Łukasz A. Małek

Cytochrome P450 2C19 polymorphism, suboptimal reperfusion and all-cause mortality in patients with acute myocardial infarction.

Objectives: To determine whether the 681 G>A (*2) polymorphism of cytochrome P450 (CYP2C19) is related to suboptimal reperfusion and mortality in patients with acute myocardial infarction (AMI) pretreated with clopidogrel. Methods: Thestudy included 276 consecutive patients with AMI in whom percutaneous coronary intervention (PCI) with stenting was attempted. Four-year follow-up for all-cause mortality was obtained. Results: There were 15 failed procedures (5.4%). In the remaining 261 patients, suboptimal reperfusion (post-PCI TIMI flow <3) was observed in 12.6% of the cases. There were 56 carriers (50 heterozygous and 6 homozygous) of CYP2C19*2. The prevalence of carriers in patients with suboptimal flow was 39.4% in comparison to 18.9% in the other patients (p = 0.01). Independent predictors of suboptimal reperfusion were initial TIMI flow ≤1 (OR = 5.9, 95% CI 2.2–16.2, p = 0.001) and CYP2C19*2 (OR = 2.9, 95% CI 1.3–6.6, p = 0.01). Thirty patients died during follow-up (11.5%). Four-year mortality tended to be higher in carriers of CYP2C19*2 (17.9%) versus non-carriers (9.8%; p = 0.09), but the only independent predictors of death were age (HR = 2.0, 95% CI = 1.4–2.8, p = 0.0001) and suboptimal reperfusion (HR = 3.6, 95% CI 1.5–8.8, p = 0.004). Conclusions: The CYP2C19*2 allele is an independent predictor of suboptimal reperfusion in patients with AMI undergoing PCI with stenting after pretreatment with clopidogrel and may increase the risk of all-cause mortality.

Right ventricular outflow tract obstruction as a confounding factor in the assessment of the impact of pulmonary regurgitation on the right ventricular size and function in patients after repair of tetralogy of Fallot.

To compare right ventricular (RV) size and function between patients with combined pulmonary regurgitation (PR) plus RV outflow tract (RVOT) obstruction (RVOTO) and patients with isolated PR.

Influence of different antiplatelet treatment regimens for primary percutaneous coronary intervention on all-cause mortality

AIMS The aim of this analysis was to examine the influence of different in-cath-lab antiplatelet regimens for the primary percutaneous coronary intervention (PCI) on all-cause mortality. METHODS AND RESULTS The study group consisted of 7193 patients (pts) undergoing primary PCI in 38 centres in 2003 in Poland. All patients received pretreatment with 300 mg of aspirin, 992 pts (14%) received glycoprotein (GP) IIb/IIIa inhibitors, 2690 pts (37%) were treated with 300 mg loading dose of clopidogrel, and 1566 (22%) received combined antiplatelet treatment with both GP IIb/IIIa inhibitors and clopidogrel. Remaining 1945 patients (27%) did not receive GP IIb/IIIa inhibitors or clopidogrel. Primary endpoint of the study was all-cause mortality up to 1 year from ST-segment elevation myocardial infarction (STEMI). One year mortality rates in the four groups were: 10.4%, 9.0%, 9.7%, and 15.3%, respectively. Propensity-adjusted survival analysis showed significant reduction of mortality for combination therapy with GP IIb/IIIa inhibitors and clopidogrel, clopidogrel alone, and GP IIb/IIIa inhibitors alone over aspirin alone. No additive effect on survival was seen for a combination therapy with GP IIb/IIIa inhibitors and clopidogrel in comparison to treatment with clopidogrel alone. CONCLUSION In this large cohort, multicentre STEMI registry in-cath-lab use of GP IIb/IIIa inhibitors and clopidogrel alone or in combination was associated with the reduction of 1 year all-cause mortality in the setting of primary PCI in comparison with aspirin only. However, the use of GP IIb/IIIa inhibitors on top of 300 mg loading dose of clopidogrel did not further reduce mortality.

A study in Polish patients with cardiomyopathy emphasizes pathogenicity of phospholamban (PLN) mutations at amino acid position 9 and low penetrance of heterozygous null PLN mutations.

BackgroundIn humans mutations in the PLN gene, encoding phospholamban - a regulator of sarcoplasmic reticulum calcium ATPase (SERCA), cause cardiomyopathy with prevalence depending on the population. Our purpose was to identify PLN mutations in Polish cardiomyopathy patients.MethodsWe studied 161 unrelated subjects referred for genetic testing for cardiomyopathies: 135 with dilated cardiomyopathy, 22 with hypertrophic cardiomyopathy and 4 with other cardiomyopathies. In 23 subjects multiple genes were sequenced by next generation sequencing and in all subjects PLN exons were analyzed by Sanger sequencing. Control group included 200 healthy subjects matched with patients for ethnicity, sex and age. Large deletions/insertions were screened by real time polymerase chain reaction.ResultsWe detected three different heterozygous mutations in the PLN gene: a novel null c.9_10insA:(p.Val4Serfs*15) variant and two missense variants: c.25C > T:(p.Arg9Cys) and c.26G > T:(p.Arg9Leu). The (p.Val4Serfs*15) variant occurred in the patient with Wolff-Parkinson-White syndrome in whom the diagnosis of cardiomyopathy was not confirmed and his mother who had concentric left ventricular remodeling but normal left ventricular mass and function. We did not detect large deletions/insertions in PLN in cohort studied.ConclusionsIn Poland, similar to most populations, PLN mutations rarely cause cardiomyopathy. The 9thPLN residue is apparently a mutation hot spot whereas a single dose of c.9_10insA, and likely other null PLN mutations, cause the disease only with low penetrance or are not pathogenic.

Influence of left ventricular hypertrophy on infarct size and left ventricular ejection fraction in ST-elevation myocardial infarction

BACKGROUND Left ventricular hypertrophy (LVH) predisposes to larger infarct size, which may be underestimated by the left ventricular ejection fraction (LVEF) due to supranormal systolic performance often present in patients with LVH. The aim of the study was to compare infarct size and LVEF in patients with ST-segment elevation myocardial infarction (STEMI) and increased left ventricular mass on cardiac magnetic resonance (CMR). METHODS The study included unselected group of 52 patients (61±11 years, 69% male) with first STEMI who had CMR after median 5 days from the onset of the event. Left ventricular hypertrophy (LVH) was defined as left ventricular mass index exceeding 95th percentile of references values for age and gender. Infarct size was assessed with means of late gadolinium enhancement (LGE). RESULTS LVH was found in 16 patients (31%). In comparison to the rest of the group, patients with LVH had higher absolute and relative infarct mass (p=0.002 and p=0.02, respectively). LVH was related to higher prevalence of microvascular obstruction and myocardial haemorrhage and higher number of LV segments with transmural necrosis (p=0.02, p=0.01 and p=0.01, respectively). Despite marked difference in the infarct size between both studied subgroups there was no difference in LVEF and mean number of dysfunctional LV segments. CONCLUSIONS Patients with LVH undergoing STEMI have larger infarct size underestimated by the LV systolic performance in comparison to patients without LVH.

Quantitative assessment of pulmonary regurgitation in patients with and without right ventricular tract obstruction

BACKGROUND There are concerns whether there is a difference in clinical utility of pulmonary regurgitation (PR) fraction (PRF) and PR volume (PRV) in subgroups of patients with isolated PR and individuals with combined PR and right ventricular outflow tract obstruction (RVOTO). The aim of the study was to compare PRF and PRV in patients with or without RVOTO. METHODS AND RESULTS 82 consecutive patients after repair of tetralogy of Fallot (TOF) who underwent cardiovascular magnetic resonance and echocardiography were studied. There was no difference in PRF between patients with moderate and severe right ventricular (RV) dilatation (32±13% vs. 37±12%; p=0.18). Significant difference in PRV was observed between these groups (23±10 ml/m2 vs. 31±12 ml/m2, respectively; p=0.02). PRV had better ability than PRF in identification of severe RV dilatation, both in group with RVOTO [area under the curve (AUC) 0.82 vs. 0.72, p=0.005] and in patients without RVOTO (AUC 0.83 vs. 0.77, p=0.04). A strong correlation was seen between PRF and PRV both in patients with and without RVOTO [r=0.93, p<0.0001 and r=0.92, p<0.0001, respectively]. In both subgroups high variability of PRF was found in subjects with similar degree of PRV. CONCLUSIONS PRV shows better ability than PRF in evaluating influence of PR on RV in patients after TOF repair, both in population with and without concomitant RVOTO.

The size does not matter - the presence of microvascular obstruction but not its extent corresponds to larger infarct size in reperfused STEMI.

BACKGROUND Microvascular obstruction (MVO) is a cardiac magnetic resonance (CMR) marker of no-reflow in ST-segment elevation myocardial infarction (STEMI). It remains unresolved whether the infarct size corresponds only to the presence of MVO or also to its extent. METHODS The study included 53 patients with first STEMI (median age 61.5 years, 77% male) treated with percutaneous coronary intervention (PCI) who underwent CMR after median 5 days from PCI. Small MVO was defined as patchy, non-confluent spots of dark areas of absent contrast surrounded by late gadolinium enhancement (LGE). Large MVO was defined as confluent areas of MVO comprising a large amount of the infarct zone. RESULTS Microvascular obstruction was observed in 32 patients (60%) including 18 patients with small MVO (36%) and 14 patients with large MVO (24%). Patients with MVO were more likely to have TIMI 0/1 grade flow on initial angiogram, higher levels of necrotic markers, larger infarct size, larger left ventricular end-diastolic and end-systolic volume and lower ejection fraction in comparison to patients without MVO. These differences were not observed between patients with large and small MVO. CONCLUSIONS The presence of MVO but not its extent corresponds to larger infarct size in STEMI.

Platelet Reactivity and Intramyocardial Hemorrhage in Patients With ST-Segment Elevation Myocardial Infarction.

The aim of the study was to analyze the relation between platelet reactivity and intramyocardial hemorrhage (IMH) in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. Platelet reactivity was measured in 49 patients with means of impedance aggregometry (Multiplate) before reperfusion and repeated in the subacute phase of STEMI. Cardiovascular magnetic resonance was used to detect IMH, which was found in 16 (33%) patients. There were no differences in platelet reactivity between patients with and without IMH before reperfusion. Reassessment in the subacute phase of STEMI demonstrated that patients with IMH had lower thrombin receptor activating peptide (TRAP)-induced platelet aggregation (P = .004) and trends toward lower values of ristocetin and collagen-induced platelet aggregation (P = .09 and P = .07). The TRAP-induced platelet aggregation and initial perfusion grade were the factors independently associated with IMH. Intramyocardial hemorrhage is related to more potent inhibition of platelet aggregation in the subacute phase of STEMI.

The ratio of right ventricular volume to left ventricular volume reflects the impact of pulmonary regurgitation independently of the method of pulmonary regurgitation quantification

BACKGROUND Previous studies have advocated quantifying pulmonary regurgitation (PR) by using PR volume (PRV) instead of commonly used PR fraction (PRF). However, physicians are not familiar with the use of PRV in clinical practice. The ratio of right ventricle (RV) volume to left ventricle volume (RV/LV) may better reflect the impact of PR on the heart than RV end-diastolic volume (RVEDV) alone. We aimed to compare the impact of PRV and PRF on RV size expressed as either the RV/LV ratio or RVEDV (mL/m(2)). METHODS Consecutive patients with repaired tetralogy of Fallot were included (n=53). PRV, PRF and ventricular volumes were measured with the use of cardiac magnetic resonance. RESULTS RVEDV was more closely correlated with PRV when compared with PRF (r=0.686, p<0.0001, and r=0.430, p=0.0014, respectively). On the other hand, both PRV and PRF showed a good correlation with the RV/LV ratio (r=0.691, p<0.0001, and r=0.685, p<0.0001, respectively). Receiver operating characteristic analysis showed that both measures of PR had similar ability to predict severe RV dilatation when the RV/LV ratio-based criterion was used, namely the RV/LV ratio>2.0 [area under the curve (AUC)(PRV)=0.770 vs AUC(PRF)=0.777, p=0.86]. Conversely, with the use of the RVEDV-based criterion (>170mL/m(2)), PRV proved to be superior over PRF (AUC(PRV)=0.770 vs AUC(PRF)=0.656, p=0.0028]. CONCLUSIONS PRV and PRF have similar significance as measures of PR when the RV/LV ratio is used instead of RVEDV. The RV/LV ratio is a universal marker of RV dilatation independent of the method of PR quantification applied (PRF vs PRV).

A new c.1621 C>G, p.R541G lamin A/C mutation in a family with DCM and regional wall motion abnormalities (akinesis/dyskinesis): genotype–phenotype correlation

Mutations in the lamin A/C gene (LMNA) are established causes of familial dilated cardiomyopathy (DCM) with atrio-ventricular block although relatively little is known about genotype–phenotype correlations. We describe a 23-year-old patient who presented with inferolateral wall thinning and akinesis with evidence of mid-myocardial fibrosis on cardiac magnetic resonance. Molecular analysis driven by clinical similarities with a previously described case harboring the p.R541C LMNA mutation revealed a novel c.1621 C>G, p.R541G substitution whose pathogenicity was confirmed by transfection of mouse myoblasts. Our results emphasize the role of LMNA mutations at position R541 in DCM cases with segmental LV wall motion akinesis/dyskinesis.