usefulness in the prediction of CHD events over and above conventional risk factors. Its low predictive value creates difficulty in interpreting the CRP data in an individual patient. Current scientific literature does not support measurement of CRP in individual patients in clinical medicine. In this review, we critically appraise role of CRP in cardiovascular medicine.

Enhanced 11beta-hydroxysteroid dehydrogenase activity, the metabolic syndrome, and systemic hypertension.

Metabolic syndrome, with its attendant cardiovascular complications, is reaching epidemic proportions worldwide; hence, there is intense interest in understanding the pathogenesis of and developing therapy for these common disorders. Recent studies have suggested that metabolic syndrome may be a stress response, with an underlying abnormality in the enzyme 11beta-hydroxysteroid dehydrogenase. At the cellular level, the enzyme hydroxysteroid dehydrogenase type 1 (HSD1) locally regenerates active cortisol from inactive cortisone, amplifying glucocorticoid receptor activation and promoting preadipocyte differentiation and adipocyte hypertrophy. Although initial studies in transgenic mice and humans are encouraging, more data are required to conclusively prove the hypothesis that the adipose-tissue-specific overexpression of HSD1 and the resultant increase in tissue-specific cortisol concentrations result in human obesity, insulin resistance, high blood pressure, and metabolic syndrome. Currently, selective inhibitors of HSD1 are not available for human use; however, their development is under way. The use of potent and selective HSD1 inhibitors will finally confirm or refute this hypothesis and may turn out to be an effective strategy for combating these common maladies.